Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2023

Topics 002–Novel therapies, gene therapies and bone marrow transplant

F. Locatelli¹, P. Lang², S. Corbacioglu³, A. Li⁴, J. de la Fuente⁵, D. Wall⁶, R. Meisel⁷, A. Shah⁸, R. Liem⁹, M. Mapara¹⁰, B. Carpenter¹¹, J. Kwiatkowski¹², M.D. Cappellini¹³, A. Kattamis¹⁴, S. Sheth¹⁵, S. Grupp¹⁶, P. Kohli¹⁷, D. Shi¹⁷, L. Ross¹⁷, Y. Bobruff¹⁷, C. Simard¹⁷, L. Zhang¹⁷, P.K. Morrow¹⁸, B. Hobbs¹⁷, H. Frangoul¹⁹

IRCCS, Ospedale Pediatrico Bambino Gesù Rome, Catholic University of the Sacred Heart¹, University of Tübingen², University of Regensburg³, BC Children's Hospital, University of British Columbia⁴, Imperial College Healthcare NHS Trust, St Mary's Hosp ital⁵, The Hospital for Sick Children/University of Toronto⁶, Heinrich-Heine-University⁷, Stanford University⁸, Ann & Robert H. Lurie Children's Hospital of Chicago⁹, Herbert Irving Comprehensive Cancer Center, Columbia University¹⁰, University College Hospital NHS Trust¹¹, Children's Hospital of Philadelphia¹², University of Milan¹³, University of Athens¹⁴, Joan and Sanford I Weill Medical College of Cornell University¹⁵, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania¹⁶, Vertex Pharmaceuticals¹⁷, CRISPR Therapeutics¹⁸, Sarah Cannon Center for Blood Cancer at The Children's Hospital at TriStar Centennial¹⁹

Background: Exagamglogene autotemcel (exa-cel) is a one-time non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells.

Aims: Evaluate efficacy and safety of exa-cel in patients (pts) with transfusion-dependent β-thalassemia (TDT) in a pre-specified interim analysis of the CLIMB THAL-111 trial.

Methods: CLIMB THAL-111 is an ongoing phase 3 trial of exa-cel in pts age 12–35 y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions 2 y before screening. Primary and key secondary efficacy endpoints are proportion of pts who maintain a weighted average hemoglobin (Hb) ≥9g/dL without RBC transfusion for ≥12 mos (TI12; primary) and ≥6 mos (TI6; key secondary). Evaluable pts were followed for ≥16 mos after exa‑cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131.

Results: As of 6 Sept 2022, 48 pts (median age 20 [range 12–35] y; 16 [33.3%] age ≥12 to <18 y; 28 [58.3%] with severe genotypes [β0/β0 or β0/β0-like]) received exa-cel. Of the 27 pts evaluable for primary and key secondary endpoints, 24 (88.9%) achieved TI12 and TI6 (95% CI: 70.8%, 97.6%; p < 0.0001). Pts achieving TI12 had a mean time to last transfusion of 37 (SD, 20.6) days after exa-cel infusion and remained transfusion independent (mean [range] duration 20.5 [12.1, 40.7] mos; Fig[LR1]). 3 pts not achieving TI12 had substantial reductions (70.3%, 79.6%, and 95.5%) in transfusion volume from baseline. For all pts, mean total Hb was ≥11 g/dL at Month 3 (≥12 g/dL from Month 6), and mean HbF was ≥;6g/dL at Month 3 (≥9 g/dL from Month 6) with pancellular distribution. Mean proportion of edited BCL11A alleles was stable over time in bone marrow CD34+ and peripheral blood nucleated cells. Pts not yet evaluable and with sufficient follow-up were also transfusion-free. Quality-of-life (QOL) measures showed clinically significant improvements from baseline in mean EQ VAS (21.0 points), FACT-G (17.0 points) and BMTS (7.8 points) scores at Month 24.

All pts with sufficient follow-up engrafted neutrophils and platelets (median 29 and 44 days, respectively). All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 41 (85.4%) pts had AEs of Grade 3 or 4 severity. Most common AEs were febrile neutropenia (58.3%), headache (54.2%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 3 mos after infusion. 2 pts had SAEs considered related to exa-cel: 1 pt had SAEs of headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH, and another pt had SAEs of delayed engraftment and thrombocytopenia (both also considered related to busulfan). All SAEs resolved. There were no deaths, discontinuations or malignancies.

Conclusion: In this pre-specified interim analysis of the pivotal trial of exa-cel in TDT, almost all pts achieved transfusion independence, with early and sustained Hb and HbF increases, durable allelic editing, and improved QOL. Safety profile of exa‑cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel can deliver a one-time functional cure to pts with TDT.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

K.Z. Summers¹, O.A. Agrippa¹, K.A. Anie², P. Telfer³, S. Lugthart⁴

Sanius Health¹, London North West University Healthcare NHS Trust², Barts Health NHS Trust³, University Hospitals Bristol and Weston NHS Foundation Trust⁴

Background: Sickle cell disease (SCD) is a genetic disorder characterised by the sickled morphology of red blood cells as a result of a structural variant of haemoglobin, which polymerises upon deoxygenation. This can lead to acute pain episodes (vaso-occlusive crises, VOC) that are linked to severe end-organ damage in the long term, a shortened lifespan, and an estimated 95% of SCD hospitalisations. As a key predictor of death, it is critical to find new ways to enable early VOC detection to in turn drive preventative interventions.

Aims: This work aimed to utilise longitudinal physiological and patient-reported outcomes (PROs) data, captured by a wearable smartwatch and specialised mobile phone application, respectively, to develop a machine learning (ML) algorithm capable of predicting the potential onset of a VOC.

Methods: All participants provided informed consent, after which they were given access to a mobile phone application encompassing their health data and access to a PRO entry portal, as well as a wearable device (Withings ScanWatch). This allowed for daily recording of PROs including EQ-5D-5L, pain, mood, fatigue scores, and self-reported VOCs, in addition to physical activity, sleep quality, and heart rate data captured in an automated manner. Medical records were obtained through participant completion of a Subject Access Request form at the point of consent and included healthcare utilisation, pathology, and demographic data.

Data for a snapshot cohort of 264 patients over a 3.5-month period (May–Aug 2023) were analysed through an ensemble of ML models: gradient boosting machine, neural network, and k-means clustering. Excluding hospitalisation as an “a posteriori" variable, all captured metrics were included within the model, to ensure predictions were based on appropriate variables and not strengthened by self-confirming factors. Each day, participants' likelihood of a VOC was calculated by the model on a scale from 0-100%. Those above 75% were deemed a predicted VOC and assessed against the true incidence of participants' self-reported VOCs, defined as an entry of “yes” into the portal by patients in response to the question “Are you currently experiencing a VOC?”.

Results: The mean age was 34 (SD 12.9) years, and most patients were female (73%). The HbSS genotype was most common (74%), followed by HbSC (17%), and HbS Beta + Thalassemia (5%). 189,915 datapoints across 90 distinct variables were collated during the period of analysis. Of the 163 VOCs self-reported by participants, 134 (82%) were accurately predicted by the algorithm. A negative predicted value of 85% was generated, with 5840 of 6833 instances of no participant-reported VOCs predicted. Figure 2 highlights the breakdown of individually predicted VOC likelihood scores per patient, per day, against the incidence of patient-reported VOCs.

Summary/Conclusions: This work provides an important translation of daily trackable metrics through a remote, digital ecosystem, to the real-world prediction of potential VOCs in SCD. The algorithm's purpose is to provide an early warning system for patients and care teams to initiate proactive behavioural changes or pre-emptive interventions. The prediction of additional potential risk scores above the 75% threshold therefore reflects an approach of ‘over-predicting’ that is considered a preferable strategy in the context of the severity of VOCs and resulting impacts on patient health should an event be missed.

Our ongoing aim is to optimise the algorithm and its contributing metrics against medical data, in addition to patient self-reported events. This includes the curation of metrics with the strongest predictive weighting, but with as minimal manual patient input required as possible. This would in turn help to reduce the rate of missing datapoints within the core variables that feed into the algorithm and thereby reduce the rate of unpredicted VOCs. Ultimately, we hope to provide an early alert system that will help patients to identify their VOCs sooner, and thus action the next steps that may prevent possible hospital admissions.

Topics 004–Clinical, public health and epidemiological studies

P. Eleftheriou¹, J. Sharif², R. Kesse-Adu³, E. Drasar⁴, A. de Kreuk⁵, M. Czachorowski⁶, M. Araghi⁶, S. Sharif⁶, G. Barcelos⁷, P. Telfer⁸

University College Hospital London¹, Manchester University NHS Foundation Trust², Guy's and St Thomas’ Hospital³, The Whittington Hospital⁴, King's College Hospital⁵, Pfizer Ltd.⁶, Pfizer Inc⁷, Queen Mary University of London⁸

Background: Voxelotor, a first-in-class sickle hemoglobin (Hb) polymerization inhibitor, is currently approved in Great Britain as monotherapy or in combination with hydroxyurea (HU) for the treatment of hemolytic anemia due to sickle cell disease (SCD) in patients aged ≥12 years. Prior to voxelotor approval, eligible patients in the UK with SCD received voxelotor through the Early Access to Medicines Scheme (EAMS) and the Named Patient Program (NPP), both of which allow patients to receive new, unlicensed medicines when there is a clear unmet need. This report describes real-world data from the patient population who participated in the voxelotor EAMS and NPP and provides a final analysis of changes in Hb and markers of hemolysis as a result of voxelotor treatment.

Aim: This report describes real-world data from the patient population who participated in the voxelotor EAMS and NPP and provides a final analysis of changes in Hb and markers of hemolysis as a result of voxelotor treatment.

Methods: Eligible patients were aged ≥12 years, with Hb ≤10.5 g/dL. Demographics, comorbidities, concomitant medications, adverse events, markers of hemolysis, vaso-occlusive crises (VOCs) requiring treatment and/or hospitalization, and therapy discontinuation were collected.

Results: A total of 150 patients (132 EAMS, 18 NPP) were enrolled. The mean age (range) was 38 (12–69) years; 51% (77/150) were female, and the most common genotype was HbSS (96%, 144/150). Among EAMS patients, the baseline mean (SD) Hb was 7.61 (1.39) g/dL; the proportion of patients taking HU at baseline was 43% (57/132), and 17% of patients (22/132) had discontinued previous use of HU.

In the 12 months before initiating voxelotor, the mean (SD) number of VOCs requiring hospitalization among EAMS patients was 1.31 (2.60). Reasons for hospitalization included VOC (30%, 39/132), acute chest syndrome (5%, 7/132), transfusion (11%, 14/132), and hyperhemolysis (3%, 4/132). Overall, 15% of patients (20/132) reported ≥3 emergency department admissions, and alloimmunization was reported in 26% of patients (34/132).

Over an average of 19.7 weeks of voxelotor treatment, 79% of patients (75/95) had an increase in Hb. Among all patients, the mean (SD) peak Hb change from baseline was 1.05 (1.43) g/dL (Figure). Markers of hemolysis were reduced, with a mean (SD) change from baseline in reticulocytes of −2.10% (6.69%) and indirect bilirubin of −7.56 (26.75) µmol/L. Adverse events were consistent with the known safety profile of voxelotor, with the most common (≥5%) being diarrhea (8%) and nausea (7%).

Conclusions: The improvement in clinical measures of patients participating in the voxelotor EAMS and NPP illustrates a previously unmet treatment need and the effectiveness of voxelotor among representative patients with hemolytic anemia due to SCD in the UK.

Funding: Global Blood Therapeutics, Inc., which was acquired by Pfizer Inc on October 5, 2022.

Topics 001–Basic and translational

M.J.M. Traets¹, S. Van der Veen², J.F. Bos¹, L. van Pelt¹, A. Kidane Gembremeskel³, B.A. van Oirschot¹, W.W. van Solinge¹, S.E.M. Schols⁴, M.N. Lauw⁵, M.H. Cnossen³, E. Nur⁶, B.J. Biemond⁶, E.J. van Beers², A.W. Rijneveld⁵, R. van Wijk¹, M.A.E. Rab¹

Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht¹, Center for Benign Hematolo gy, Thrombosis and Hemostasis-Van Creveldkliniek, University Medical Center Utrecht², Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, University Medical Center³, Department of Hematology, Radboud university medical center⁴, Department of Hematology, Erasmus MC, University Medical Center⁵, Department of Hematology, Amsterdam University Medical Center⁶

Background: Red blood cells (RBCs) from patients with sickle cell disease (SCD) are less deformable and take on the shape of sickle upon deoxygenation. This results in multiple downstream effects including RBC adhesion, microvascular occlusion and hemolysis. Activity and stability of pyruvate kinase (PK), a key enzyme in the last step of glycolysis, are decreased in SCD. Currently there are several clinical trials ongoing investigating the efficacy of PK activation by small molecules. In this study we aim to investigate how PK properties correlate to sickle RBC properties to explore if impaired PK function is associated with specific features of the complex SCD pathophysiology.

Methods: Homozygous HbS (HbSS) and HbS/β0 thalassemia patients were eligible to participate. Patients who received blood transfusion (<3 months) were excluded. Dense RBCs (MCHC >41 g/dL, Advia; Siemens) and HbF and HbS levels (Tosoh G8) were measured. PK and hexokinase (HK) activity were measured on purified RBCs. PK thermostability (reflected by % residual PK activity) was measured on purified RBCs lysates after 1 h of incubation (53°C). RBC adhesion to laminin (Biolamina) was measured using a microfluidic device (IBIDI µ-Slide I 0.4). RBC hydration (Ohyper), RBC deformability (EImax) and point of sickling (PoS) were assessed by osmotic and oxygen gradient ektacytometry using the Laser-Optical Rotational Red Cell Analyzer (Lorrca; RR Mechatronics). Oxygen affinity (P50) was measured with the Hemox-Analyzer (TCS).

Results: Fifty-seven SCD patients (53 HbSS, 4 HbS/β0 thalassemia) were included. Baseline characteristics are depicted in Table 1.

Figure 1 shows a correlation heatmap of laboratory parameters measured in this cohort. When focusing on PK properties we found that SCD patients with lower PK thermostability had higher absolute reticulocyte counts (ARC, p < 0.0001), lower hemoglobin (p = 0.012) and HbF (p = 0.020) levels and increased RBC adhesion to laminin (p = 0.007). Furthermore, PK thermostability was correlated with EImax (p = 0.017) and inversely correlated with PoS (p = 0.011) and P50 (p = 0.003), indicating that patients with less stable RBC PK had less deformable RBCs which sickled at a higher oxygen tension. RBC adhesion to laminin was correlated with both ARC (p = 0.0003) and dense RBCs (p = 0.019). To explore whether our findings were a reflection of reticulocytosis, whole blood samples of HbSS patients were fractioned by cell density. We found that RBCs from the most dense fraction adhered more to laminin than from the less dense, reticulocyte enriched, fraction, even though RBCs from this less dense fraction had reduced PK-thermostability. Additionally, the most dense RBCs had the lowest PK activity, were less deformable and had a higher PoS (data not shown). Altogether these findings indicate that the reduced PK thermostability we found in our SCD cohort is associated with an overall functionally impaired RBC population with increased RBC adhesion and ARC.

Summary/Conclusion: This study shows for the first time a significant correlation between PK thermostability in sickle RBCs and RBC functions, such as adhesion, deformability and oxygen affinity. Our results suggest that enhancing the activity and stability of PK, with PK activators, is an attractive target in SCD that might improve other pathophysiological targets outside RBC metabolism. Future studies are needed to explore how activation of PK will affect these altered sickle RBC properties in vivo.

Table 1.

Topics 001–Basic and translational

M.J. Telen¹, M. Batchvarova¹, M. Delahunty¹, L. Boateng¹, K. Boyle¹, M.A. Suggs¹, G.M. Lee¹

Duke University¹

Background: SCD has a complex and multisystem pathophysiology arising from the numerous red cell (RBC) abnormalities engendered by the presence of HbS. Abnormal sickle (SS) RBCs are abnormally adhesive to both endothelium and other circulating blood cells. SS RBCs have increased expression and activation of various endogenous signal transducing proteins, contributing to activation of the normally inactive erythroid adhesion molecules Lutheran/basal cell adhesion molecule (Lu/BCAM), intercellular adhesion molecule 4 (ICAM4) and CD44. SS RBCs also express increased amounts of phosphatidylserine (PS) on their surface. Neutrophils play a role in vaso-occlusion by adhering to endothelium, promoting “capture” of SS RBCs in small vessels, and secretion of pro-inflammatory substances. Neutrophils isolated from patients with SCD are significantly more adherent to endothelial cells (HUVECs) compared to neutrophils from normal healthy subjects (healthy donor 19.97% ± 9.26% vs. SCD 64.49% ± 15.04%, p < 0.0001). In addition, plasma from patients with SCD at steady state demonstrates higher levels of matrix metallopeptidase 9 (MMP9), a marker of tertiary granule release, compared to healthy subjects.

Aim: To demonstrate that isolated SS RBCs can directly activate normal neutrophils, resulting in both neutrophil adhesion to endothelial cells as well as degranulation with release of MMP9.

Methods: Using both isolated neutrophils and whole blood, we performed assays of adhesion to HUVEC cells using graduated height flow chambers (1) and ELISA assays to quantitate MMP9 (2).

Results: AA RBCs fail to stimulate neutrophil adhesion, with or without pre-treatment of RBCs with epinephrine. However, SSRBCs induce neutrophil adhesion to HUVECs (neutrophils alone vs. SSRBCs 27.04% ± 10.89%, p < 0.01), and epinephrine-treated SSRBCs do so even more robustly (neutrophils alone vs. epi-treated SSRBCs 41.32% ± 14.01%, p < 0.001; SSRBCs vs. epi-treated SSRBCs p < 0.001). Further investigation of the mechanism by which contact with SS RBCs may result in neutrophil activation in vitro first asked whether RBC adhesion molecules mediate neutrophil activation. Compared to neutrophils exposed to SS RBCs incubated with a nonreactive monoclonal antibody (mAb), incubations of SS RBCs with mAbs against the RBC adhesion receptors ICAM4 and BCAM/Lu demonstrated inhibition of subsequent SS RBC-induced neutrophil adhesion by 56% and 75% respectively (p = 0.0427 and p = 0.0024).

Additionally, in an observational study of adults with SCD, we observed that plasma MMP9 levels were strongly associated with RBC surface expression of PS (p < 0.0001, N = 101). We therefore determined whether increased exposure of PS by SS RBCs would increase the degree of neutrophil activation. While addition of SS RBCs to normal neutrophils increased MMP9 release 2.16 fold, SS RBCs first treated with calcium ionophore to augment PS exposure, and then washed, increased MMP9 release 3.91 fold (p = 0.009 and p = 0.0016, respectively, p for difference = 0.0108). Furthermore, in blood from SCD patients, extent of PS exposure by RBCs strongly correlated with plasma MMP9 levels (p = 0.0052, N = 101), thus supporting an association of RBC PS exposure with neutrophil activation. We also showed that epi-stimulation of SS RBCs increased PS exposure significantly.

Summary: We conclude, therefore, that both activated RBC adhesion molecules, as well as PS exposure, likely contribute to the ability of SS RBCs to activate circulating neutrophils in SCD. Improving our understanding of this mechanism may offer new therapeutic targets useful for decreasing vaso-occlusive events in SCD.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

H. Frangoul¹, F. Locatelli², A. Sharma³, M. Bhatia⁴, M. Mapara⁵, L. Molinari⁶, D. Wall⁷, R. Liem⁸, P. Telfer⁹, A. Shah¹⁰, M. Cavazzana¹¹, S. Corbacioglu¹², D. Rondelli¹³, R. Meisel¹⁴, L. Dedeken¹⁵, S. Lobitz¹⁶, M. de Montalembert¹¹, M. Steinberg¹⁷, M. Walters¹⁸, S. Imren¹⁹, D. Shi¹⁹, L. Bower¹⁹, C. Simard¹⁹, L. Zhang¹⁹, P.K. Morrow²⁰, W. Hobbs¹⁹, S. Grupp²¹

Sarah Cannon Center for Blood Cancer at The Children's Hospital at TriStar Centennial¹, Catholic University of the Sacre d Heart, Rome, IRCCS, Ospedale Pediatrico Bambino, Gesu², Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital³, Department of Pediatrics, Columbia University Irving Medical Center, New York–Presbyterian-Morgan Stanley Children's Hospital⁴, Department of Medicine, Division of Hematology/Oncology, Columbia University⁵, Sarah Cannon Pediatric Transplant and Cellular Therapy Program at Methodist Children's Hospital⁶, The Hospital for Sick Children/University of Toronto⁷, Ann & Robert H. Lurie Children's Hospital of Chicago⁸, Royal London Hospital, Barts Health NHS Trust⁹, Stanford University¹⁰, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), University of Paris¹¹, University of Regensburg¹², University of Illinois at Chicago¹³, Heinrich-Heine-University¹⁴, Hopital Universitaire des Enfants Reine Fabiola¹⁵, Gemeinschaftsklinikum Mittelrhein¹⁶, Boston University Chobanian & Avedisian School of Medicine¹⁷, UCSF Benioff Children's Hospital¹⁸, Vertex Pharmaceuticals¹⁹, CRISPR Therap eutics²⁰, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania²¹

Background: Exagamglogene autotemcel (exa-cel) is a one-time nonviral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells.

Aims: Evaluate efficacy and safety of exa-cel in patients (pts) with severe sickle cell disease (SCD) in a pre-specified interim analysis of the CLIMB SCD-121 trial.

Methods: CLIMB SCD-121 is an ongoing Phase 3 trial of a single dose of exa-cel in pts aged 12–35 yr with SCD and a history of ≥2 vaso-occlusive crises (VOCs)/yr in 2 yr prior to screening. Primary efficacy endpoint is proportion of pts free of severe VOCs for ≥12 mos (VF12); key secondary efficacy endpoint is proportion of pts free from inpatient hospitalization for severe VOCs for ≥12 mos (HF12). Evaluable pts were followed for ≥16 mos after exa‑cel infusion. Evaluation of VF12 and HF12 began 60 days after last RBC transfusion for post-transplant support or SCD management. Pts completing trial enrolled in long-term follow-up Study 131.

Results: As of 16 Sept 2022, 35 pts with SCD (median age 21 [range 12–34] yr; 8 [22.9%] age ≥12 to <18 yr) received exa-cel. Of the 17 pts evaluable for primary and key secondary endpoints, 16 (94.1%) achieved VF12 (95% CI: 71.3%, 99.9%; p = 0.0001) and all achieved HF12 (95% CI: 80.5%, 100.0%; p < 0.0001). One pt did not achieve VF12 but achieved HF12; this pt had multiple complex comorbidities, including a history of chronic pain. Mean VOC-free duration in pts achieving VF12 was 18.7 (range: 13.1–36.5) mos; 15 pts remained VOC-free through follow-up and 1 pt had an adjudicated VOC in the setting of a parvovirus infection ~22.8 mos after exacel; pt recovered fully and has since been VOC free. For all pts, mean total Hb was 12.0 g/dL at Month 3 and was maintained at ≥12.0 g/dL through follow-up; mean HbF was 36.8% at Month 3 and was maintained at ≥40.0% through follow-up, with pancellular distribution. Mean proportion of edited BCL11A alleles was stable over time in bone marrow CD34+ and peripheral blood nucleated cells. 31 of 33 pts (including those not yet evaluable) remained VOC-free starting 60 days after last RBC transfusion (up to 36.5 mos). Quality-of-life (QOL) measures showed clinically significant improvements from baseline in mean EQ VAS (33.1 points), FACT-G (27.2 points), and BMTS (6.7 points) scores at Month 18.

All pts engrafted neutrophils and platelets (median 27 and 33 days, respectively). All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 34 (97.1%) pts had AEs of Grade 3 or 4 severity. Most common AEs were nausea (74.3%), stomatitis (68.6%), and vomiting (60.0%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. No pts had SAEs considered related to exa-cel. As previously reported, 1 pt died from respiratory failure due to COVID-19 not considered related to exa-cel. There were no study discontinuations or malignancies.

Conclusion: This pre-specified interim analysis of the pivotal trial of exa-cel in SCD demonstrated transformative benefit: 94.1% of pts were free of VOCs and 100% were free of inpatient hospitalization for VOCs, with early and sustained Hb and HbF increases, durable allelic editing, and improved QOL. Safety profile of exa‑cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel can deliver a one-time functional cure for pts with SCD.

Topics 004–Clinical, public health and epidemiological studies

C. Jonassaint¹, B. Eppinger², D. Friend², G.L. Green², M. Robinson³, T. Woolford⁴, D. Wyant², J. Davis⁵, A. Oluyadi⁵, A.U. Zaidi⁵, H. John⁵, W. Smith⁶

School of Medicine, University of Pittsburgh¹, Independent Contributor², Sickle Cell Awareness 365³, Sickle Cell Reproductive Health Education Directive⁴, Agios Pharmaceuticals⁵, Virginia Commonwealth University School of Medicine⁶

Background: In many clinical trials, patient involvement in the design process is often delayed, inadequate, or completely absent. And when patients are involved, the focus tends to be on meeting enrolment goals rather than addressing the needs and challenges faced by potential participants. Due to inadequate patient engagement throughout the various stages of clinical development, patient participation in these trials is often low, leading to outcomes that may not be representative of, nor align with specific patient needs. As a consequence, the uptake of the treatment in real-world settings is often unsatisfactory or ineffective. To address this situation in sickle cell disease (SCD), new approaches are needed to overcome barriers such as mistrust of the medical system, transportation issues, and/or protocol burdens. Without addressing these barriers, low levels of enrolment and public awareness can restrict the effectiveness of clinical trials. Here, we describe how sickle cell warriors (i.e., adults living with SCD) were engaged to address these issues with the RISE UP[i] campaign.

Aims: To describe how sickle cell warriors were engaged to develop the RISE UP campaign—an innovative patient-led approach to raising clinical trial awareness and supporting enrolment among the disease community.

Methods: A steering committee of seven warriors (whose activities were convened and sponsored by Agios Pharmaceuticals) was brought together to provide the guidance needed to develop a meaningful and impactful trial awareness campaign, from naming, to creative development, to launch. The campaign sought to educate the community about the clinical trial process and highlight the importance of involvement. Based on the warriors' input, a creative agency developed campaign options. The warriors were then asked to select the campaign they felt would most effectively address the community's needs and expectations.

The campaign launch coincided with World Sickle Cell Day 2022 and incorporated various outreach strategies, including national communications, in-person events, and other activities to maximize reach and impact, and generate awareness about the trial. To measure campaign impact, descriptive social media metrics including campaign video views, traffic to the clinicaltrials.gov web page, as well as paid and organic social media clicks and views, were collected. Reach metrics were gathered by platforms and included: views, defined as instances of the campaign video being played; clicks, defined as individuals clicking through to a webpage via a provided link; and visits, defined as the opening of a webpage either through links, search engines or manually entering the URL.

Results: Pre-post analyses of engagement showed that the campaign effectively generated heightened interest in clinical trial participation among the target audience. Table 1 provides a comprehensive summary of the overall results achieved through the RISE UP campaign. Paid media efforts on YouTube amassed 140,000 views in just 12 days, and the video continued to gain traction with over 3 million views since its launch. On Twitter, sponsored ads received 6000 clicks in July 2022, contributing to the campaign's reach and impact. The campaign garnered a significant share of voice during key events, such as the Cayenne Wellness Instagram activity on World Sickle Cell Day. Following the campaign launch there was a positive impact on clinicaltrials.gov traffic, with an average of 2–3 clicks per day post-event, indicating sustained interest and engagement with the trials even after the campaign's conclusion. In addition, the campaign website saw a substantial increase in traffic, reaching key information and messaging exposure to over 278,000 users. On average, each user was exposed to the campaign's messaging approximately three times.

Conclusion: The RISE UP campaign successfully engaged sickle cell warriors in the development of an innovative approach to raise awareness about clinical trials. This patient-led approach was an effective means of reaching and engaging the target audience, building awareness and engagement with patients, families, and advocacy groups, as well as national decision-makers and influencers. The impact of the RISE UP campaign is a testament to the value of patient participation. Learning and best practices from this innovative patient-led approach can potentially be applied to other activities in the drug development process.

Table 1. Main metrics following RISE UP campaign launch.

None to declare.

Topics 007–Health services and outcomes research including psychology

D. Dwuma-Badu¹, C. Segbefia², I. Kanyoke¹, A. Peprah¹, I. Odoom-Brown¹, N. Harith¹, E. Nkansah¹, M. Ampadu¹, B. Goka², J. Welbeck², I. Odame³

Korle Bu Teaching Hospital¹, Korle Bu Teaching Hospital and University of Ghana Medical School², The Hospital for Sick Children and University of Toronto³

Background: Despite the high prevalence of sickle cell disease (SCD) in Africa, newborn screening (NBS) for SCD and follow-up care programmes are not universally available. NBS enables early diagnosis, initiation of penicillin prophylaxis and parental education, which help reduce SCD morbidity and mortality. To achieve these goals, all screen-positive babies must be enrolled and followed-up in comprehensive sickle cell clinics. Nurse-led care for follow-up of babies identified through NBS for SCD is a practical approach, especially in regions with large deficits in the physician workforce.

Aim: To describe our experience of nurse-led follow-up care of babies identified through NBS for SCD at Korle Bu Teaching Hospital (KBTH), Accra, Ghana.

Methods: NBS for SCD at KBTH was launched in June 2017 in partnership with the Centre for Global Child Health, SickKids, and Toronto. The NBS for SCD nursing team comprises of 4 nurses who perform initial counselling and dried blood spot sampling on the hospital postnatal wards, 1 senior nursing officer at the pediatric sickle cell clinic, and 1 hematology nurse specialist. Administrative and clinical support are provided by a NBS manager and pediatric hematologist, respectively. There is a dedicated newborn clinic with written protocols to ensure standardization of care.

Results: Families of all babies with screen-positive test results are contacted by a nurse on the SCD screening team or the NBS manager and informed of their first clinic appointment date. Those not reached by telephone are “tracked” within the community based on home address details provided on the screening form. Upon arrival at KBTH for a clinic visit, a team nurse assists the parent(s) to navigate the health system administrative procedures. Clinic activities by nurses, overseen by the nurse specialist, include anthropometric measurements, clinical assessment, caregiver education on SCD, screening of family members, baseline labs including confirmatory SCD testing (HPLC/electrophoresis), initiation of penicillin prophylaxis, and planning subsequent follow-up visits. Home visits are conducted for babies who have not attended clinic after several telephone contacts, and indigent families receive support from the SCD programme amenities fund. Screening and clinic data are shown in Table 1. The main challenges encountered are difficulties with caregivers accepting a diagnosis of SCD, unsuccessful tracking of screen-positive babies and adherence to follow-up.

Conclusion: The KBTH nurse-led SCD newborn clinic has been useful in providing care in a resource-constrained setting for infants identified through NBS. Challenges identified may be addressed with strategies such as intensifying culturally sensitive public education on SCD and training more community-based nurses on SCD to improve geographic access to care.

Table 1. Summary of babies screened, contacted and enrolled from June 2017 to December 2022.

Funding: Pfizer.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

N.H.A. Hussien¹, S.M.M. Makkeyah¹, N.M.S. Shaheen², A.M.O. Okba¹, S.M.A. Mohamed¹, F.S.E. Ebeid¹

Ain Shams University¹, Misr's Children Hospital, Health Insurance Organization²

Introduction: Vaso-occlusive crisis (VOC) episodes are the cause of almost 95% hospitalizations for patients with sickle cell disease (SCD). VOCs cause continual or unpredictable episodes of acute pain. This usually begins in infancy and continues throughout life. Preventing pain is therefore more important than treating pain once it has been evoked.¹ Although L-glutamine has been approved by the FDA for the prevention of acute complications in SCD, many gaps exist in our understanding of its therapeutic implications in SCD.²

Aim: To evaluate the safety and efficacy of L-glutamine in reducing the number of VOCs in patients with SCD, as well as to assess the effect of glutamine on the cerebral arterial blood flow as assessed by transcranial Doppler (TCD).

Methods: We initiated a single-center, investigator-initiated phase 4 interventional nonrandomized controlled trial at Ain Shams University Children's Hospital. Eligible patients had SCD, had at least two documented pain crises (no upper limit) during the last 12 month prior to screening, and were on a stable dose of hydroxyurea (HU) for at least 3 months before screening. Sixty participants were randomly assigned in a 1:1 ratio to receive glutamine at a dose of 0.3 g/kg/dose twice daily orally (up to a maximum of 15 g/dose) for 24 weeks or the standard of care (SoC) without glutamine intake. The primary endpoint was the cumulative number of VOCs at 24 weeks, and the secondary endpoint was the change in TCD [Time-Averaged Mean Maximum Velocity (TAMV) in the middle cerebral artery (MCA), anterior cerebral artery (ACA) and internal carotid (ICA)] at 24 weeks.

Results: The mean ± SD age of the study subjects was 9.2 ± 3.7 years. They were 35 males and 25 females. Thirty-seven (62%) had HbSS with 38% had other sickle cell variants. All participants were receiving HU therapy. Almost half of the patients (48%) were on chelation therapy with deferasirox. The baseline characteristics between the two study groups were relatively similar. For the primary endpoint, at week 24 timepoint the cumulative number of VOCs was not significantly different between the glutamine and the SoC group [median (IQR): 2.0 (2.4.25) in the glutamine group versus 3.0 (2–4) in the SoC group (p = 0.471)]. However, the L-glutamine group had fewer hospitalizations for VOC when compared to the SoC group (median of 0.0, range 0–2 in the L-glutamine versus a median of 1.0 (0–2) and range 0–4 for the control group, p = 0.0001). When comparing TAMV for the glutamine group at baseline and week 24, we found that both MCA had a marginal increase in TAMV although all values remained normal within a range of 100–118 cm/s, while both ICA showed a significant increase from an abnormally low value of less than 70 cm/s to normal ranges (p < 0.005).

Conclusion: Glutamine reduced the number of hospitalizations for VOC in our cohort with SCD. It has a potential favorable impact on the cerebral arterial flow velocities, however, larger studies are needed to confirm this effect.

Topics 007–Health services and outcomes research including psychology

B. Andemariam¹, M. Idowu², N. Shah³, R. Drachtman⁴, A. Sharma⁴, A. Glaros⁵, M. Achebe⁶, A. Nero⁷, R.M. Xu⁸, S. Curtis⁹, C. Minniti⁹

New England Sickle Cell Institute, University of Connecticut Health¹, University of Texas Health², Duke University School of Medicine³, Rutgers Medical School⁴, Division of Pediatric Hematology/Oncology, Central Michigan University⁵, Brigham and Women's Hospital⁶, University of Texas Southwestern Medical Center⁷, Pfizer Inc.⁸, Albert Einstein College of Medicine⁹

Background: Sickle cell disease (SCD) is an inherited disorder driven by polymerization of deoxygenated sickle hemoglobin (HbS). Polymerized HbS causes red blood cell (RBC) sickling, which leads to chronic hemolytic anemia, painful vaso-occlusive crises (VOCs), and end-organ damage. Voxelotor is a HbS polymerization inhibitor approved in the US and UAE for patients aged ≥4 years and in the EU, Great Britain, Oman, and Kuwait in patients aged ≥12 years. In the pivotal HOPE trial, voxelotor increased hemoglobin and reduced hemolytic markers in patients with SCD. Real-world evidence with voxelotor is emerging; however, little information is available on real-world patterns of voxelotor use and its impacts on safety and effectiveness.

Aim: To examine patterns of voxelotor use in patients from 9 clinical sites in the US as part of the Retrospective Real World Oxbryta Data Collection and Analysis Study (RETRO; NCT04930328).

Methods: RETRO is a postmarketing, multicenter, retrospective data collection and analysis study. Eligible patients were aged ≥12 years, were diagnosed with SCD (any genotype), had been receiving voxelotor for ≥2 consecutive weeks, and had laboratory and clinical data available from 1 year before and up to 1 year after their first voxelotor dose. Institutional review boards issued informed consent waivers.

Results: Data from 216 patients were collected and analyzed. Mean (SD) patient age was 33.5 (14.2) years, and 14.4% of patients were aged <18 years. A total of 120 patients (55.6%) were female, 189 (87.5%) were African American or Black, and 199 (92.1%) had the HbSS genotype.

Sixty percent of patients were treated with voxelotor for ≥9 months during the 12-month study period. Most patients (86%) were prescribed an initial dose of 1500 mg once daily, and 14% were prescribed an initial dose lower than that recommended in the label. Twenty-three percent of patients had a physician-initiated dose modification. Treatment discontinuation was reported for 21.8% of patients; reasons included adverse events (8.3%) and “other” (13.5%), which included loss to follow-up, physician's decision, and study withdrawal.

Preliminary safety analyses suggest that there was no evidence of drug interruption or discontinuation leading to rapid onset of adverse events (including VOCs), as suggested previously for patients with severe SCD.¹ In the 45 patients (20.8%) who had a VOC after drug interruption or discontinuation, the median (25th to 75th percentile) time to onset of a VOC was 74 (29–138) days. Two patients had a VOC within 1 week of dose interruption or discontinuation; both events were deemed unrelated to voxelotor by investigators.

These data align with preclinical findings suggesting that the impact of voxelotor on red cell rheology is acutely sustained after voxelotor dose interruption or discontinuation.² Analyses are ongoing to further understand the effects of voxelotor dosing patterns on safety and effectiveness.

Conclusion: RETRO is the largest multicenter study to retrospectively collect and analyze real-world data from voxelotor-treated patients with SCD. Most patients did not require dose modification or treatment discontinuation. Discontinuation and dose interruption were not found to be related to subsequent onset of VOCs. Data on patterns of voxelotor use in the real-world setting can provide valuable insights into the impacts of prescribing and dosing practices that are different from those on the label.

Funding: Pfizer.

Topics 001–Basic and translational

I.P. Ijei-Enesi¹, H. Isah², M. Shuaibu³, G.Y. Bahago³, J. Yakubu², L.G. Dogara¹

Barau Dikko Teaching Hospital/Kaduna State University¹, Consa Data Management Office², Barau Dikko Teaching Hospital³

Background: Newborn screening (NBS) for inheritable diseases has been utilized as a strategy for the early detection of sickle cell disorders (SCD) and the prompt initiation of basic health interventions has significantly reduced under 5 (U5) morbidity and mortality especially in high prevalence countries (Green et al., 2022; Lees et al., 2000]. Sub-Saharan Africa bears over 80% of global SCD burden (Inusa et al., 2015). There is no universal NBS program in any African country.

Experts identify factors complicating initiation, operation & expansion of NBS programs and stress government engagement for sustainable screening initiatives (Archer et al., 2022).

ARISE, through & with its Fellows, work on the CONSA-supported Kaduna State NBS program to assess SCD birth incidence, early care impact (Green et al., 2022). The CONSA program, operates through a network of rural and urban facilities offering primary through to tertiary level public health care, by partnering with state, local and international partners to increase the diagnostic and clinical management capacity for SCD. Dried blood spots (DBS) collected by heel prick are tested using iso-electric focusing (IEF), a costeffective technology capable of identifying clinically significant hemoglobin (Hb) variants in the first week of life.

Methodology: Approval was obtained from the Health Research Ethics Committee of the Kaduna State Ministry of Health & Barau Dikko Teaching Hospital (BDTH), Kaduna. Babies were recruited from labour rooms, immunization clinics and well-baby clinics. Isoelectric focusing (IEF) was performed at two NBS reference laboratories, using ASH-CONSA standard operating procedures, on DBS samples obtained from post-consent heel pricks in babies less than three months old, from NBS core treatment hubs and linked primary health care centers (PHCs) in Kaduna State. Validated results were released to parents via sending sites through a standardized counselling process. Data obtained between April 2019 and March 2023 was analyzed using Microsoft Excel® Version 2016 and results displayed as frequencies and percentages.

Results: Total of 8202 babies screened aged 0–1 years (mean 0.09 ± 0.13): males 50.1% (n = 4110), females 49.9% (n = 4093). Results released to affected families; 78.1% (n = 6405).

Hemoglobin phenotypes detected: FA 72.06%, FAS 23.16%, FAC 0.47%, FS 1.05%, FSA 0.93%, FSC 0.12%, other variants 2.21%.

Annual target achievements: 2019: 2.47%, 2020: 0.4%, 2021: 18.09%, 2022: 45.14%, 2023: 10.05%. Noteworthy uptake in 2022 (36.31% of samples) due to NBS deployment to PHCs.

SCD positive babies: 1st clinic visit 29%, 2nd 9%, 3rd 2%. Clinical indicators: Bed nets 89%, vaccines (Haemophilus, pneumococcal) 64.6%, folic acid & penicillin 91.7% issuance rates.

Conclusion: Study shows fluctuating screening and uptake, potentially highlights healthcare access gaps. These urge NBS implementation, better access and follow up. Efforts are needed to raise community awareness, enhance uptake, and strengthen healthcare infrastructure to reduce SCD burden in Nigeria and other similar regions.

Topics 007–Health services and outcomes research including psychology

V. Paintsil¹, L.T. Chikelu², E. Baafi-Boateng³, C.S. Anthony⁴

Department of Child Health, Kwame Nkrumah University of Science and Technology¹, Bangor University², Novartis Ghana Limited³, Novartis Pharma Corporation⁴

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy with increasing public health burden affecting ~8 million globally with the majority in Sub Saharan Africa (SSA).¹ A needs assessment conducted with Ghanian SCD experts identified limited access to SCD specialists, knowledge gaps in SCD management and available treatment options, and lack of synergies with SCD experts in tertiary centers as key challenges to comprehensive SCD care in rural Ghana.

Aim: To assess the impact of a peer-to-peer (P2P) round table educational program on the improvement in Ghana healthcare professionals' (HCP) knowledge on SCD management.

Methods: A pilot training program was designed to facilitate P2P education on SCD in rural Ghana. The program aimed to increase knowledge of HCPs on screening, early diagnosis, and management of SCD, including mechanisms of action, dosing, efficacy, and safety of available treatment options. The target audience for this program included HCPs (nurses, pharmacists, physicians and physician assistants). The curriculum comprised of the following 3 modules: (1) Overview of SCD and current management options; (2) Early public health strategies and interventions, and the spectrum of SCD pain; (3) Complications of SCD including mental health.

Each module was presented quarterly at 2 rural clinics: Holy Family Hospital (HFH), Techiman, and Mampong Government Hospital (MGH), Mampong, and was facilitated by a local Ghana medical SCD expert. A similar training program was also conducted at Onwe Government Hospital, but responses were not reported here. Attendees' details and perceptions on diagnosis and management of SCD were collected in Quarter (Q)1 using paper-based survey questionnaire. Pre-and post-knowledge assessments, and impact of the program assessed using Novartis training impact tool were recorded digitally in Q2 and Q3. All responses were summarized descriptively.

Results: Overall, 90 attendees underwent training at MGH (N = 50) and HFH (N = 40). As per Q1 survey responses, attendees at MGH and HFH were physicians (14 [45%]; 13 [59%]), nurses (3 [10%]; 0), and other staff (14 [45%], 9 [41%]), respectively. Nearly 70% had ≤5 years of practice in their role (23 [68%], 16 [73%]), and the majority (31 [91%]; 22 [100%]) had prior experience in managing SCD, respectively. Almost half the responders perceived appropriate SCD diagnosis as the most valuable information for SCD care.

Knowledge assessment responses showed that the proportion of responders who answered correctly after training was higher than before the training at both centers (MGH [Q2: 74%, 63%; Q3: 79%, 44%]; HFH [Q2: 87%, 76%; Q3: 82%, 44%]).

Post-training impact scores of almost all the responders showed that the training curriculum was more likely to improve their knowledge and clinical management of patients with SCD, and they were more likely to recommend it to peers.

Summary/Conclusion: This program was well received, with the responders expressing positive views about its potential to improve knowledge, relevance to clinical practice, and recommendation to peers. Additionally, the program's success led to the establishment of a dedicated SCD clinic and a peer mentoring platform. This program is being extended to other local centers in SSA. Scaling up such educational initiatives in low- and middle-income countries would help build capacity and strengthen the healthcare system, thus enabling access to comprehensive SCD care.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

J.E. Poole¹, T.G. St Pierre², S. Muth³, J. Mahlangu¹

University of the Witwatersrand¹, The University of Western Australia², Resonance Health Analysis Services Pty Ltd.³

Background: Measurement of liver iron concentration (LIC) by MRI with expert data analysis is an acceptable approach in guiding the management of iron overload in patients receiving chelation therapy. LIC is a surrogate measure of total body iron stores and informs clinical decisions on when to change the dose of iron chelators or add another iron chelator.¹ In the South African context, access to routine liver MRI for LIC measurement is limited. Image data acquisition and analysis services have previously been available in the context of clinical research. Therefore there is a need for alternative tools to evaluate iron overload in patients which are accessible, affordable and simple to perform.

Aims: In this study we compared the analytical performance of the new fully automated AI-trained analytical tool, DLA R2-MRI (Resonance Health Ltd., Australia) for the evaluation of LIC by MRI in patients with inherited transfusion dependent anemias in South Africa.

Methods: This study was approved by the University of the Witwatersrand Human Research Ethics Committee. Image data from participants (24 β-thalassemia major; 1 β-thalassaemia intermedia; 1 Diamond-Blackfan anaemia; 1 transfusion dependent hereditary anemia NOS) acquired previously for evaluation of LIC were reanalysed using the fully automated AI-trained software. The LIC values generated by the automated software (index method) were compared with the LIC values previously obtained from expert analysts using the spindensity-projection assisted R2-MRI (reference) method.² In cases where the reference result was >43 mg Fe/g dry tissue, the reference reported liver R² value was converted to LIC by extrapolating the calibration curve.^2,3 Bland and Altman method⁴ was used to determine the bias and 95% limits of agreement between the index and reference methods. The sensitivity and specificity of the index method for predicting reference method LIC results above the clinically relevant thresholds of 3, 5, 7, and 15 mg Fe/g dry tissue together with their 95% CIs were calculated using the Wilson-Brown method.⁵

Results: MR image datasets (42) were available from 27 patients with 14 patients having 1 scan, 11 patients 2 scans, and 2 patients 3 scans. Patients ranged in age from 8.3 to 42.8 years at the time of scanning. Values of LIC by the index method are plotted against those from the reference method in the figure. The geometric mean ratio of LICs by the index method to those from the reference method was 0.96 [95% CI: 0.91–1.03]. The upper and lower 95% limits of agreement between the two methods represented as ratios of the index method to the reference method results were 1.43 and 0.65 respectively. The sensitivities and specificities of the index method for predicting reference method LIC values above clinically relevant thresholds are shown in the table.

Summary/Conclusion: The parameters of diagnostic accuracy determined in this study show a low bias between the index and reference methods, and high sensitivities and specificities of the index test. The 95% confidence intervals are rather wide owing to the limited number of datasets available and hence expanding the dataset with data from other sites will likely strengthen the evidence supporting the use of the index method in the management of South African patients with inherited transfusion dependent anemias who are at risk of iron overload.

Topics 004–Clinical, public health and epidemiological studies

A.R. Rankine Mullings¹, R. Keenan², S. Chakravorty³, B. Inusa⁴, P. Telfer⁵, M. Velangi⁶, R. Ware⁷, J. Moss⁸, A.L.M. Lloyd⁸, S.E. Edwards⁹, H. Mulla⁹

The University of the West Indies, Caribbean Institute for Health Research¹, Liverpool Paediatric Haemophilia Centre, Hae matology Treatment Centre, Alder Hey Children's Hospital, NHS Foundation Trust², Department of Paediatric Haematology, Kings College Hospital, NHS Foundation Trust³, Department of Paediatric Haematology, Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust⁴, Department of Paediatric Haematology, Royal London Hospital, Barts Health NHS Trus⁵, Department of Paedi atric Haematology, Birmingham Children's Hospital NHS Foundation Trust⁶, Division of Hematology and Global Health Center, Cincinna ti Children's Hospital⁷, BAST Inc Ltd⁸, Nova Laboratories Limited⁹

Background: Hydroxyurea is highly effective in treating sickle cell anemia, but the absence of an approved child-friendly, homogenous, and stable oral formulation with documented pharmacological profile makes dosing in young children challenging.

Aims: This multi-center, prospective, open-label study investigated the pharmacokinetics (PK), safety, efficacy, and palatability of a new oral liquid hydroxyurea formulation.

Methods: Between January 2019 and December 2021, 32 hydroxyurea naïve children, aged 6 months to 18 years, initiated hydroxyurea at 15 mg/kg once daily and treated for 12–15 months, escalating to maximum tolerated dose with mild myelosuppression. Blood sampling for safety parameters and PK was done every 2–12 weeks. Informed consent was obtained from all parents/participants.

Results: The PK profile was described with a 2-compartment model with linear elimination and only bodyweight influencing clearance, in line with previous reports. Area under the curve at steady state increased with age (and body weight) but peak concentration did not.

The expected trends in fetal haemoglobin, biomarkers and clinical outcomes were observed consistently across age groups, suggesting age does not impact the therapeutic dose range. Adverse reactions were typically mild. Hydroxyurea related cytopenias were transient and benign. Children and parents found dosing with the liquid formulation easy, palatable, and convenient.

Summary/Conclusion: Weight based dosing of liquid hydroxyurea resulted in similar systemic exposure and clinical responses across the pediatric age range. The new liquid formulation provides increased flexibility for personalized dosing in pediatrics with a similar safety profile to that seen with other oral preparations. Favorable palatability/acceptability can potentially improve adherence for children unable to tolerate capsules or tablets.

Topics 006–Ageing and end organ damage

V.V.Q. Virginia Velez Quinones¹, C.O.P. Catherine Ostos Perez¹, M.D. Mariel Duchow¹, K.M. Kristina Menchaca¹, S.I. Shaun Isaac¹

University of Miami/JFK Medical Center¹

Background: Sickle cell disease is a cause of anemia frequently requiring blood transfusions. The current treatments for red blood cell sickling and sickle cell anemia include hydroxyurea, or the recently approved medication in 2019, Voxelotor. There was one study that showed that patients with sickle cell disease transitioning to adult care received less transfusions, less hydroxyurea and less iron chelation therapy when compared to pediatric patients, but there is limited data associating age with number of transfusions in adult hospitalized patients with Sickle Cell disease on either Hydroxyurea or Voxelotor. We conducted a retrospective cohort study to determine the agerelated blood transfusion requirements in hospitalized patients with sickle cell disease who were on either taking Voxelotor or Hydroxyurea.

Methods: This retrospective cohort study identified 8815 patients across several facilities diagnosed with sickle cell disease who were taking outpatient Voxelotor or Hydroxyurea. Patients who had CKD Stage 4 or 5, ESRD, pregnancy, major surgery, normal hemoglobin levels, and elevated liver enzymes were excluded with a final sample of 6240. Patients were stratified into two groups based on the treatment they were on, a group taking Voxelotor (243 patients 3.92%) and a group taking Hydroxyurea (5961 96.08%) outpatient. We assessed patient's characteristics such as age, sex, race, smoking status and events during hospitalization. The primary outcome was the number of blood transfusions required with either treatment in relation to the patient's age. Zero-inflated Poisson regression was used to determine the quantity and prediction of blood transfusions required according to age in each medication group.

Results: Of the 6240 with sickle cell disease who were either on Voxelotor or Hydroxyurea the mean age was 31.32 years, 58.11% were female and 41.89% were male, 94.63% were African-American and 5.37% were non-African-Americans. Age was significantly associated with the log count of transfusions, when controlling for other variables (χ² = 14.88, p < 0.001). When the patient's age increases by one year, the expected number of transfusions increases by a factor of 1.007.

Conclusion: Age is significantly associated with increased number of blood transfusion in hospitalized patients with Sickle Cell Disease taking Voxelotor or Hydroxyurea outpatient. There was one study that showed that patients with Sickle Cell Disease transitioning to adult care received less transfusions, less hydroxyurea and less iron chelation therapy when compared to pediatric patients, but there is limited data associating age with number of transfusions in adult hospitalized patients with Sickle Cell disease on either Hydroxyurea or Voxelotor. Our study was the first to identify that increasing age is significantly associated with increased number of blood transfusions in these patients (Wald Chi Square 14.88, p < 0.0001, CI 1.0032–1.0098). However, the limitation is having a relatively small sample size, and possible confounders from the patients and the disease itself

Topics 004–Clinical, public health and epidemiological studies

C. Vuong¹, C.L. Eckhardt¹, H. Heijboer¹, M. Suijker², L.A. de Ligt¹, M. Bartels², P. Brons³, H.L. Hooimeijer⁴, E. Rettenbacher¹, F.J. Smiers⁵, M.A. Stein-Wit⁴, A. van den Veer⁶, A. Verbaan⁷, M.H. Cnossen⁸, K. Fijnvandraat¹

Amsterdam University Medical Centers¹, University Medical Center Utrecht², Radboud University Medical Center³, Univer sity Medical Center Groningen⁴, Leiden University Medical Center⁵, Maastricht University Medical Center⁶, Hagaziekenhuis⁷, Erasmus University Medical Center⁸

Background: Sickle cell disease (SCD) is a genetic red blood cell disorder associated with increased morbidity and mortality. Newborn screening for SCD was introduced in January 2007 in the Netherlands to enable early diagnosis and initiation of preventive measures.

Aims: The objective of this study was to assess the effect of newborn screening on the morbidity and mortality of children living with SCD in the Netherlands, 16 years after its implementation.

Methods: In this national cohort study all children with SCD diagnosed by newborn screening were included. Patients were followed between 1 January 2007 and 31 March 2023 until end of follow-up, death or successful stem cell transplantation. Following informed consent, data were collected from medical files on SCD genotype, treatment, mortality and development of SCD-related complications. The incidence rate of SCD-complications was presented as lifetime-event per 100 person-years for the total duration of follow-up and for the age categories: 0–4, 5–11, and 12–16 years.

Results: In total, 391 out of 540 eligible patients (72%) with SCD were included in all hospitals with patients with SCD under treatment, accounting for 3047 person-years. The mean age at the end of follow-up was 7.8 years (SD±4.5). The majority of patients had SCD genotype HbSS (58%), followed by HbSC (28%). As for the mortality, five patients died during follow-up, primarily at or below the age of 2 years (4/5, 80%). In three patients, the cause of death was related to SCD, including infection (n = 2; aged 1.2 and 2.0 years) and acute splenic sequestration (n = 1; 2.0 years). The SCD-related complications are presented in Table 1. The most common SCD complication in this cohort was vaso-occlusive crisis (including dactylitis) with hospitalization. SCD-related complications that mainly developed within the first 4 years of life, were vaso-occlusive crisis, acute hemolytic crisis, aplastic crisis, severe infections, splenic sequestration and ischemic cerebral infarction. Acute chest syndrome occurred equally in all age categories. Other SCD-related complications developed to a lesser extent in our cohort, and at a later age in adolescence or adulthood.

Conclusion: In this cohort of neonatally screened children with SCD, a substantial number of SCD-complications occurred in the first 4 years of life. This study underlines the importance of parental education and 24/7 availably, high level acute specialized clinical care for these children from birth on. Further analysis to identify risk factors at young age for a severe phenotype will be conducted, to enable more targeted interventions in a timely manner. Hopefully, this will lead to reduction of disease burden, improving the quality of life in children living with SCD in the Netherlands.

Topics 001–Basic and translational

C.A. Hernández¹, M.J.M. Traets¹, W.W. van Solinge¹, F.A. Kuypers², M.A.E. Rab¹, E.J. van Beers³, R. van Wijk¹

Department Central Diagnostic Laboratory - Research, University Medical Center Utrecht¹, Department of Pediatrics, Divis ion of Hematology, University of California at San Francisco², Center for Benign Hematology, Thrombosis and Hemostasis - Van Crevel dkliniek, University Medical Center Utrecht³

Background: Red blood cells (RBCs) are biconcave cells with viscoelastic membranes that are adapted for oxygen delivery and gas exchange during their lifespan. Reactive oxygen species (ROS) continuously challenge the viability of RBCs. Despite the compounds arsenal to protect the RBC, like Glutathione (GSH), superoxide dismutase (SOD) and Catalase, damage can easily be inflicted that disrupts cellular properties. The susceptibility to oxidative stress in people with Sickle Cell Disease (SCD) is believed to be linked to multiple factors. These include free heme from hemolysis, inflammation processes, and antioxidant defenses.

Aim: Explore RoxyScan outcome parameters as a novel biomarker for oxidative stress sensitivity in SCD.

Methods: Susceptibility to oxidative stress was assessed with the Roxyscan, a novel application of the Lorrca MaxSis (RR Mechatronics) measuring rheological behavior of RBCs in response to cumene hydroperoxide (CHP, 100 µM) at 30 Pa shear. The method uses the Lorrca's peristaltic pump and suction needle, directing blood and CHP to the instrument's cup mixing them during approximately 30 s until the cell stability test starts. RBCs deformability in response to CHP was determined by the elongation index (EI) decrease over time. PoX is defined as the time until a 10% decrease in EI. EIstart: EI t = 0, EIfinal: EI t = 1600s, ΔEI (EIstart-EIfinal). RoxyScan measurements used blood samples from 16 adult SCD patients (HbSS, HbS/β0, HbS/β+) and 19 healthy controls (HC). Outcome PoX from fitted curves was correlated to RBC sickling tendency (Point of Sickling, PoS, assessed by oxygen gradient ektacytometry), complete blood count and Hb variants.

Results: (Figure 1A) RBCs from untreated HC show stable EI over time. HC exposed to CHP, show a small decrease in EI, mean decrease 0.055, range (0.017–0.10). Mean/median calculated PoX in HC is 1723s/1702s. In contrast, SCD RBC showed earlier and more pronounced loss of EI in response to CHP (examples Figure 1A). PoX comparison between HC and SCD revealed significant differences (mean PoX HC: 1723s (SD 329) vs. SCD: 725s (SD 472), p < 0.0001). (Figure 1B) Analyzing PoX to routine laboratory parameters in SCD gave a correlation with Hb levels (p = 0.002) and inverse correlation with reticulocyte count (p = 0.0014). Negative significant correlation was found with Hb distribution width (HDW, p < 0.001). Similar negative correlations were found for EIstart and EIfinal (p < 0.001). Interestingly, PoX significantly correlated negatively to PoS (p = 0.004). PoX showed no significant correlations with HbS/HbF levels.

Conclusion: We demonstrate the applicability of the RoxyScan as a novel method to assess RBC resilience to oxidative stress. SCD RBCs show a pronounced response to oxidative stress. A negative correlation of PoX with reticulocytes may indicate increased susceptibility to oxidative stress due to hemolysis. The inverse correlation with Hb levels supports this. PoX shows strong correlation with laboratory parameters, implying association with susceptibility to oxidative stress. Interestingly, on a functional level is the correlation between oxidative stress resilience and sickle tendency. Overall, our study highlights the potential use of the RoxyScan and its associated biomarkers as functional analysis of RBCs their oxidative resistance. Further research will investigate clinical applicability.

Topics 004–Clinical, public health and epidemiological studies

F.R. Rodigari¹, G.B. Brugnera¹, T.A.N. Abi Nassif², G.R. Reggiani³, M.P.B. Boaro³, D.S. Sirico⁴, M.A. Abboud², Z.B. Bulbul⁵, R.C. Colombatti ³

ARISE Secondee, Dipartimento della salute della donna e del bambino, Università degli Studi di Padova¹, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center², UOC Oncoematologia pediatrica, Dipartimento dell a salute della donna e del bambino, Università degli Studi di Padova³, UOC Cardiologia Pediatrica, Dipartimento della salute della don na e del bambino, Università degli Studi di Padova⁴, Division of Cardiology, Department of Pediatrics and Adolescent Medicine, Americ an University of Beirut Medical Center⁵

Background: Cardiovascular disease is among the leading causes of premature death in people affected by sickle cell disease (SCD). In SCD patients diastolic dysfunction appears early in life, while systolic dysfunction usually appears later and it is associated with other comorbidities. Echocardiographic evaluation of the left ventricle longitudinal strain (LS) through speckle tracking echocardiography (STE) allows to detect early variation of the systolic function and can precede traditional echocardiographic measures of the ventricular systolic function in identifying cardiac subclinical systolic dysfunction. However, few studies reported the evaluation of ventricular systolic function in SCD patients through MS.

Aims: This study aims to investigate the left ventricular systolic function through LS in a cohort of children and young adults with SCD. Changes in conventional echocardiographic measures throughout time have also been investigated.

Methods: This is a retrospective observational, single-center study performed within the ARISE Project on the SCD population followed at the Children's Heart Center of the American University of Beirut Medical Center (AUBMC) between 2015 and 2023. We analyzed standard morphological and functional echocardiographic measures along with left ventricular function through speckle tracking echocardiography (STE) myocardial strain. For each patient, baseline echocardiographic data have been compared to the latest followup study. Baseline echocardiographic data have also been compared to age and sex-matched healthy controls.

Results: 129 patients have been enrolled in the study. We present preliminary data about 34 patients (20 males and 14 females), mean age 16.3 ± 3.5. Comparing the baseline studies to the latest echocardiographic follow-up (mean interval between studies 3.5 ± 1.3 years), patients showed a reduction of LVEDd/BSA (from 35.2 ± 4.4 to 33.1 ± 3.1 mm/m²; p value 0.028), a reduction of MV E (from 109.6 ± 19.1 to 97.5 ± 17.5 cm/sec; p value 0.007) and E/E′ (from 5.8 ± 1.3 to 5.7 ± 1.6; p value 0.057), an augmentation of mitral valve DecT (from 168.5 ± 28.9 to 204.6 ± 68.2 msec; p value 0.021) and IVRT (from 63.7 ± 13.4 to 72.5 ± 12.1 ms; p value 0.023).

The subgroup of patients that had a follow-up of at least 4 years (12 patients) also showed a reduction of the left ventricle longitudinal strain (LV-GLS) (from −21.5 ± 0.9 to −20.8 ± 1; p value 0.009).

Moreover, there is a significant difference between patients and controls echocardiographic parameters as regards LVEDd (52.2 ± 5.5 vs. 45.8 ± 5.3 mm; p value 0.000), LVEDd/BSA (35.2 ± 4.4 vs. 27.9 ± 3.0 mm/m²; p value 0.000), LVESd (34.3 ± 3.7 vs. 30.3 ± 4.0 mm; p value 0.000), indexed LV mass (94.8 ± 31.6 vs. 51.7 ± 16.1 g/m²; p value 0.000), indexed LA volume (29.5 ± 8.5 vs. 14.8 ± 3.3 mL/m²; p value 0.000), IVRT (63.7 ± 13.4 vs. 50.4 ± 11.1 ms; p value 0.001), with no significant variation in LV-GLS.

Summary: In this cohort, SCD patients were found to have a reduction of left ventricular dimension, MV E and E/Lat E′ and augmentation of MT DT and IVRT during a mean follow-up of 3.5 ± 1.3 years, denoting a progressive diastolic dysfunction. Patients followed up for a longer period were found to develop a reduction of the LV-GLS, denoting also a subclinical systolic dysfunction. Moreover, SCD patients were found to have significantly higher left atrial and ventricular dimensions when compared to age and sexmatched healthy controls, as well as longer IVRT.

Conclusion: Morphological and functional echocardiographic evaluation of the left ventricle is a potential tool for follow-up and stratification of patients affected by SCD, however more studies are needed to determine the clinical impact of LV-GLS reduction. Analysis will be finalized with echocardiographic data of the entire cohort of patients and will be correlated with demographic, clinical and laboratory characteristics of patients.

Topics 001–Basic and translational

O.O. Ojewunmi¹, N.E. Igbineweka², M. Sohal³, A. Luqmani³, M. Adeturinmo³, B.P.D. Inusa⁴, P. Kountouris⁵, M. Layton², J. Makani², S. Okoli³

King's College London¹, Imperial College London, Centre for Haematology, Department of Immunology & Inflammation², Department of Haematology, Imperial College Healthcare NHS Trust³, Evelina London Children's Hospital, Guy's and St. Thomas' NHS Foundation Trust⁴, The Cyprus Institute of Neurology and Genetics⁵

Background: Sickle cell disease (SCD) is a monogenic disorder characterised by diverse clinical phenotypes that extend beyond the polymerisation of haemoglobin S. While the genetic factors underpinning numerous SCD phenotypes have been investigated in many studies, the causal and sickle-specific genes influencing the clinical manifestations have not been identified due to the limitations of underpowered studies. For instance, only half of the HbF heritability (~45%) have been explained by BCL11A, HBS1L-MYB intergenic polymorphism, and XmnI-HBG2 in SCD and non-SCD; the causal SNPs with functional, clinical relevance are still largely unknown. To overcome the challenges of previous studies such as small sample sizes and low statistical power, INHERENT (INternational HEmoglobinopathy REsearch NeTwork) was established to conduct a large-scale, multi-ethnic genome-wide association study.

Aim: To discover and validate novel genetic modifiers of hemoglobinopathies and their influence in disease manifestations and severity.

Methods: Imperial College Healthcare, London is a collaborating centre for the INHERENT initiative. Our facility currently has 400 registered patients, and we plan to include 50 SCD patients (≥2 years old) from the 200 patients enrolled in the National Institute of Health Research (NIHR) BioResource for INHERENT project. We shall obtain ethical approval from the Imperial College Hospitals Ethics Committee prior to study enrolment. We shall hold various patient engagement events to sensitise patients and families/caregivers about the study protocol. After obtaining written consent, we will collect 5 mL of blood from each participant and complete a study proforma to capture essential clinical and laboratory data. Following DNA extraction from the blood samples, SNP array genotyping will be performed. The data generated shall be used for genome-wide association studies, contributing to the broader research efforts aimed at gaining insights into the genetic basis of sickle cell disease.

Results: This large-scale study will uncover previously unknown genetic factors that contribute to the clinical phenotypes of hemoglobinopathies. By identifying these genetic modifiers and understanding their impact on disease presentation and severity, we hope to pave the way for genetic risk prediction and more targeted, effective, and personalised treatments that will significantly improve quality of life and life expectancy of the affected persons.

Conclusions: A large, multi-ethnic, and well-characterised global repository of patients’ data holds the promise of transforming research in the field of hemoglobinopathies by facilitating evidence-based treatments.

Topics 001–Basic and translational

A.I. Ladu¹, M.U. Kadura², M. Dauda², S.B. Abubakar², N.G. Zango², A. Farate², C. Jeffery³, A. Adekile⁴, I. Bates¹

Liverpool School of Tropical Medicine¹, University Of Maiduguri Teaching Hospital², University of Liverpool³, Kuwait University⁴

Background: Malaria is considered an important cause of morbidity and mortality among people living with sickle cell disease (SCD). This has partly been attributed to the loss of splenic function that occurs early in the disease process. We aimed to study the prevalence of malaria infection among Nigerian SCD patients and explore the association with spleen size and function.

Methods: This was a hospital-based, cross-sectional study performed at the University of Maiduguri Teaching Hospital in North-Eastern Nigeria from October 2020 to November 2021. Giemsa-stained blood smears for malaria parasites, Howell-Jolly body (HJB) red cells enumeration for spleen function evaluation and ultrasonography for spleen size assessment, were performed in acutely-ill SCD patients. Results of malaria parasitaemia and parasite density were compared with those of steady-state SCD patients and non-SCD controls.

Results: A total of 394 participants consisting of 119 acutely-ill SCD patients, 167 steady-state SCD controls and 108 non-SCD controls were studied. The prevalence of P. falciparum parasitaemia was 51.3% in acutely-ill SCD patients, 31.7% in steady-state SCD controls and 13.0% in the non-SCD controls. In the SCD group, the mean parasite density was significantly higher among the acutely-ill SCD patients than the steady-state SCD controls (29,747 vs. 18,563 parasites/μL; p = 0.001). Although parasitaemia prevalence was lower among the non-SCD controls, parasite density (100,512 parasites/uL) was significantly higher compared to both SCD groups (p = 0.0001). Among the acutely-ill SCD patients, the prevalence of clinical malaria and severe malaria anaemia were highest among children less than 5 years of age. Prevalence of parasitaemia (p = 0.540) and parasite density (p = 0.975) among acutely-ill SCD patients with visualized spleens on ultrasonography were not statistically different compared to those with absent spleens. Similarly, the frequency of HJB red cells among patients with parasitaemia was not significantly different compared to patients without parasitaemia (p = 0.183).

Conclusion: Our study highlights the frequency and role of malaria infection in acutely-ill SCD patients, especially in those younger than 5 years. Although we have found no evidence of an increased risk of malaria parasitaemia or parasite density with markers of hyposplenism, the role played by an underlying immunity to malaria among SCD patients is not clear. Further studies are required to elucidate the role of hyposplenism and malaria in SCD patients in malaria-endemic regions.

Fig. 1:

Title: Charts showing the distribution of malaria parasitaemia and parasite density based on spleen ultrasonography among the acutely-ill SCD patients. Prevalence of malaria parasitaemia (Figure A) (p = 0.540; Logistic regression analysis) or parasite density (Figure B) (p = 0.975; Kruskal–Wallis test) was not significantly different between patients with visible or absent spleens on ultrasonography.

Table 1: Summary of malaria episodes across age groups among acutely-ill SCD (n-119) patients.

Topics 001–Basic and translational

M.J.M. Traets¹, A. Idrizovic², J.F. Bos¹, M. Veldthuis³, M. van der Hoorn⁴, M.J. van Dijk¹, R. Balvert¹, S. van der Veen⁵, M. D'Agnolo⁶, M. Marin⁷, E. Bourdelier⁷, M. de Montalembert⁸, E. Adu⁹, N. Hebert⁹, P. Bartolucci⁹, M.P. Boaro⁶, R. Colombatti⁶, E.J. van Beers⁵, V.A. Sheehan¹⁰, R. van Wijk¹, M.D.M. Mañú-Pereira², R. van Zwieten³, M.A.E. Rab¹

Department of Central Diagnostic Laboratory-Research, University Medical Center Utrecht¹, Rare Anemia Disorders Res earch Laboratory, Cancer and Blood Disorders in Children, Vall d'Hebron Institut de Recerca², Department of Red Blood Cell Diagnosti cs, Sanquin Research Laboratory³, Department of Cryobiology, Sanquin Research and Lab services⁴, Center for Benign Hematology, T hrombosis and Hemostasis-Van Creveldkliniek, University Medical Center Utrecht⁵, Department of Women's and Children's Health, U niversity of Padova⁶, Université Paris Cité and Université des Antilles, INSERM, BIGR, F-75014⁷, Department of General Pediatrics an d Pediatric Infectious Diseases, Sickle Cell Center, Necker-Enfants Malades Hospital, AP-HP⁸, Henri Mondor Hospital, Sickle cell referr al center, UMGGR, APHP, Université Paris-Est Créteil, INSERM U955, IMRB, EFS⁹, Department of Pediatrics, Aflac Cancer Center an d Blood Disorders Service of Children's Healthcare of Atlanta¹⁰

Background: In sickle cell disease (SCD), the red blood cell (RBC) tendency to sickle can be tested in vitro by oxygen gradient ektacytometry (oxygenscan). This is a functional assay used to measure RBC deformability, expressed as the elongation index (EI), under deoxygenation. The point of sickling (PoS) is the partial oxygen pressure (pO₂) at 5% decrease from the maximum EI (EImax). The oxygenscan is used to assess differences in deformability and sickling tendency between patients with SCD. Despite a standard approach during oxygenscan measurements, there are differences in oxygenscan curves and outcome parameters between ektacytometry devices even when analyzing the same sample. This hampers longitudinal and collective analysis of oxygenscan results between laboratories, such as within the GenoMed4All consortium led by ERN-EuroBloodNet members. Therefore, a SCD red blood cell (RBC) standard is urgently needed.

Aims: To assess the stability of oxygenscan parameters over time, and to compare oxygenscan parameters between devices on different locations.

Methods: Blood from SCD patients was collected in EDTA tubes. Plasma with buffy coat was removed after centrifugation. RBCs were diluted 1:1 to a concentration of 19% glycerol, collected in cryostraws and initially frozen in the damp phase and later stored in liquid nitrogen. After cryopreservation on day of blood draw (D0), regular oxygenscan measurements were performed using the Laser-Optical Rotational Red Cell Analyzer (Lorrca; RR Mechatronics) in all laboratories included in the GenoMed4All consortium. Before measurements the cryo straws were thawed and washed following a standardized protocol. Samples were standardized to a fixed RBC count and diluted in polyvinylpyrrolidone. Oxygenscan derived parameters include: EImax, EImin, delta EI (difference between EImax and EImin), PoS, minimal pO2 (pO2 min) and recovery (EI after reoxygenation reflected as percentage of EImax).

Results: Two SCD cryo standards (batch A and B; different patients) were included in this study. Figure 1 shows stability of the PoS of batch A and B at different timepoints measured on one device. EImax, EImin, pO2 min and recovery were also stable over time (data not shown). Both batches were measured in five different laboratories between day 450 and day 550 (batch A), and D50 and D150 (batch B) after cryopreservation. Table 1 shows the results of multiple measurements of the two batches measured on devices in different laboratories. The ratio of EImax, EImin and recovery of batch A vs batch B is similar between all five devices. This indicates that a mathematical correction factor is possible for pooling these specific parameters measured in the different laboratories. However, the ratio of the PoS ranges from 1.72 to 2.45, suggesting that additional factors must be taken into consideration for the different dynamical range between oxygenscan devices.

Summary/Conclusion: A SCD cryo standard can be used to compare oxygenscan devices. The oxygenscan is a valuable research tool that with proper use, data correction, and SCD cryo standards can be expanded to clinical use. Especially longitudinal studies, measured on one device, can be performed reliably with the use of a SCD cryo standard. Data pooling of the PoS in multi center studies is more challenging due to variations in the dynamic range between different devices. Therefore, future studies will be performed to investigate how to harmonize the PoS.

Topics 001–Basic and translational

J.A.A. Antongiorgi¹, M.F. Ferranti¹, R.G. Goodrich¹, X.G. Gao¹, N.O. Okeke¹, K.L. Liu¹, M.T. Tarasev¹, P.C.H. Hines¹

Functional Fluidics¹

Background: Sickle cell disease is characterized by hemoglobin S (HbS) inability to bind oxygen (O₂), resulting in red blood cell (RBC) sickling in hypoxic environments due to polymerization of O₂-free HbS. Hypoxic stress causes RBCs to sickle, which leads to health complications such as vaso-occlusive crises.^1,2 Hemoglobin-modifying therapies increase HbS-O₂ affinity, possibly decreasing RBC sickling. Monitoring biomarkers are needed to objectively assess target engagement and pharmacodynamic impact of Hb modifying therapies. Voxelotor is an FDA approved drug that reversibly binds to HbS.^1,2 This modified HbS has an increased affinity for O₂, delaying HbS polymerization. Functional Fluidics has developed the dynamic sickling assay (DSA) which utilizes an enzymatic O₂ scavenging system to assess hypoxia-induced RBC sickling in real-time. DSA regulates the rate and depth of hypoxia induction while measuring the kinetics of morphologic RBC sickling. The DSA assesses hypoxia-induced RBC sickling as a function of time (tDSA). Obtaining real-time O₂ measurements simultaneously with sickling kinetics could further increase the clinical validity and utility of DSA as a pharmacodynamic monitoring tool.

Aim: The aim of this study was to assess the pharmacodynamic impact of voxelotor on sickling kinetics with simultaneous O2 measurement using the modified of DSA (oDSA).

Methods: Blood was collected from 8 individuals with HbSS under IRB #041718MP2E & IRB #Pro00066220. Each sample was incubated with varying concentrations of voxelotor to reach Hb modification levels at 25%, 50%, 75%, 100%, and 125% along with a vehicle control. oDSA captured kinetics of morphologic RBC sickling with simultaneous O₂ monitoring. The pH and temperature were monitored to ensure condition stability. Microscopic images were analyzed by a proprietary AI algorithm. RBC sickling profiles are characterized using morphologic point of sickling at 50% of induced sickling (mPoSi@50%, oDSA: torr), sickling rate at 50% of induced fraction (Ratei@50%, oDSA: %/torr) and area under the curve (AUCmax: %torr). Statistical significance for student paired t-test was p < 0.05.

Results: oDSA showed dose response on par with tDSA as shown in Table 1. oDSA showed a statistically significant reduction of AUCmax (%torr) at 25% occupancy (2716 ± 823 vs. 2414 ± 933, p = 0.0020), mPoSi@50% (torr) at 25% occupancy (38 ± 8 vs. 35 ± 10, p = 0.0387), and Ratei@50% (%/torr) at 50% occupancy (8 ± 1 vs. 6 ± 1, p = 0.0017) averaged across 8 patients.

Summary: The data presented in this study represent the first report of the pharmacodynamic response of voxelotor treated sickle RBCs using oDSA. A statistically significant change in both AUCmax and mPoSi@50% at only 25% occupancy, which approximates the HbS occupancy was achieved by clinical voxelotor doses.¹ A statistically significant reduction in Ratei@50%was not observed until 50% occupancy was achieved. Setting the threshold for mPOS at a lower % sickling could give mPOS values in the mild to moderate hypoxia range (50–74 Torr) may predict an individual's risk of sickling in more physiologic hypoxia conditions. In summary, oDSA represents a useful biomarker to assess target engagement and pharmacodynamic impact of Hb-modifying therapies. This biomarker could be an important tool to monitor target engagement and response to Hb-modifying therapies. Future studies are underway to determine the utility of utilizing oDSA to assess sickling kinetics on a population scale.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

E. Dovern¹, M. Aydin¹, K. Alizade¹, B.J. Biemond¹, E. Nur¹

Amsterdam University Medical Centers, location University of Amsterdam¹

Background: Allogeneic haematopoietic stem cell transplantation (HSCT) is the only established curative treatment option for patients with sickle cell disease (SCD). One of the main indications for HSCT is SCD-related organ damage, which is a major cause of morbidity and early mortality. However, whether HSCT is effective in recovering SCD-related organ dysfunction has not been systematically reviewed.

Methods: This is a systematic review and meta-analysis investigating the effects of HSCT on organ function in patients with SCD. We performed a comprehensive search in MEDLINE/PubMed and EMBASE up to June 2023, focusing on studies reporting pulmonary, cardiac, renal, splenic, and/or cerebral function parameters, as well as retinopathy and/or avascular osteonecrosis (AVN) before and after HSCT. Continuous data were analysed using the weighted inverse-variance random effects meta-analyses, reported as standardized mean difference (SMD) and 95% confidence intervals (95% CI). Binomial data were analysed using the Mantel-Haenszel random effects meta-analyses, reported as risk ratio (RR) and 95% CI. A negative SMD indicates an improvement and a positive SMD indicates a worsening of the measured parameter post-HSCT. A RR <1 indicates a result in favour of the transplantation and a RR >1 indicates a worsening of the measured parameter after HSCT. The “Newcastle-Ottawa Quality Assessment Scale” and the “Clinical Diversity in Meta-analysis” (CDIM) tool were used to assess the quality and the clinical heterogeneity of the studies.

Results: Thirty-two of 476 studies met our inclusion criteria, of which 17 were used for the meta-analyses and 15 for the qualitative part of the review. Of the studies that were included in the meta-analyses, 4 comprised adult patients (n = 184) and 13 paediatric and/or young adults <22 years old (n = 591). The majority of donors were matched sibling donors (86.4%), and studies with both myeloablative and/or reduced intensity conditioning regimens were included. The CDIM score was low or moderate for all performed meta-analyses, suggesting fair clinical comparability among the studies. Summary plots of the meta-analyses are shown in Figure 1. Pulmonary function test parameters remained stable following HSCT (SMD −0.08, p = 0.64 for forced expiratory volume in 1 s; SMD −0.13, p = 0.35 for forced vital capacity; and SMD −0.95, p = 0.30 for diffusing capacity). Mean tricuspid regurgitation velocity (TRV) did not change significantly in the meta-analysis (SMD −0.34, p = 0.14). However, 3 studies used for the qualitative review reported normalization in patients with prior elevated TRV. Whole brain cerebral blood flow improved significantly after transplantation (SMD −1.39, p = <0.01). Several studies reported an absent or very low incidence of new (silent) cerebral infarcts and a decrease of transcranial Doppler velocities following successful HSCT. In paediatric patients, creatinine clearance decreased significantly following HSCT (SMD −0.80, p = 0.01) and the presence of proteinuria increased (RR 2.00, p = <0.01). Furthermore, splenic uptake (99mTc) and phagocytic function of the spleen improved (RR 0.31, p = <0.01 and RR 0.23, p = <0.01, respectively). Retinopathy and AVN before and after HSCT were investigated in only one study in children with SCD, both showing no significant changes post-HSCT.

Discussion and Conclusion: Allogeneic HSCT has the potential to stabilize or recover pulmonary and cardiac function parameters in SCD patients. In paediatric patients, measures of splenic function parameters showed impressive improvement following HSCT. On the other hand, creatinine clearance decreased significantly in children. This might be a reflection of either normalization of SCD-related hyperfiltration or transplantation-related toxicity, which may also have contributed to the increased prevalence of proteinuria after HSCT. With respect to cerebral damage, cerebral perfusion parameters improved and progression of silent cerebral infarctions was prevented following HSCT. Last, we demonstrate a paucity of evidence regarding the course of renal function, retinopathy, and AVN in adult SCD transplant recipients. More research is needed to define which patients with SCD-related organ damage might benefit most from HSCT and which organ functions are less likely to recover.

Topics 007–Health services and outcomes research including psychology

C. Udeze¹, N.F. Ly², F.C. Ingelby², S.D. Fleming², S. Conner¹, J. Howard¹, N. Li¹, F. Shah³

Vertex Pharmaceuticals¹, IQVIA UK&I², Whittington Hospital³

Background: Sickle cell disease (SCD) is characterized by vaso-occlusive crises (VOCs) and a progressive clinical course leading to end-organ damage and early mortality. SCD complications are multifactorial and driven by vaso-occlusion, haemolysis, and vasculopathy associated with the disease.

Aims: To describe the mortality and clinical complications among patients with SCD with recurrent VOCs in England.

Methods: This longitudinal, retrospective cohort study used the Clinical Practice Research Datalink linked with secondary care data (Hospital Episode Statistics) in England to identify patients with a diagnosis of SCD between 1 July 2008 and 30 June 2018. Eligible patients with SCD were required to have ≥2 VOCs per year in any 2 consecutive years. A VOC was defined as SCD with crisis, priapism, or acute chest syndrome. Patients were required to have ≥1 year of follow-up data after their index date (second VOC in the second year of 2 consecutive years). Those with hereditary persistence of fetal haemoglobin, HbSC genotype, or evidence of haematopoietic stem cell transplantation were excluded. Patients were matched to up to 5 controls without SCD by age, sex, region, and ethnicity. The pseudo-index date for controls was the same as the index date for patients. Patients were followed from index until a censoring event (e.g., death or study period end [30 June 2019]). Demographics were assessed at index. Mortality (proportion of total population and rate [deaths per 100 person-years; overall rate and rate by index date]) and clinical complications (proportion of total population) were summarised descriptively during the study period. A Z-test was used for significance testing (p < 0.05) for mortality proportion.

Results: Overall, 1117 patients with SCD met inclusion/exclusion criteria and were matched with 5585 controls. The mean age of patients at index was 24.96 years, 51.39% were female, and 91.58% were Black. Controls had similar demographics. Mortality proportion (SCD: 41/1,117 [3.67%] vs. controls: 38/5585 [0.68%]; p < 0.001) and rate per 100 person-years (0.78 vs. 0.16, respectively) were higher for patients with SCD than for controls. Mortality rates were similar for patients with a more recent or older index date (2008–2013: 0.77 vs. 2014–2018: 0.81). The most prevalent chronic complications in patients were cardiopulmonary complications (30%), bone/joint problems (26%), retinopathy (19%), mental health complications (16%), and chronic pain (15%).

Conclusion: Patients with SCD with recurrent VOCs had significantly higher mortality than controls, with no notable improvements over time. Despite the best available care, patients experience significant SCD-related clinical complications.

Topics 007–Health services and outcomes research including psychology

L. Thaniel¹, S. Majumdar¹, A. Zhang¹, D. Darbari¹

Children's National Hospital¹

Background: Sickle cell disease (SCD) is a chronic illness that affects approximately 100,000 individuals in the United States and more than 3 million worldwide. Pain is the hallmark of SCD. Standard treatment for SCD pain includes hydration, non-steroidal antiinflammatory drugs, and opioid pain medications. While most studies show that opioids provide short-term relief, they are associated with numerous side effects including constipation, opioid induce hyperalgesia, and risk of addiction. Despite increasing interest in the use of complementary and integrative medicine (CIM) for adult patients with SCD, few studies have examined its use in pediatric patients with SCD.

Aims: The aims of this study were to assess current or past use of complementary and integrative medicine (CIM) in a population of pediatric patients with SCD, the type of CIM used, and sociodemographic and health-related factors associated with their use of CIM.

Methods: Parents of children (≤21 years old) with SCD were approached about the study during clinic visits. They were asked to complete a 22-item survey about their child's use of CIM. Descriptive statistics were used to generate frequency or percentage for categorical variables. Chi square or Fisher's exact was performed with a p < 0.05 to test the association between CIM and sociodemographic characteristics in the collected sample.

Results: A total of 109 parents were approached about the study and ten parents declined to participate due to time constraints. The response rate was 91.7%. Ninety-nine parents completed the survey during clinic visits. Eighty-five percent of parents reported current or past use of CIM for their child's SCD. The most commonly used techniques were prayer (68%), massage (53%), thermotherapy (30%), relaxation techniques (24%), aroma therapy (23%), exercise (21%), herbal medicine (16%), spiritual healing/Reiki (12%), acupuncture (8%), and mindfulness (8%). Nineteen percent of foreign born and 15% of US born parents reported using herbal and folk remedies. Nine percent of parents reported using cannabidiol products and 4% of parents reported using cannabis for their child's SCD. Fifty-six percent of parents reports that CIM helped a lot and 36% reported that it helped some. Seventy-five percent reported discussing their use of CIM with their child's hematology provider. Every parent (N = 99) reported that we should provide more opportunities for families to learn about safe CIM approaches. Seventy-five percent of parents reports that they did not know if their health insurance covered some evidence-based CIM approaches.

Conclusion: Health care providers should be prepared to integrate CIM into their discussions with patients and families and provide more opportunities for families to learn about safe CIM approaches. Providers should encourage parents to speak with their insurance representative to learn whether some CIM approaches such as massage therapy and acupuncture are covered by their plan.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

S. Trompeter¹, A. Harmer², C. Brown², L. Quaye², J. Stephens³, V. Chalker², D. Roberts², N. Gleadall³

University College London Hospitals Biomedical Research Council¹, NHS Blood and Transplant², University of Cambridge³

Background: People with sickle cell (SCD) and thalassaemia (THAL) are at high risk of red blood cell (RBC) alloimmunisation due to antigen mismatch. The feasibility of extended blood group matching at scale requires affordable high-throughput antigen typing. Following an earlier proof-of-concept study, our consortium presents here the development and validation of a tailored universal blood donor typing (UBDT) Axiom array and how NHSBT with support from NHSE plans to offer this free of charge for all such patients in England.

Aims: The aims were twofold: firstly to develop a fully validated low-cost high throughput blood group and HLA typing platform. Secondarily to apply such technology to testing in patient and donor cohorts to increase the feasibility of extended blood group matching for those most at risk of blood group alloimmunisation and to increase the availability of matched units for those already alloimmunised.

Methods: The custom designed AxiomTM array contains probes for nearly 20,000 variants relevant for blood services. It has a 384 sample format and runs on GeneTitan-MCTM instrument, now in place at NHSBT, which can generate data for 3000 samples/week. The array allows simultaneous typing of clinically relevant human erythroid (HEA), platelet (HPA), and leukocyte (HLA) antigens. DNA samples and clinical antigen typing data from 13,908 donors provided by seven blood services were analysed at three blood services in the Netherlands, USA, and UK. Array-inferred antigen types were analysed for concordance with provided clinical antigen types for the first 6953 samples. A programme of work at NHSBT, supported by NHSE, has been developed to offer this test to all eligible patients free of charge from Autumn 2023.

Results: Reproducibility at genotype level between sample results from the testing laboratories was impressive. The concordance for HEA, HPA, and HLA antigens with previous clinical testing was at 99.82% across ~100,000 comparisons between blood service determined HEA types and array determined types. Over 80% of the discordances have been resolved by algorithmic modifications and over half of the remaining ones were caused by incorrect serology. The results of were generated with DNA samples representing the main ethnicities and the HEA concordance for 778 samples of African ancestry showed was >99.7%.

Conclusions: An affordable and comprehensive DNA-based test for automated high-throughput typing of donors and patients is reported here. The universal blood typing array is tailored for the needs of transfusion services and validated in an international, diverse cohort. An NHSBT programme of work to test both patients (NHSE supported) and donors (NIHR BioResource supported) represents a promising new development in brining extended blood matching to the bedside to reduce sensitisation and increase the availability of matched blood for patients requiring regular transfusion and those with complex transfusion needs.

Topics 004–Clinical, public health and epidemiological studies

S.M. Makkeyah¹, A.A. Adly¹, A.M. Aboata¹, G.O. Wassif¹, M.A. Nassef¹, M.Z. Mohammed¹

Ain Shams University¹

Background: The pathophysiology of pain in sickle cell disease (SCD) is complex and not fully understood. Neuropathic pain (NP) is an emerging theory of chronic pain in SCD. Nevertheless, assessment of NP is not a part of standard care of patients with SCD. We aimed to detect the frequency of neuropathic pain in SCD and its association with pain behavior and interference and the health-related quality of life (HRQoL) among pediatric patients with SCD.

Methods: Patients with SCD were recruited and data were collected on sociodemographic and clinical criteria of the disease. ID Pain (ID-P) questionnaire was used as a screening tool for NP. The Patient-Reported Outcome Measurement Information System, PROMIS® was used to record six measures: Pain Intensity, Pain Quality (sensory), Pain Quality (affective), Pain Behavior, Pain Interference (child), and Pain Interference (parent proxy)). HRQoL was assessed using PedsQL™ Sickle Cell Disease Module by the child's and parent's reports. We performed a bedside clinical sensory testing (CST) including nine tests: cold, warm, and pressure detection, cold, heat, mechanical and pressure pain threshold, wind up pain scale and dynamic mechanical allodynia to all patients. Sensory nerve conduction velocity on extremities was measured in the area of highest pain frequency and intensity as reported by the participants.

Results: Fifty-six participants were screened for eligibility and twelve of them were excluded; ten had stroke and two patients were diabetic. A total of 44 participants (25 males and 19 females) were included, their mean age was 12.4 years (SD 4.8; range 5.9–25 years). Screening of NP using the ID-P questionnaire revealed that 20.5% of the study cohort likely had NP. On the other hand, 34% of the participants had abnormal CST; 10 patients (22.7%) had abnormal mechanical pain threshold, 6 (13.6%) showed abnormal cold pain threshold, 2 (4.5%) had abnormal heat pain threshold and 2 (4.5%) with abnormal pressure threshold, while only one patient had delayed cold detection. All patients underwent sensory NCV on the most symptomatic limb; only two of them (4.5%) showed slowing of the conduction velocity. On the PROMIS pain scores, the mean T-score for pain intensity was 57.7 ± 7.2 indicating mild increase. Pain interference was the most affected domain in both patients and parents (mean ± SD 63.2 ± 6.6 and 65.1 ± 6.7 respectively) which was worse than other domains including pain quality-sensory and affective, and pain behavior (47.9 ± 4.8, 58.5 ± 7.9, and 56.0 ± 4.1 respectively). The mean global HRQoL score of the children was 50.3 ± 12.1, indicating poor quality of life.

Conclusion: Neuropathic pain, as assessed by CST, is not uncommon in patient with SCD, and it interferes with patients' activities and negatively impacts their HRQoL.

Topics 007–Health services and outcomes research including psychology

S. Hamdule¹, J.M. Kawadler¹, F.J. Kirkham¹

UCL GOS Institute of Child Health¹

Background: Individuals with sickle cell anaemia (SCA), even in the absence of stroke and infarction, tend to struggle with cognitive functioning.¹ Cognitive deficits are mainly seen in the form of executive function (EF) issues which refer to executive abilities such as planning, coordinating, and exercising control over one's behaviour to accomplish daily tasks.²

In patients with SCA with or without stroke or silent cerebral infarction, poor oxygen delivery is compensated by increasing cerebral blood flow (CBF), meaning that the cerebrovascular reserve to further increase CBF is limited, which not only poses a risk for stroke but also may be associated with cognitive deficits.³ Transcranial Doppler studies show associations between CBF velocities and verbal as well as working memory functioning in young children with SCA.⁴ ASL MRI studies note associations between performance IQ and CBF in patients with SCA.³ In a previous study by Kawadler et al.,⁵ CBF in the anterior, middle, as well as posterior cerebral arteries (ACA, MCA, and PCA), were elevated in younger patients with SCA but this same pattern was not present in the older children.⁵ Building on the same study, we aimed to investigate differences in cognition and associations with CBF in the two groups. Hence, the purpose of our study is to examine the association between CBF measured using ASL MRI and EF subtests measuring verbal fluency (VF) and working memory (WM) from the Delis Kaplan Executive Function System (D-KEFS).

Methods: In this study, 37 patients and 19 controls underwent MRI and cognitive assessment. MRI data was collected at 1.5 T and included haemodynamic parameters from a multi-inflow-time ASL acquisition. The cognitive assessment included Weschler Abbreviated Scales of Intelligence (WASI-2) and the D-KEFS.

Results: Younger patients under the age of 13 with SCA displayed significantly lower scores in verbal IQ and the D-KEFS VF: Category fluency subtest when compared to controls.⁵ However, in the older patient group (ages 13–18), no substantial differences in cognitive test performance were observed between the patients and controls.⁵ Correlation analyses focused on the younger SCA patient group unveiled significant positive associations between CBF in all three arteries (ACA, MCA, PCA) and the D-KEFS VF letter fluency subtest. Surprisingly, these correlations were absent in the older children's group.

Multiple regression analyses were conducted, accounting for age, sex, and oxygen saturation. In younger children, ACA-CBF and MCA-CBF significantly predicted performance in the D-KEFS VF: letter fluency subtest. Meanwhile, in the older children's group, PCACBF and MCA-CBF emerged as predictors for the D-KEFS design fluency: Switching subtest (working memory), along with ACACBF predicting performance in the D-KEFS card sorting: sort recognition subtest (working memory) and VF: switching subtest. Notably, these associations were not evident within the control groups.

Discussion: Building on the findings of Kawadler et al.,⁵ we demonstrate that CBF in younger patients is associated with verbal functioning while CBF in older patients with SCA is associated with working memory function. Previous literature on CBF in patients with SCA also reports language and working memory impairment,⁴ which not only should be a target for intervention, but clinicians are also recommended to monitor language and EF skills in routine medical assessments.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

R.R. Liu¹, L. Wang², H. Xu³, X.L. Yin⁴, J.B. Liang³, W.Q. Xie¹, G.H. Yang¹, Y.Y. Li², Y.L. Zhou⁴, L. Shi³, B. Xiao², L.L. Shi¹, Z.Y. Shi¹, X.M. Zhou¹, J.P. Fang⁵, X.M. Xu⁶, Y.R. Lai¹, J.J. Huang⁷, X.H. Zhang⁴

Department of Hematology, The First Affiliated Hospital of Guangxi Medical University¹, Department of Pediatrics, 923rd H ospital of the People's Liberation Army², Reforgene Medicine³, Department of Hematology, 923rd Hospital of the People's Liberation Army⁴, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University⁵, Department of Medical Genetics, School of Basic Medical Sciences, S outhern Medical University⁶, School of Life Sciences, Sun Yat-sen University⁷

Background: Reactivating fetal globin (HbF) is a promising treatment for β-hemoglobinopathies. Natural mutations in the promoter region of γ-globin genes (HBG1/2) that disrupt the binding of the transcriptional repressors BCL11A could lead to a lifelong persistence of fetal γ-globin expression. Using gene editing to mimic these mutations should reactivate γ-globin in patients with transfusion-dependent βthalassemia (TDT) and ameliorate the symptoms of patients. RM-001 is a novel cell therapy that uses non-viral, ex vivo CRISPR- Cas9 gene editing in autologous hematopoietic stem and progenitor cells (HSPCs) at the promoter of the γ-globin genes (HBG1/2) to disrupt the binding site of BCL11A.

Aims: ChiCTR2100053406 and ChiCTR2100052858 are ongoing multi-center, first-in-human studies of RM-001 for TDT. Here, we present available safety and efficacy results from 6patients that have been dosed with RM-001 and followed up more than 3 months.

Methods: Patients (6–35 y of age) with TDT receiving packed red blood cell (pRBC) transfusions of ≥100 mL/kg/y or ≥10 units/y in the previous 2 y were eligible. Peripheral CD34+ HSPCs were collected by apheresis after mobilization with G-CSF and plerixafor. CD34+ cells were edited with CRISPR-Cas9 using a guide RNA specific for the binding site of BCL11A on the HBG1/2 promoter. Prior to RM-001 product infusion (day 0), patients received myeloablative conditioning with Busulfan from day-7 to day-3. Patients were monitored for stem cell engraftment/hematopoietic recovery, adverse events (AEs), Hb production, HbF and F-cell expression, and pRBC transfusion requirements. Bone marrow cells were obtained at 3, 6, 12, and 24 months after RM-001 infusion to measure the on-target allelic editing frequency using next-generation sequencing.

Results: Data presented here for 6 TDT patients have been treated with RM-001 and followed up at least 3 months. As of July 31, 2023, patients were followed up from 7 to 20 months and 5 of them have been followed up more than 15 months. Five patients have β0/β0 genotype (CD17/CD41-42, n = 1; CD41-42/CD41-42, n = 4) and the other has β0/β+ genotype (CD41-42/IVS-II-654). In addition to βthalassemia (CD41-42/CD41-42), the sixth patient (25yo) also carries two α-globin genes deletion (--SEA/αα). Patients had received a mean of 56.2 units/y pRBC transfusions (range: 39–79.6 units/y).

All patients received a single dose of RM-001 cells, and achieved both neutrophil and platelet engraftments 2 to 3 weeks after RM-001 infusion (neutrophil: day 11–19, platelet: day 10–22). All patients ceased pRBC transfusions within 1 month after RM-001 infusion and achieved transfusion-independent (TI, total Hb continued ≥ 9g/dL) within 2 months (Figure). At 4 month post-RM-001 infusion, HbF reached 9 g/dL in all 6 patients and continuously maintained over this level through the reported period. From 6 month post-RM-001 infusion, hemoglobin of all 6 patients consists of HbF (97.6%–99.8%) and HbA2 only, including the fifth patient who has a β0/β+ genotype (99.5% HbF). Five participants have remained transfusion independent more than 15 months and the mean HbF in the first 4 patients was 11 g/dL(10.9–11.3 g/dL) at 18 month post-RM-001 infusion.

The safety profile was generally consistent with busulfan myeloablation and autologous hematopoietic stem cell transplantation. No RM-001 related SAE report.

Summary/Conclusion: This updated data reported here from 6 patients with TDT infused with RM-001 demonstrated clinically meaningful increases in total hemoglobin (Hb) and HbF levels. All patients stopped receiving pRBC transfusions within 1 month after RM-001 infusion and remained transfusion-free through the time of this analysis. The safety profile of RM-001 is generally consistent with myeloablative conditioning and autologous hematopoietic stem cell transplantation. These results strongly support continued investigation of RM-001 as a potential cure for patients with TDT.

Data will be updated for the presentation.

Submitted on behalf of the RM-001 Investigators.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

J. Kanter¹, G. Helleman¹, A. Cohen², D. Manwani³, F. Sayani⁴, M. Idowu⁵, S. Guarino⁶, R. Cronin⁷, S. Saif Ur Rehman⁸, A. Owusu Ansah⁹, J. Little¹⁰, M. Madisetti¹¹, M. Treadwell¹², S. Lanzkron¹³

University of AL at Birmingham¹, Albert Einstein College of Medicine², Albert Einstein College of Medicine, The Children's Hospital at Montefiore³, Perelman School of Medicine University of Pennsylvania,⁴, University of Texas at Houston⁵, Sickle Cell Progra m at Center for Special Health Care Needs⁶, The Ohio State University⁷, Washington University in St. Louis⁸, Case Western Reserve U niversity⁹, University of North Carolina¹⁰, Medical University of South Carolina¹¹, UCSF Sickle Cell Center of Excellence¹², Johns Hopki ns University¹³

Background: Acute painful episodes or vaso-occlusive crises (VOCs) are the most common complication of sickle cell disease (SCD). Crizanlizumab, an anti-P-selectin monoclonal antibody, was FDA-approved in November of 2019 to prevent/reduce VOCs in SCD pts aged ≥16 yrs after the phase II SUSTAIN study. More recently, an early evaluation of the phase 3 study of crizanlizumab, STAND, failed to show benefit resulting in withdrawal of approval by the European Medical Association.

Aims: To understand the use and impact of crizanlizumab, the National Alliance of Sickle Centers (NASCC) performed a retrospective assessment of crizanlizumab use at 12 centers. NASCC is a non-profit organization established to support SCD centers in delivering high-quality comprehensive care in the US.

Methods: A REDCap database was created for this study. Acute care was defined as day hospital/SCD infusion visits, emergency department, and/or hospitalizations for VOC (not including hospitalizations for COVID-19). The index date for each individual was defined as the initial crizanlizumab infusion date. Chart review was used to identify all acute care visits in the 12-months preceding the index date and up to 12-months post index date. Data were extracted from electronic health records and de-identified (date shifted). Aggregated data were analyzed for this study.

Evaluation of patient characteristics, outcomes, and treatment discontinuation were summarized by cohort using means, standard deviations (std), and medians for continuous variables, and frequency counts and percentages for categorical variables. VOC characteristics are being summarized using medians, median differences, and 95% confidence intervals. This study is also evaluating the efficacy of crizanlizumab based on concomitant hydroxyurea use, pre-treatment VOC burden and SCD genotype.

Results: In total, 338 patients received >/=1 dose of crizanlizumab (starting January 2020). Mean age of patients was 32.1 years (std 10.6, range 16–62) and 59% were female. The majority (61%) had HbSS disease and 25% had HbSC disease. Assessment of the patients' co-morbidities demonstrated that 66% had chronic pain, 43% had avascular necrosis, and 9% had priapism. As of July 31, 2022, 187 individuals (55%) were still receiving crizanlizumab and had received a mean number of 13.1 infusions (std. 9.8).

One hundred fifty-one (45%) patients discontinued crizanlizumab after a mean of 6.1 doses (std 5.3). The most common reasons for discontinuation included “the medication was not working” (n = 38, 25%), infusion related reaction (n = 17, 11.2%), or provider choice (n = 18, 12%). Thirty-five (14.5%) patients experienced some type of infusion-related reaction (IRR). There were no statistically significant differences in age, genotype, or body mass index in patients who had IRR or between those who continued versus stopped the medication. Additional analyses are ongoing including the frequency of VOC both pre/post treatment which will be presented.

Summary: SCD is a complex, multisystem disorder in which VOC is the most common reason for acute care. This is the first multicenter, real-world analysis of crizanlizumab since its approval. A slight majority of patients who initiated the therapy have continued it and some individuals have expressed improvement in SCD symptoms including VOC. It will be very important to identify which subset of patients demonstrate improvement with this medication. There are a few patients who reported increased pain or felt the medication as not useful, resulting in discontinuation. There were also patients who experienced IRRs usually associated with pain. Importantly, all centers included in this analysis are recognized SCD centers led by SCD-experts. NASCC uses specific criteria for multi-center care and these data must be understood in this context. Improving our understanding of the phenotype-specific benefit of novel medications including crizanlizumab, using longitudinal clinical registries, will be key to the long-range incorporation of these medications into quality care.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

J.P. Gross¹, M. Reschke², G. Sürücü³, J. Seiler⁴, D. Weschke⁴, D. Higgins⁴, L. Oevermann²

Charité–Universitätsmedizin Berlin, Department of Pediatric Oncology and Hematology¹, Charité-Universitätsmedizin B erlin, Department of Pediatric Oncology and Hematology², Institute of Transfusion Medicine, H&I Laboratory, Charité-Universitätsmedizi n Berlin³, Berlin Institute of Health at Charité - Universitätsmedizin Berlin⁴

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment option for patients with hemoglobinopathies and is performed in over 50.000 children and adults with malignant and non-malignant diseases annually.¹ Nevertheless, HSCT still holds life-threatening complications such as Graft-versus-Host disease (GvHD), graft rejection, and infections. 30% to 50% of all patients undergoing HSCT will develop GvHD, causing high morbidity and mortality (grade 4 GvHD up to 90%)² as well as generating significantly higher treatment costs than a HSCT without GvHD.³ MatchGraft.AI is an AI based ML algorithm which predicts the absolute, individual risk of acute GvHD occurrence for every possible HSCT donor-recipient couple based on data available before the start of conditioning for HSCT.

Aims: The aim of this study is to establish feasibility of predicting the occurrence of GvHD with an AI ML based approach.

Methods: The ML model uses a gradient boosted tree, among other things due to its ability to handle missing data. Analysis followed best practices.⁴ The data is split into a stratified training and validation set with a ratio of 80%/20%. We calculated the confusion matrix statistics on the validation set. This are raw performance scores for the ability of the model to distinguish outcomes correctly (e.g. acute GvHD occurrence). Derived performance scores include area under the curve (AUC), F1-score and accuracy, which convert the confusion matrix scores into single metrics.

Results: The model was trained at the Charité University against a retrospective, single center data set of 232 patient/donor couples. 53 cases were excluded due to insufficient data. The following analysis focuses on the 179 included patient/donor couples (143 in training set and 36 in validation set) pediatric HSCTs. HSCTs were performed between January 2013–December 2019. Male:Female = 104:75; age 0–21yrs. (median: 8 yrs.). Indications for HSCT were malignant diseases (hematological neoplasms, lymphomas, solid tumors) in 98 patients and benign (hemoglobinopathies, immune deficiencies, bone marrow failure) in 81 cases. Table 1 lists the input parameters. Initial model performance of predicting absolute individual risk for GvHD was good with an estimated AUC of 0.69. This is an improved performance outcome in comparison to current literature.⁵

Conclusion: The prediction of the individual absolute risk of GvHD occurrence using MatchGraft.AI is feasible. With an improved and precise prediction of HSCT complications such as GvHD, we expect the pool of possible donors to increase as well as an optimized donor selection. Furthermore, physicians will have information that is more accurate and will be able to develop a treatment plan that is proactive with the individual patient's specific risk profile. Continuous training, testing and adapting on retrospective and prospective as well as international, multicenter data is necessary and in progress to further improve the performance of MatchGraft.AI. A well established and validated prediction algorithm such as MatchGraft.AI can aid physicians in donor selection and treatment planning.

Topics 007–Health services and outcomes research including psychology

N. Li¹, C. Udeze¹, N.F. Ly², F.C. Ingleby², S.D. Fleming², S. Conner¹, J. Howard¹, F. Shah³

Vertex Pharmaceuticals¹, IQVIA UK&I², Whittington Hospital³

Background: Transfusion-dependent β-thalassaemia (TDT) is a rare genetic disorder wherein patients have reduced or absent βglobin production and require regular red blood cell transfusions (RBCTs) and iron chelation therapies (ICTs) for survival. TDT is associated with iron overload complications and early mortality.

Aims: To describe the mortality and clinical complications associated with TDT in England.

Methods: This longitudinal, retrospective cohort study used the Clinical Practice Research Datalink linked with secondary care data (Hospital Episode Statistics) in England to identify patients with a diagnosis of β-thalassaemia between 1 July 2008 and 30 June 2018.

Eligible patients with TDT were required to have ≥8 RBCTs per year in ≥2 consecutive years and ≥1 year of follow-up data after the index date (eighth RBCT in the second year of 2 consecutive years). Those with hereditary persistence of fetal haemoglobin, sickle cell disease, α-thalassaemia, or evidence of haematopoietic stem cell transplantation were excluded. Patients were matched to up to 5 controls without TDT by age, sex, region, and ethnicity. The pseudo-index date for matched controls was the same as the index date for patients. Patients were followed from the index date until a censoring event (e.g., death or study period end [30 June 2019]). Demographics were assessed at the index date. Mortality (proportion of total population and rate [death per 100 person-years; overall rate and rate by index date]) and clinical complications (proportion of total population) were summarised descriptively during the study period. A Z-test was used for significance testing (p < 0.05) for mortality proportion.

Results: Overall, 237 patients with TDT were matched with 1184 controls. The mean age of patients at index was 24.84 years, 52.32% were female, and 53.59% were South Asian. Matched controls had similar demographics. The mortality proportion (TDT: 17/237 [7.17%] vs. controls: 14/1184 [1.18%]; p < 0.001) and rate per 100 person-years (1.19 vs. 0.20, respectively) were higher for patients with TDT than for controls. Mortality rates were similar for patients with a more recent or older index date (2008–2013: 1.15 vs. 2014–2018: 1.38). The most prevalent complications in patients were endocrine complications and bone disorders (58%), as well as urinary tract (18%), mental health (15%), cardiopulmonary (14%), and liver (14%) complications.

Conclusion: Patients with TDT had significantly higher mortality than the matched general population. Despite the evolving and currently available care, patients experience significant clinical complications associated with the disease and their mortality rates have not improved over time.

Topics 007–Health services and outcomes research including psychology

D.L. Clayton-Jones¹, J. Lucas², E. Jenkins², A. Costello¹, J. Totka³, S. Peña¹, L. Za Ong¹, K. Haglund¹, A. Bekhet¹, K.L. Powell-Roach⁴, L. DeVries¹, J. Griffin², K. Henderson², L. Ventura¹, J. Davis-Joiner¹, J.J. Field⁵, B.S. Pace⁶, Y.A.A. POSSE Young Adult Advisory Board²

Marquette University¹, Community Partner², Marquette University, Children's Hospital of Wisconsin³, University of Tennes see Health Science Center,⁴, Medical College of Wisconsin⁵, Augusta University⁶

Background: Sickle cell disease (SCD) is a chronic, progressive red blood cell disorder affecting millions globally. Inequalities in social determinants of health, stigma, and poor preparation for transition from pediatric to adult-centric care contribute to health disparities among young adults living with SCD. Through community-based participatory research (CBPR) and human-centered design (HCD), young adults can be empowered to co-develop interventions that change negative stigmatizing discourses and close the health equity gap in marginalized communities. Use of community based participatory research (CBPR) optimally involves the community as an equal partner from conception to evaluation and beyond. Human Centered Design (HCD) is a technique that includes people at the center of the design process to identify solutions that address their needs. Strategies are developed in alignment with the needs and priorities of the community.

Aims: The aim for this research was to use CBPR and HCD principles in the concept, design, and development of simulation scenarios for The POSSE (Purpose, Opportunity, Support, Scientific Discovery, Empowerment) Project. The POSSE Project is a CBPR and HCD partnership bringing together key stakeholders to generate sustainable and effective solutions to advance health equity and support young adults living with SCD in having thriving lives. Strategies used to engage young adults and community stakeholders are described.

Methods: Two groups provided guidance to advise development of the simulation scenarios. The advisory board consisted of 12 members including young adults, parents of young adults, health care providers, and advocates who met from January 2022 to June 2023 to discuss the content and structure for the scenarios. The community stakeholder simulation group was comprised of a parent, an adult living with SCD, and two nurse faculty members, who also met during this time to discuss the concept, design, and development of the simulation scenarios. Summaries from the meetings were shared with each group.

Results: During the community advisory board and community stakeholder simulation meetings, participants identified challenges that are unique for young adults living with SCD including (1) their experience in an emergency department during a pain crisis, (2) their transition from high school to college, and (3) their desire to experience a social life that is uninterrupted by a pain crisis or hospitalization. The content and structure of the simulation scenarios were discussed. During the pilot intervention, one simulation episode with discussion questions was created. During the full-scale implementation, episode one was used as a foundation to design and develop a total of three episodes, each with two scenes. Young adults emphasized the need for simulated scenarios to generate conversations among the sickle cell and health provider communities to positively impact communications and health outcomes.

Conclusion: Future research is needed to elicit the perspectives of young adults and other community stakeholders regarding innovative solutions to advance health equity. Furthermore, engaging representative voices as collaborators in eliminating health inequity using simulation scenarios is warranted.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

B. Andemariam¹, P. Højlund Nielsen², R. Zillmer², J. Derving Karsbøl²

University of Connecticut Health¹, Novo Nordisk A/S²

Background: Fetal hemoglobin (HbF) mitigates the effects of polymerized mutated hemoglobin in sickle cell disease (SCD), but HbF gene expression is silenced in infancy by DNA methyltransferase 1 (DNMT1). Decitabine directly inhibits DNMT1, inducing HbF expression. NDec is an innovative combination treatment comprising decitabine and pharmacokinetic enhancer tetrahydrouridine (THU). Hydroxyurea (HU), current standard of care, indirectly induces HbF but its effect is clinically variable. Direct HbF induction by NDec is hypothesized to be a sustainable treatment option for patients (pts) with SCD.

In high-risk pts with SCD, oral decitabine (0.16 mg/kg) and THU vs placebo significantly increased total Hb, HbF, %F-cells of total red blood cells (RBCs), and improved RBC health markers, without triggering grade ≥3 non-hematologic toxicity.¹ Phase 1 trials evaluated the pharmacokinetics and pharmacodynamics of a combination oral formulation of THU and decitabine in healthy participants.²

Aims: ASCENT1 (NCT05405114) will study the efficacy and safety of once- or twice-weekly NDec vs placebo in pts with SCD.

Methods: ASCENT1 is a randomized, placebo-controlled, phase 2 trial with an additional exploratory open-label HU block (Figure). Experts, study nurses and coordinators informed the design; pt groups advised on the set-up. HU non-eligible pts are HU-naïve or cannot be treated with HU. HU active pts are prescribed HU in the preceding 6 months and are on a stable dose for >3 months; if randomized to NDec they will discontinue HU during a 4-week washout period. All SCD genotypes are eligible for inclusion; other criteria are age ≥18 years, 2–10 documented vaso-occlusive crises (VOCs) ≤12 months before screening, Hb ≥5.0–≤10.5 g/dL and reticulocyte count above upper limit of normal at screening. Exclusion criteria include chronic transfusion therapy (episodic transfusion permitted), treatment with hematopoietic growth factors 28 days before screening, first dose and during trial or treatment with voxelotor, crizanlizumab, or L-glutamine 12 weeks before consent and during trial. HU non-eligible (n = 60) and HU active (n = 24) pts will be randomized 1:1:1 to NDec once weekly and placebo, NDec twice weekly, or placebo/open-label HU. Dosing for all NDec/placebo arms will be administered orally, with a meal on two consecutive days. NDec will be administered according to body weight intervals to attain a dose level of 0.16−0.25 mg/kg for decitabine and 8−12.5 mg/kg for THU. The trial comprises main and extension phases. Primary endpoint is change in total Hb (g/dL) from baseline (BL) to Week 24. Secondary endpoints include change in HbF (g/dL and %HbF of total Hb), %F-cells of total RBCs, and hemolysis markers from BL to Week 24, as well as numbers of VOCs, acute chest syndrome and transfused RBC units from BL to Week 48. Safety endpoint is number of grade ≥3 adverse events from BL to Week 52. Changes in ptreported outcomes from BL to Week 48 will be assessed by validated questionnaires. Primary endpoint will be analyzed by a mixed model for repeated measurements; with treatment, historical VOC rate, region, sex, and visit as fixed factors, and Hb at BL as covariate. VOCs are defined as ≥1 predefined clinical event requiring a medical visit (home and telemedicine).

Results: ASCENT1 is active and opened for recruitment in Q2/3 2022.

Summary: ASCENT1 will provide proof of concept for NDec in pts with SCD and determine the optimal dose for future trials.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

C. Vuong¹, K. Utkarsh², R. Stojancic³, A. Subramaniam⁴, O. Fernandez³, T. Banerjee⁵, D.M. Abrams², K. Fijnvandraat¹, N. Shah³

Amsterdam University Medical Centers¹, Northwestern University², Duke University Medical Center³, The Brody School of Medicine⁴, Wright State University⁵

Background: Sickle cell disease (SCD) is an inherited disorder of red blood cells affecting millions of people worldwide. SCD is characterized by recurrent episodes of severe pain attacks, also called vaso-occlusive crisis (VOC), and are the most common reason for hospitalization. Approximately 90% of the hospital admissions are for pain treatment and the hospital readmission rate is alarmingly high, as 30%–50% are re-admitted within 30 days.

Aim: We aimed to predict reutilization of care within 30 days in patients with SCD treated for a VOC.

Methods: Patients with SCD aged 18 years and above, who were admitted for a VOC to the day hospital or Duke University Hospital between April and June 2022, were eligible for this study. Following informed consent, demographics, SCD genotype, details from the hospitalization such as length of stay, pain scores, as well as vital signs measured per standard of care were collected from the electronic medical records. Baseline vital signs during regular visits were collected 6 months before and after the hospitalization. We used the values of nearest neighbors to fill in the empty entries. The vital signs over the whole hospital stay were averaged and those numbers were used as the predictor values for the model. The primary outcome was reutilization of care defined as readmission within 30 days to the day hospital and/or hospital. The predictors were used to fit 3 different machine learning classification models for the prediction of reutilization of care: random forest, logistic regression, gradient boosting. By fitting random forest model on the whole dataset, we were able to rank all the features using mean decrease in impurities. To avoid overfitting, we only used the best four predictors which were diastolic blood pressure, pulse rate, respiratory rate and pain score. The performance of the machine learning models was evaluated using the following metrics: accuracy, precision, recall, F1 score and area under the receiver-operating-curve (AUC).

Results: 18 participants with SCD were included in this study. The median age at inclusion was 30 years (IQR 22–34). The majority of the participants had SCD genotype HbSS (68%). There were 10 participants treated at day hospital (56%), while the other 8 participants were admitted to the hospital with a median length of stay of 7.5 days (IQR 2.5–10). After discharge, 15 participants sought medical care at least once within 30 days (83%); 8 were hospitalized (44%), and 13 were readmitted to the day hospital (72%). This pilot study consisted of 88 vital sign data points across the 18 patients. The metrics of our best-performing machine learning model, the random forest model, were: accuracy 70%, precision 0.94, recall 0.71, F1 score 0.81 and AUC 0.61 (Figure 1). The difference in precisions and recalls for all the models reflects the class imbalance in the dataset. To test how the model will perform for independent data sets, we used 5-fold cross-validation, and the cross-validation accuracy was 66% with a standard deviation of 7.7%.

Conclusion: In this pilot study, our machine learning model was able to accurately predict health care reutilization within 30 days following discharge, with real-time vital signs data collected during clinic visits and hospital admissions in participants with SCD. Prediction of reutilization may help healthcare providers identify those at high risk and allow considerations for inpatient and outpatient strategies for patient management.

Topics 004–Clinical, public health and epidemiological studies

V. Voi¹, S. Yukeb², E. Salzedo³, N. Rebaudengo³, G.B. Ferrero¹

Department of Clinical and Biological Science, Centre for Hemoglobinopathies, University of Turin¹, School of Medicine, University of Turin², Neurology, Humanitas-Gradenigo Hospital³

Background: Despite advancements in understanding the complex pathophysiological mechanisms underlying large-vessel cerebral vasculopathy and stroke in sickle cell disease (SCD), challenges persist.¹ Factors such as anemia contribute to an increased risk of stroke.^2,3 Unfortunately, stroke and abnormal or conditional transcranial Doppler (TCD) velocities continue to burden children with SCD in various national cohorts, leading to chronic organ damage and premature mortality.⁴

Aim of the Study: To study the relationship between cerebral hemodynamics and hematologic and biochemical markers in order to better understand the clinical aspects of the disease and help physicians to decrease the risk of stroke.

Methods: Here we report a single-site, real world, retrospective analysis of a long-term follow-up of children: we evaluated the relationship between some biochemical markers and TCD velocities. Kaplan–Meier survival analysis and univariate and multivariate Cox's regression were used to identify markers associated with an increased risk of pathologic TCD during the observation period. Only significant results are reported.

Results: The study enrolled 127 children that performed a total of 387 regular TCD screening: median follow-up 85.2 months (14.4 198), the study covers a total observation time of 2756 patient-year. Only HbSS children registered an abnormal TCDs (n=9; 2.3%), in 2.0% (n = 1) of Hbβ0S and 6.4% (n = 20) of HbSS patients TCD was conditional. Five (1.3%) patients had an abnormal TCD at the first examination with a median age of 3.5 years (IQR 3–5.7; range 2.6–9.5).

Children with higher hemoglobin and lower Absolute Neutrophil Count (ANC) have a lower risk for a pathologic TCD; (see table). No strokes were observed in our cohort.

Conclusion: An increase of 1 g/dL of hemoglobin reduces the risk of an abnormal TCD in life by nearly 50%, concurrently an increase of 1000 neutrophils/µL increases the risk of almost 17%. The main findings of our analysis reaffirm that control of anemia and neutrophil count are the key points to better prevention of cerebrovascular injury in children with sickle cell disease. This extensive real-world study underscores the direction of proper assistance in long-term follow-up and stroke prevention in pediatric sickle cell patients, reinforcing the significance of early detection and intervention to mitigate the impact of the disease.

Topics 007–Health services and outcomes research including psychology

A.L. Langer¹, L. Lombard², A. Rane², K.S. Gilroy², J. Li², J. Zhao², C.R. Lew³, B.M. Davis³, S. Sheth⁴

Hematology Division, Brigham and Women's Hospital¹, Agios Pharmaceuticals², Merative³, Department of Pediatrics, Divi sion of Hematology/Oncology, Weill Cornell Medicine⁴

Background: Thalassemia leads to ineffective erythropoiesis, chronic hemolytic anemia (HA), and associated complications. There is limited research on healthcare resource use (HCRU) and economic burden of α-thalassemia and non-transfusion-dependent thalassemia (NTDT; α- and β-thalassemia).

Aim: To evaluate HCRU and healthcare costs in adult patients with thalassemia compared to controls.

Methods: Patients with ≥1 inpatient (IP) claim or ≥2 claims in any setting with α- or β-thalassemia International Classification of Diseases (ICD)-9/ICD-10 codes from 1/1/2013–6/30/2021 were selected from the MarketScan® Commercial and Medicare and Multi-State Medicaid claims databases in the US. Index date was defined as the first α- or β-thalassemia ICD code. Adults (≥18 years) with at least 12 months of follow-up from index date to end of enrollment, IP death, or study end were included. Controls with no history of thalassemia or other HAs were matched 5:1 to thalassemia cases on age, sex, payer, follow-up time, and race (Medicaid only). Mortality data were reported with variable length follow-up while HCRU and costs were assessed 12 months post-index. Patients were stratified by α- and β-thalassemia and by transfusion-dependent thalassemia (TDT) and NTDT. TDT was defined as ≥8 transfusions within first 12 months post-index, each within 42 days of each other. Chi-square and t-tests were used for outcome comparison (twosided α = 0.05).

Results: In the Commercial/Medicare data, 4,183 patients with thalassemia (1675 [40.0%] α-thalassemia and 2,508 [60%] β-thalassemia) and 20,915 matched controls were analyzed. In the 12 months post-index, 2 (0.1%) patients with α-thalassemia had TDT (1673 [99.9%] NTDT) and 84 (3.3%) with β-thalassemia had TDT (2424 [96.7%] NTDT). Mean (SD) age was 46.1 (14.8) years, and 29.7% were male. Compared to matched controls, a significantly higher proportion of patients with α-thalassemia had ≥1 IP admission (19.8% vs. 5.6%; p < 0.001), emergency room (ER) visit (27.9% vs. 17.1%; p < 0.001), or outpatient physician visit (99.5% vs. 85.7%; p < 0.001), and significantly higher mean (SD) total healthcare costs ($21,710 [$55,981] vs. $8641 [$26,570]; p < 0.001). Similarly, a significantly higher proportion of patients with NTDT had ≥1 IP admission (20.0% vs. 5.7%; p < 0.001), ER visit (28.2% vs. 17.6%; p < 0.001), or outpatient physician visits (99.5% vs. 84.4%; p < 0.001), and significantly higher total healthcare costs ($21,989 ($53,588) vs $8686 ($28,949); p < 0.001) than matched controls. Similar patterns were seen for TDT and β-thalassemia (Table 1). Eight (0.5%) all-cause IP deaths occurred in patients with α-thalassemia (over mean [SD] follow up of 1132 [615] days), 7 (0.3%) in patients with β-thalassemia (1080 [590] days), 13 (0.3%) in patients with NTDT (1101 [599] days), 2 (2.6%) in patients with TDT (1091 [690] days) compared to no deaths in any control group (all p < 0.05). Medicaid data showed mostly similar trends across outcomes (data not shown).

Summary/Conclusion: Patients with thalassemia, including those with α-thalassemia and NTDT, had significantly higher HCRU, total costs, and higher IP mortality rates than matched controls. This study may underestimate burden of NTDT since some patients with thalassemia trait/minor may have been included in the NTDT group due to coding errors. Additional therapies are needed to address the underlying pathophysiology of thalassemia to prevent serious complications and reduce HCRU.

Topics 004–Clinical, public health and epidemiological studies

K.S. Srisurapanont¹, P.D. Danpanichkul², E.U. Uawithya³, R.W. Worapongpaiboon⁴, C.A. Angkurawaranon⁵

Faculty of Medicine, Chiang Mai University¹, Immunology Unit, Department of Microbiology, Faculty of Medicine, Chiang Mai University², Faculty of Medicine Siriraj Hospital, Mahidol University³, Faculty of Medicine, Chulalongkorn University⁴, Department o f Family Medicine, Faculty of Medicine, Chiang Mai University⁵

Background: Thalassemia presents a global public health challenge, particularly in malaria-endemic areas. However, a comprehensive analysis of the global burden of thalassemia is lacking.

Aims: This systematic analysis of the Global Burden of Disease (GBD) Study 2019 aimed to quantify the global burden of thalassemia disease from 1990 to 2019.

Methods: We obtained publicly available data from the GBD study 2019. Thalassemia prevalence, incidence, mortality, disabilityadjusted life years (DALYs), and cause-specific years lived with disability (YLDs) were estimated using the GBD 2019 analytical tools, along with corresponding 95% uncertainty intervals (UIs). The outcomes were stratified according to World Health Organization (WHO) regions.

Results: In 2019, there were approximately 1.06 (95% UI 0.86–1.33) million people living with thalassemia and 0.15 (95% UI 0.12–0.20) million new cases of thalassemia, resulting in age-standardized mortality and DALY rates of 0.14 (95% UI 0.12–0.17) and 11.05 (95% UI 9.25–13.22) per 100,000 population, respectively. Among the WHO regions, the Eastern Mediterranean region had the highest DALY rate from thalassemia (41.42; 95% UI 31.63–55.18 per 100,000 population). Anemia and heart failure were the main impairments in thalassemia, causing age-standardized YLD rates of 0.28 (95% UI 0.17–0.45) and 0.03 (95% UI 0.02–0.04) per 100,000 population, respectively. From 1990 to 2019, the absolute number of prevalent and incident thalassemia changed by −3% (95% UI −7%–1%) and −21% (95% UI −25 to −18%), respectively. The age-standardized mortality and DALYs during the same period changed by −0.48 (95% UI −0.62 to −0.23) and −0.50 (95% UI −0.64 to −0.24) per 100,000, respectively.

Conclusions: The global burden of thalassemia is decreasing, likely due to advancements in prevention and treatment. Efforts should be directed towards improving the quality of life for individuals living with thalassemia.

Topics 007–Health services and outcomes research including psychology

C. Trimnell¹, N. Badalamenti², R. Blaylark³, R. Colasanti⁴, R. Colombatti⁵, R. Grace⁶, C. Jonassaint⁷, K. Kuo⁸, L. Levine², C. Lobo⁹, T. Schryver¹⁰, N. Shah¹¹, S. Sheth¹², A. Watson¹³, J. Welle², T. Woolford¹⁴, H. John¹⁵, J. Davis¹⁵, A.U. Zaidi¹⁵, E. Gallagher¹⁵, S. Gheuens¹⁵, B. Andemariam¹⁶

Sickle Cell 101¹, Independent Contributor², Sickle Cell Foundation of Minnesota³, Cooley's Anemia Foundation⁴, Pediatric Hematology Oncology Unit, University of Padova⁵, Boston Children's Cancer and Blood Disorders Center⁶, School of Medicine, Univer sity of Pittsburgh⁷, Division of Hematology, University of Toronto⁸, Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti (HE MORIO)⁹, Thrive with Pyruvate Kinase Deficiency¹⁰, Department of Medicine, Duke University¹¹, Department of Pediatrics, Weill Cornel l Medicine, Cornell University¹², Pyruvate Kinase Deficiency Foundation¹³, Sickle Cell Reproductive Health Education Directive¹⁴, Agio s Pharmaceuticals¹⁵, New England Sickle Cell Institute, University of Connecticut Health¹⁶

Background: Sickle cell disease (SCD), thalassemia, and pyruvate kinase (PK) deficiency are three rare conditions with commonalities that go beyond their classification as hereditary hemolytic anemias (HHAs). The Red Cell RevolutionTM (RCR) is an advocacy advisory council, supported by Agios Pharmaceuticals, made up of members from these disease communities including patients, caregivers, advocates, company representatives, and health care professionals (HCPs). The need for such a multidisciplinary, pan-disease collaboration between those impacted by HHAs became clear as the earliest council members uncovered that while each disease has its own unique needs, they share many common needs.

Aims: Through the founding of this unique cross-indication council, the RCR aims to collect the evidence needed to raise a unified voice around issues in the HHA community, and shape solutions with broad applicability. This presentation will discuss best-practices for establishing a research-focused, community-based council, and highlight the priority areas agreed upon by the RCR and ongoing research strategy.

Methods: The idea of a cross-indication advisory council was conceived based on insights provided by patients, caregivers, advocates, and HCPs as part of a patient engagement initiative supported by Agios, during which participants highlighted that the unmet needs of those impacted by HHAs were frequently shared across all three disease areas. The RCR council was established according to Advocacy Advisory Council (AAC) model standards, as previously described.^1,2

A combination of qualitative and quantitative insights was used to develop the council's core vision and priority areas for focus. This took place through an unmet needs cluster analysis undertaken with the council, whereby participants shared their experiences, and the unmet needs were distilled and refined through a series of facilitated workshops. Unmet needs were ranked by the council based on whether (1) the topic had global scope; (2) there was a high potential for lasting impact; and (3) the idea could lead to a “revolutionary” (a complete or dramatic) change in care.

Results: The cluster analysis revealed that emotional and physical fatigue was a particularly prominent and common unmet need among those with SCD, thalassemia, and PK deficiency, and therefore the most appropriate area for further research.

Conclusions: Initial outputs from the project suggest the ability of a pan-disease advisory council and the results it can deliver in terms of defining an authentic set of core unmet patient needs and a community-based patient advocacy research strategy. Further, uniting participants within a pan-disease advisory council has the potential to amplify the voices of those affected by HHA and increase impact by addressing issues faced by patients of all three conditions.

The RCR council will now oversee an evidence audit to identify the knowns and unknowns around this priority area, and then develop a research hypothesis and conduct patient advocacy research to fill the knowledge gaps, ultimately writing up and disseminating its findings among community members.

Table/Chart: The chart below outlines the strategy for the Red Cell Revolution advisory council, and the process followed to define a research project. Green checks indicate steps completed.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

L. Wang¹, P. Li¹, Y. Wang¹, K. Lan¹, H. Zheng¹, D. Zhu¹, Y. Zhang¹, R. Guo¹, H. Ma¹, J. He¹, Q. Su¹, R. Gao¹, L. Zhang¹, Z. Bao¹, J. Hou¹, L. Ji¹, J. Zhang¹, S. Wu¹, Y. Li¹, B. Luo¹, B. Wu¹, S. Mou¹, J. Chen²

CorrectSequence Therapeutics¹, School of Life Science and Technology, ShanghaiTech University²

Background: β-thalassemia and sickle cell disease (SCD) are among the most prevalent monogenic disorders worldwide and both these βhemoglobinopathies are caused by mutations in the β-globin gene HBB. Reactivating the expression of the γ-globin genes (HBG1/2) mimicking the naturally occurring hereditary persistence of HbF (HPFH) is expected to be a universal strategy to treat β-thalassemia and SCD by the induction of fetal hemoglobin (HbF).

Aims: CorrectSequence Therapeutics' first pipeline, CS-101, uses transformer Base Editor (tBE) to precisely edit human hematopoietic stem cells (HSC) ex vivo to induce the expression of γ-globin for treatment of β-thalassemia and sickle cell disease.

Methods: Compared with the commonly used gene editing methods such as CRISPR/Cas nucleases or other base editors, tBE is a base editing system that avoids to cause DNA double strand breaks (DSB) or off-target mutations. With the safety advantages of tBE, CS-101 targets one of the most potent targets to activate γ-globin expression without the concern of unexpected off-target mutations. HSCs isolated from healthy or patient donors were transfected with tBE system by electroporation and tested in vitro and in vivo for the efficacy and safety.

Results: Pre-clinical in vitro and in vivo studies showed that while tBE-mediated editing in HSC induces robust γ-globin expression and elevated HbF, no off-target mutations or adverse effect on the engraftment or differentiation of the HSC in mice after transplantation were detected. A commercial scale manufacturing process to ex vivo edit HSC has been developed and validated with more than 10 batches of commercial scale production, all of which exhibited consistent process performance and product quality.

Summary: Preclinical results showed that tBE-mediated editing in HSC induces efficient γ-globin expression and elevated HbF without safety risks of off-target mutation, DSB or affecting the normal function of HSC. Clinical trials for CS-101 is underway and it's expected to benefit the patients of β-thalassemia and sickle cell disease soon.

Conclusion: With the best editing system and the most potent target, CS-101 holds great promise to become the best-in-class gene editing treatment for β-hemoglobinopathies.

Topics 005–Clinical, infection and nutritional deficiencies

M. Delgadinho¹, C. Ginete¹, B. Santos², J.N. Vasconcelos², M. Brito¹

H&TRC-Health & Technology Research Center, ESTeSL-Escola Superior de Tecnologia da Saúde, Instituto Politécnico de Lisboa¹, Centro de Investigação em Saúde de Angola (CISA)²

Background: Sickle cell disease (SCD) is a growing health problem in Sub-Saharan Africa, where about 300,000 affected children are born with this condition every year. The severity of this disease is aggravated by parasitic infections, which are prevalent in low- and middle-income countries and strongly associated with the development of anemia as they cause malabsorption, nutritional deficiencies, and gastrointestinal blood loss. Studies have suggested that helminths and protozoa parasites can affect the composition of the bacterial gut microbiota. On the other hand, the presence of specific bacterial communities can also influence parasite establishment.

Aims: Considering this, our main goal was to detect gut parasites in SCD patients from Angola and associate the obtained data with the microbiome composition and clinical parameters.

Methods: Stool samples were collected, and gut microbiome analysis was performed by 16S sequencing for the V3-V4 region. Realtime PCR was used to detect protozoan and helminths in 113 samples, which included SCD patients before and after hydroxyurea treatment and siblings without the disease (control group).

Results: The prevalence of Giardia intestinalis was 31%, Entamoeba histolytica 9.7%, Ascaris lumbricoides 14.2%, Strongyloides stercolaris 3.5% and Hymenolepis nana 3.5%. In our population, 44.2% of children had at least one parasitic infection and of these, 34% had a co-infection. 57% of the SCD children shared the infection with the respective sibling, and there was a reduction of 54% in SCD Giardia-positives after hydroxyurea treatment. The majority of parasitic infections were from a rural area in Bengo (64%) rather than urban Luanda (36%), with p < 0.001 in Pearson's Chi-square test. We noticed that SCD children with ascariasis had higher values of leukocytes (p = 0.008) and neutrophils (p = 0.022), assessed by the Student's t-test. In what concerns gut microbiome, infected children had a higher prevalence of Enterococcos and Desulfovibrio, whereas the non-infected had a higher abundance of Lactobacillus, Cuneatibacter, Veillonella, and Bacteroides uniformis. The prevalence of Bifidobacterium was also lower in children positive for Entamoeba and Ascaris, and Lactobacillus was reduced in Giardia and Entamoeba positives.

Conclusion: Parasites are known to induce immunoregulatory mechanisms and modify the host's immune response. However, these parasites can also disrupt different homeostatic relations, affecting the gut microbiota composition, as demonstrated in this study. The most prevalent parasite detected in our population, Giardia intestinalis, often leads to gut dysfunction and may cause long-term changes in commensal microorganisms. Moreover, the lack of access to clean water and inadequate sanitation system, typically found in rural areas of developing countries, can increase the risk of Entamoeba and Giardia infections, explaining the higher parasite burden found in children from Bengo. SCD patients infected with gut parasites tend to have more severe steady-state anemia, so it is therefore crucial to implement periodic stool examinations to treat the infection when detected. More studies are also needed to deepen and clarify the parasites’ influence on the SCD gut microbiome. This study was supported by IPL/2022/ParasitSCD_ESTeSL.

Topics 005–Clinical, infection and nutritional deficiencies

U.B. Bhattacharjee¹, A.R.K. Khadwal¹, P.S. Sharma¹, T.D.Y. Yadav¹, C.S. Singh¹, A.J. Jandial¹, K.K. Kaur², K.K. Kaur², S.K. Kaur², N.S. Samyal², A.J. Jain¹, D.P.L. Lad¹, G.P. Prakash¹, R.D. Das¹, D.B. Bansal¹, A.T. Trehan¹, P.M. Malhotra¹

Postgraduate Institute of Medical Education and Research¹, Thalassemic Charitable Trust²

Background: Splenectomy is often necessary for transfusion-dependent thalassemia patients in developing countries. Despite reducing the need for transfusions, it is associated with significant complications such as sepsis, thrombosis, and pulmonary hypertension.

Aim: We aimed to study the long-term efficacy, survival, and incidence of infectious, and non-infectious complications in splenectomised transfusion-dependent thalassemia patients.

Methods: In this retrospective study, we reviewed the medical records of all the splenectomised transfusion-dependent thalassemia patients registered with the adult thalassemia clinic of a tertiary care centre in North India from July 2013 to June 2023.

Nontransfusion-dependent thalassemia patients who underwent splenectomy and thalassemia patients who had undergone splenic embolisation were excluded. The variables of interest included demographic and clinical characteristics, haematological parameters pre- and post-splenectomy, surgery details, vaccination and antimicrobial prophylaxis, infectious and non-infectious complications, and survival. For the purpose of analysis, infectious complications were classified into early (within 2 years of splenectomy) and late (beyond 2 years of splenectomy). Infections were further subcategorised into overwhelming post-splenectomy infection syndrome (OPSI), non-OPSI bacterial, viral, tubercular and malaria.

Results: Of the 290 thalassemia patients registered, 103 (35.5%) were transfusion-dependent and underwent splenectomy. The median age at splenectomy was 12 (range 5–34) years. A total of 101 (98.1%) patients underwent open splenectomy, while only 2 patients (1.9%) underwent laparoscopic splenectomy. All patients received pre-splenectomy vaccination, and 101 (98.1%) patients received post-splenectomy penicillin prophylaxis. The median duration of penicillin prophylaxis was 3.5 (range 0.5–17) years. The median pretransfusion haemoglobin at the last follow-up post-splenectomy was significantly increased compared to the median pretransfusion haemoglobin 1-year pre-splenectomy (9.5 g/dL vs. 8.2 g/dL, p < 0.0001). The median yearly transfusion volume (mL/kg/year) at the last follow-up post-splenectomy was significantly less compared to 1-year pre-splenectomy (146.2 vs. 276.7, p < 0.0001). Surgical complications were observed in 3 (2.9%), thrombosis in 5 (4.8%) and pulmonary hypertension in 10 (9.7%) cases.

Iron-overload-related complications included cardiomyopathy in 17 (16.5%), endocrinopathy in 56 (54.3%), chronic liver disease in 15 (14.5%) and hepatocellular carcinoma in 1 (0.9%). Fifty-one episodes of infections were recorded in 40 (38.8%) patients, of which 17 (33.3%) were early, and 34 (66.7%) were late infectious complications. OPSI presented more as early than late infectious complications (17.6% vs. 2.9%, p = 0.06). The incidence of tuberculosis in our cohort was 7.7%, and all the cases were extrapulmonary. A total of 15 (14.5%) patients died. The most common cause of death was cardiomyopathy (53.3%). At a median follow-up duration of 15.5 years post-splenectomy, 87.1% of patients survived.

Conclusions: Although effective in decreasing long-term yearly transfusion volume, splenectomy in transfusion-dependent thalassemia patients is associated with several infectious and non-infectious complications, including a high incidence of extrapulmonary tuberculosis. Despite these complications, the majority of patients survived at 15 years post-splenectomy.

Topics 007–Health services and outcomes research including psychology

K. Sibasa¹, C. Macauley¹, A.M. Hood¹

University of Manchester¹

Background: Reports from the National Health Service (NHS) Race Observatory and an All Parliamentary Group indicate that people living with sickle cell disease (SCD) experience discrimination in the UK healthcare system. This is exacerbated when they present to Accident and Emergency (A&E) during painful episodes. They wait longer than other patients experiencing pain, face accusations of lying about their pain, and are perceived as “drug-seekers.” The negative attitudes of healthcare providers are likely reflected in the general UK population. However, this has not previously been empirically tested despite the importance of understanding the mechanism through which discrimination against people living with SCD is developed and maintained. One such mechanism could be the interplay between institutional racism and procedural justice–the perception of fair processes impacted by not only the result but the quality of experiences.

Aims: We investigated whether people would view a scenario as procedurally just when the person experiencing pain was a woman living with SCD and whether this perception differed depending on the levels of institutional racism endorsed.

Method: Eighty-eight university students aged 18–22 years provided informed consent and participated in this study (see Table 1). Participants were randomly assigned a control or experimental condition and read a vignette of a woman presenting to A&E experiencing significant pain and interacting with a nurse. In the experimental vignette, the woman's identity, that is, that she was Black and had SCD, was explicitly stated, whereas, in the control vignette, the racialised identity and medical condition were not stated. After reading the vignette, participants rated whether they viewed the encounter as procedurally just (rating on a scale of 1-7), completed an Institutional Racism Scale, and an SCD Knowledge Questionnaire. Additionally, participants indicated how often in the past 12 months they had visited the A&E.

Results: We conducted a multiple linear regression with procedural justice perspectives as the dependent variable and group status (experimental or control) and levels of institutional racism as independent predictors after controlling for A&E visits. A&E visits and levels of institutional racism were not significant predictors (p > 0.05). Against hypotheses, group status was a significant predictor (p = 0.01); we found that participants viewed the experimental condition as more procedurally unfair. However, this effect was explained by the significant interaction between group status and levels of institutional racism endorsed. Specifically, participants in the experimental condition (where it was clear that the woman was Black and had SCD) who endorsed higher levels of institutional racism perceived the encounter at the A&E to be more procedurally fair (see Figure 1).

Conclusion: This pilot study is the first step in demonstrating that public views of an A&E encounter differ depending on the levels of institutional racism endorsed. These results provide clear experimental evidence of the mechanisms through which people living with SCD experience discrimination and racism in clinical encounters for pain. The next steps will be to test these same mechanisms and hypotheses in samples of medical students and healthcare providers. Empirical studies such as these demonstrate a clear need for change and show how institutional racism changes perceptions of justice.

Topics 004–Clinical, public health and epidemiological studies

N.B. Selene¹, S.D. Iskandar¹, D.A. Amirah¹, L.D. Rahmartani¹, T.T. Sari¹, P.A. Wahidiyat¹, D. Sekarsari²

Pediatric Hematology Oncology Division, Department of Child Health, Universitas Indonesia, Cipto Mangunkusumo Nation al Hospital¹, Department of Radiology, Universitas Indonesia, Cipto Mangunkusumo National Hospital Jakarta²

Background: Excessive iron accumulation in thalassemia patients causes irreversible organ damage, which ultimately leads to organ dysfunction and failure. Serum ferritin is the serum marker of iron overload; however, the examination has low specificity. While MRI T2-star (T2*) may detect the level of iron deposits in various organs, it has limited availability. Thalassemia major, which necessitates patients to receive routine blood transfusions also known as transfusion-dependent thalassemia (TDT) patients are at risk of iron overload, due to increased intestinal absorption. The treatment modality for removing excess iron is iron chelators.

Aims: This study aims to describe patients' clinical profiles and explore the severity of iron deposition in various organs in TDT patients.

Methods: This cross-sectional study utilized medical record data of TDT patients who underwent MRI T2* examination in Cipto Mangunkusumo Hospital from 2021 to 2023. All subjects consented to the MRI examination and treatments. MRI examination was done using Siemens MRI Avanto 1.5 Tesla. Quantification of the T2* value was obtained using CMRtoolsTM software. T2* values were categorized using the following cut-off points for iron overload: Cardiac: normal >20 ms, mild hemosiderosis 14–20 ms, moderate hemosiderosis 10–14 ms, and severe hemosiderosis <10 ms; Liver: normal iron deposition >6.3 ms, mild hemosiderosis 2.7–6.3 ms, moderate hemosiderosis 1.4–2.7 ms, and severe hemosiderosis <1.4 ms; Pancreas: normal iron deposition >33 ms, mild hemosiderosis 10–33 ms, moderate hemosiderosis 2.5–10 ms, and severe hemosiderosis <2.5 ms. We calculated the mean ferritin and pre-transfusion hemoglobin levels from 6 months before MRI T2* examination. We performed one-way ANOVA to compare the mean serum ferritin level with the degree of iron overload.

Results: A total of 270 subjects were included in the study. The highest proportion of subjects were HbE/β-thalassemia (52.6%), followed by β-thalassemia major (44.4%) and α-thalassemia (3.0%). Approximately 75% of the subjects were adults, and more than half (53.7%) were female. Less than half (47.4%) of the subjects had suboptimal pre-transfusion hemoglobin levels (<9 g/dL) due to limited access to optimal blood transfusion. Up to 70.7% of the subjects consumed iron chelation monotherapy, with deferasirox as the predominant treatment. Combined use of deferasirox and deferiprone is the most commonly used combination of iron chelators (22.0%). Serum ferritin level ranges from 128 to 40,000 ng/mL. Only 1.9% of the subjects achieved the desired ferritin level (<1000 ng/mL). The MRI T2* examination revealed that no subject had normal cardiac, liver, and pancreas iron deposition. Cardiac siderosis was found in 15.9% of the subjects with mild (5.6%), moderate (2.9%), severe (7.4%). Almost half of the subjects (46.1%) had severe liver iron overload and mild pancreatic iron overload (45.0%). The mean ferritin levels were not significantly associated with the degree of iron overload in the heart (p = 0.991), in the liver (p = 0.577), and in the pancreas (p = 0.753).

Conclusion: Our study showed the challenges of managing TDT patients in Indonesia. MRI T2* examination revealed varying degrees of iron overload in different organs and these were not significantly associated with the serum ferritin levels. We recommend improving access to optimal treatment and expanding the availability of MRI T2* examination.

Topics 004–Clinical, public health and epidemiological studies

C.S. Mhando¹, M. Ally¹, O. Nyongole¹, E. Balandya¹, A. Jonathan¹, F. Urio¹

Muhimbili University of Health and Allied Sciences (MUHAS)¹

Background: Sickle cell disease (SCD) results from a single base pair alteration in the sixth codon of hemoglobin's -globin chain causing the sickled red cell, which promotes the aggregation of deoxyhemoglobin, making red blood cells stiffer and leading to hemolytic and vasoocclusive consequences.

Since its introduction and approval from FDA, Hydroxyurea (HU) has brought forth beneficial outcome in SCD patients. Studies have shown that the use of HU in SCD patients has tremendously improved morbidity, mortality and the overall quality of life of these patients and their families. Patients with SCD nowadays due to improved interventions can survive well into their adulthood, despite these advancement in interventions HU is still underutilized especially in low resource countries such as Tanzania being among countries with high disease burden. Nevertheless, studies done in Tanzania on prevalence of HU use were only single centered therefore do not give the overall prevalence of HU use of the country.

Aim of the Study: This study aimed at determining the prevalence of patients with SCD using HU, predictors for HU use among SCD patients attending different clinic sites in Tanzania, and change in severity of anemia among SCD patients after using HU for at least 3 months

Patients and Methods: A retrospective review of data of SCD patients collected at 10 hospitals from January 2017 to December 2022 was conducted at Sickle cell center (SPARCO center) in collaboration with Muhimbili University of Health and Allied Sciences. The percentage of SCD patients using HU was calculated, and the socio-demographics factors such as age, name of the hospital where patients attended, and health insurance coverage were analyzed to determine the predictors for HU use. Chi-square test was used to assess the association between socio-demographic factors and HU use. Factors with odds ratio above 1 were considered to be the predictors of HU use. A one year review of anemia severity before and 3 to 6 months after HU treatment was evaluated.

Patients' hemoglobin levels before HU use and at least 3months after HU initiation were analyzed using Wilcoxon test as they were not normally distributed. The p-value of less than 0.05 was considered to be statistically significant.

Results: Data of 6275 SCD patients were retrieved from the database from January 2017 to December 2022. The median age was 11 years (IQR 22). 77% of all patients were children below 18 years of age. The prevalence of HU use was 32%, of which majority (47.7%) were attended at Muhimbili National hospital (Upanga and Mloganzila campuses). 84.6% of patients who use HU were on Health insurance coverage. HU is only utilized by 5.2% of patients who visit district hospitals in Pwani region. Health insurance coverage and level of hospital were found to be the predictors of HU use in Tanzania. There was a significant alteration in the severity of anemia by at least 3 months of HU utilization. Before HU use 73.7% had severe anemia, 25.4% had moderate anemia and 0.9% had mild anemia. 36 months after HU use, 10.8% had severe anemia, 75.6% had moderate anemia and 13.6% had mild anemia. The change in severity of anemia before and after HU use was statistically significant with the p-value of 0.001.

Conclusion: The prevalence of patients with SCD using HU in Tanzania is still low (32%) regardless of the WHO recommendation that all patients with SCD should use HU from the age of 9 months. HU is effective in improving hemoglobin level among Tanzanian patients. The level of the hospital and health insurance coverage are positive predictors of HU use. To improve number of SCD patients using HU in Tanzania, we recommend health insurance coverage to all SCD patients, and change in policy to allow stocking and prescription of HU in the district hospitals where there are no medical specialists

Topics 004–Clinical, public health and epidemiological studies

A.S. Kidane Gebremeskel¹, M.A.E. Rab¹, K.A.C. Meeks², A.A. M'charek³, A.W. Rijneveld¹

Erasmus Medical Center¹, Center for Research on Genomics and Global Health (CRGGH), National Institutes of H ealth (NIH)², University of Amsterdam³

Background: In sickle cell disease (SCD) research studies, ethno racial categories (ERCs) are frequently used mentioned, sometimes as descriptive variables and other times also considered confounding variables. However, these ERCs are often large aggregate categories and include individuals with a diversity in phenotype, exposures and genetic make-up. Recent journal submission guidelines urge researchers, when applicable, to declare the relevance of the use of ERCs to the study as well as the modality through which an ERC is determined (e.g., self-identification, country of birth, visual identification by the observer). Providing such detailed information is important because true confounders with a specific feature might distort study results. However, when operationalizing ERCs in SCD research, there exists a risk of reification of already marginalized populations as both a social and a biological group. Therefore, contextualization is essential when deciding to use ERCs in SCD research.

Aims: This study aims to provide an overview of how ethnicity and race are applied in SCD research.

Methods: Embase and Medline were systematically searched in November 2022 for all published articles on SCD published from 2011 onwards. Studies were considered eligible when cases defined as individuals with SCD and controls individuals without SCD. A total of 1105 articles in SCD research were included. Of these articles, 1085 were domestic studies and 20 international studies. Statistical tests and models implemented in R included chi-square tests and univariate linear regression.

Results: In 27% (298/1085) of all studies, ERC confounder adjustment occurred. This methodological practice was dependent on geographical region the research subjects were sourced from (p < 0.05), as made visible in Figure 1. In 175/302 (57%) of studies with a North American study population ERC confounder adjustment took place, as well as in 45% [58/129]) of the studies reporting on a European study population. In contrast, in 6% (14/239) of sub-Saharan African study populations, ERC confounder adjustment was performed (Table 1). ERC confounder adjustment also varied with the biomedical discipline in which the article was published. Of the studies that used ERC confounder adjustment, 80% (239/298) did not explain why this was relevant. Furthermore, in 70% (209/298) of these ERC-adjusted studies, it was unclear through which modality ERCs were determined. In the papers that described modalities, 49% (44/89) used ERCs from pre-existing databases, 18% (16/89) used sibling/relative recruitment, 30% (27/89) used self-reporting ERCs and 2% (2/89) used multiple ways to classify ethnicity or race. Moreover, in 28% (83/298) of the ERC-adjusted studies, it was not clear which specific categories were used.

Conclusion: ERC confounder adjustment is a common occurrence in SCD case-control studies in the United States and Europe. Furthermore, contrary to current author guideline recommendations, the reporting on ethnicity and race in SCD studies is frequently inconsistent and incomplete. This confuses the possible relevance of ERCs to the study and inadvertently reinforces reification of these constructs. Moving forward, we recommend the promotion of global guidelines around the use of ERCs in case-control studies to stimulate further research into uncovering specific relevant mechanisms that create differences in health outcomes.

Topics 004–Clinical, public health and epidemiological studies

M. Brito¹, B. Inusa², C. Ginete¹, M. Mendes³, R. Afonso³, I. Valentim⁴, A. Siatembo⁴, J.N. Vasconcelos⁴

H&TRC, ESTeSL, IPL¹, King's College London², Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes³, Centro de Investigação em Saúde de Angola, Caxito⁴

Sickle cell disease (SCD) prevalence can reach 3.3% in Angola. The early identification of patients and their follow-up are an added value for the reduction of morbidity and mortality of children with SCD. We aim to implement a Newborn screening in Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes, a referral maternity in Luanda, Angola capital, that could be replicated in other hospitals, giving training to the health professionals, and to the laboratory technicians.

The objective of this project is to establish a neonatal screening for SCD at a main Hospital, contributing to reduce the under 5 mortality, and to support pediatric follow-up of children diagnosed with SCD. Specific aims include: record the data and medical history of babies diagnosed with SCD up to 5 years of age at regular appointments; estimate the prevalence of SCD in the municipality of Camama, Luanda; and to evaluate the costs of neonatal screening and early interventions in Angola, by supporting a registry of SCD.

The newborn screening has started in June 2023, with the training of the team and with the creation of all documents and forms needed. The project received ethical approval in June 2023. The study includes every child born in the maternity ward of the Hospital, and every child that take vaccinations there (in this way we include newborns delivered at home), that the legal guardians authorize the collection of blood sample by prick heel. The samples of filter paper duly identified with the sample number and date of collection are being sent to Lisbon (Portugal) for hemoglobin electrophoresis by isoelectric focusing (IEF) carried out in the Migele equipment.

All SS samples are being genotyped for the HbS mutation by PCR-RFLP (Figure 1). Since the start of the NBS (June 28th) we have collected 1000 samples in 4 weeks and have started the IEF analysis with MIGELE (Perkin Elmer). The preliminary results (221 samples, 177 AA, 41 AS and 3 SS) showed a 1.4% prevalence of SS, and 19.5% of AS, confirmed by PCR-RFLP (in all AS and SS). The frequencies were in Hardy-Weinberg equilibrium. We are searching for other possible hemoglobinopathies. All children diagnosed as SS (SCD) are being contacted by the Hospital, to be followed in consultation. Newborn screening and early interventions for SCD should be a health priority and implemented at national level. It is our plan to catalyze progress toward this aim by demonstrating the high prevalence of neonatal SCD in the Luanda Hospital and demonstrate the feasibility of this screening in reducing under 5 mortalities.

The present project has the support of ARISE project “African Research and Innovative initiative for Sickle cell Education: Improving Research Capacity for Service Improvement” project (GA 824021—ARISE—H2020-MSCA-RISE-2018) by supporting the secondments of Angolan Laboratory technicians in Lisbon (Portugal) to perform the IEF and genetic analysis and be trained. Until now 5 Angolan secondees, and 3 Nigerian secondees have been trained in Lisbon. Perkin Elmer (Revvity) is giving llogistical support by kindly support the low-cost acquisition, installation and training in MIGELE equipment for IEF, and being always available to technical support.

Topics 004–Clinical, public health and epidemiological studies

C. Vuong¹, P. Brinkman¹, H. Heijboer¹, E. Nur¹, C.L. Eckhardt¹, S.W.J. Terheggen-Lagro¹, B.J. Biemond¹, A.H. Maitland-van der Zee¹, K. Fijnvandraat¹

Amsterdam University Medical Centers¹

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by hemolytic anemia, inflammation and vasoocclusion. Due to the process of vaso-occlusion patients with SCD experience unpredictable and painful vasoocclusive episodes (VOE), causing stress and disruption of daily life. To date, we lack adequate markers to predict the development of a VOE before it occurs. In other conditions such as asthma, exhaled air analyses have shown to be of diagnostic value and may predict exacerbations. In the human body, metabolic processes generate volatile organic compounds, that are first released into the blood, and then exhaled by the lungs. As a result, exhaled air consists of several volatile, organic compounds that may reflect pathophysiological disease processes.

Aim: The aim of this study was to identify distinctive volatile organic compounds in exhaled air (eVOC) during VOE in patients with SCD, that may serve as predictors of VOE when detected in low quantities as a VOE is evolving.

Methods: In this longitudinal, observational single center cohort study, patients with SCD aged 6 years or older were eligible if they were hospitalized for a VOE at Amsterdam University Medical Centers between October 2021 and March 2023.

Following informed consent, an exhaled air sample was taken during hospitalization, and one at least 4 weeks after discharge from the hospital (steady state). Clinical data were collected from medical files including demographics, medical history, medication use and laboratory values during steady state, and during hospitalization for VOE. Patients were instructed not to eat, drink or take medication orally 2 h prior to the measurements. Exhaled air samples were collected in Nalophan bags, and the eVOCs were transferred to stainless steel thermal desorption tubes filled with Tenax GR for analysis by gas chromatography–mass spectrometry. The Wilcoxon signed-rank test was used to test for differences in eVOCs between VOE and steady state. Significantly different eVOCs were tentatively identified by linking raw chromatograms to corresponding metabolites based on NIST-library matching. The significance level was set to 0.05. All analyses were performed using R Studio (version 1.3.1093) software.

Results: In total, 25 patients with SCD were included in this study, providing 71 exhaled air samples. The mean age at inclusion was 25.7 years (SD ±10.2). The majority of the participants had SCD genotype HbSS (60%). At time of exhaled air measurement during hospitalization, participants had symptoms for the median number of 1 day (IQR 0.5–3), and the median pain score was 6 out of 10 (IQR 3–7). A total of 58 different fragments could be identified between VOE and steady state (Wilcoxon rank p < 0.05), representing 26 unique eVOCs. The majority of these eVOCs were alkanes, alkenes, and esters. A representing compound for each chemical group is shown in Figure 1. In the majority of the patients, cyclohexane,1,2,4trimethyl and propanoic acid, ethyl ester were upregulated during VOE, while 1-propene, 2-methyl- was downregulated.

Conclusion: This pilot study identified 26 compounds in exhaled air that differentiated VOE from steady state in patients with SCD. Thus, analysis of exhaled air could serve as a promising, non-invasive and patient-friendly biomarker to predict VOE in SCD.

Topics 005–Clinical, infection and nutritional deficiencies

M.S. Maliha Sumbul¹, M.M. Maria Ali¹, Muhammad Nadeem¹

National Institute of Cardiovascular Diseases¹

Background: It is estimated that approximately 5000 children are born with thalassemia major each year in Pakistan. There are about 9.8 million carriers of beta thalassemia with high prevalence of about 5%–8%. There are around 50,000 registered thalassemia major cases in country. It is suspected that actual figure could be higher due to many unregistered cases living in rural areas with under resourced healthcare facilities.

Beta thalassemia major is genetically inherited condition which requires lifelong transfusion support and iron chelation. The only cure for the condition is bone marrow transplant. Management of Beta Thalassemia major children put an additional burden to country's limited health budget. On contrary prevention by thalassemia carrier screening is not only economical but likewise it is an effective method. Unfortunately, there is no national screening program implemented in country. Simple screening tools for identification of cases, which can later be tested by confirmatory methods is the solution for a developing country with financial limitations.

Complete blood count and Hb electrophoresis are the first-line, cost-effective tests which should be used to investigate a suspected carrier of a thalassemia gene with hypochromic microcytic red cell indices and erythrocytosis. Blood tests can also be used for DNA analysis to confirm presence of mutated genes.

It is important to exclude iron deficiency by serum iron profile determination as low levels affect the detection of coexisting thalassemia minor due to reduction of HbA2 levels. Lamentably, nutritional anemias are again very much prevalent in population hindering the test results.

Aim: We conducted this study with an objective to find out prevalence of hemoglobinopathies and ferritin level of our staff members, voluntarily participating in CBC screening camp.

Methods:

Study design: Cross sectional/Observational.

Setting: Pathology Department, National Institute Of Cardiovascular Diseases, Karachi.

Sample size/Study Duration: 147 staff voluntarily participated in CBC screening camp at NICVD on 23rd June 2022.

Sampling Method: Venous samples for CBC were collected in EDTA tubes. Subjects with hypochromic microcytic indices were further selected for serum ferritin and hemoglobinopathy screening by HPLC method on fresh samples in red top and EDTA top respectively. Anemic subjects with macrocytosis and those who did not give fresh sample were excluded. Informed consent was taken from all the participants

Results: Total 147 staff participated in screening, 120 (81%) males and 27 (19%) females, with mean age of 38.8 ± 9.9 years. Mean hemoglobin was 13.1 ± 1.5 g/dL. Out of total, 111(75%) had normal CBC and 9(6%) were excluded from study.

Remaining 27(19%) cases with hypochromic microcytic rbc indices were further tested for haemoglobinopathy and serum ferritin.

Screening revealed 4.1% with carrier status, 5(3.4%) with Beta thalassemia minor and 1(0.7%) HbD trait.

Ferritin (ng/mL) performed on 27 participants: 4(2.7%) <10, 13 (8.8%) 11–50, 5 (3.4%) 50–100 and 5(3.4%) >100.

Conclusion: Haemoglobinopathy prevalence in study population reflects general Pakistani population. Ferritin depicting iron stores is significantly low, in both genders, showing poor nutritional status of the Pakistani community. Thalassemia is preventable with effective screening strategies. Serious efforts to create Thalassemia and Nutritional deficiency preventive measures with Public/Private partnership is the ultimate answer.

Topics 005–Clinical, infection and nutritional deficiencies

L.L. Hsu¹, J.C. Fan-Hsu²

University of Illinois at Chicago¹, private dental practice²

Introduction: Osteonecrosis, also known as avascular necrosis (AVN), is a frequent complication in sickle cell disease (SCD), across all the genotypes. Many individuals with SCD AVN go to total hip arthroplasty (THA), and then live for decades with the THA. SCD also causes increased susceptibility to osteomyelitis in the devitalized bone. Orthopedists have successful protocols to reduce THA infections in the immediate post-op period. Until the mid-2000's, bacteremia from dental procedures was suspected to cause late joint prosthesis infections and bacterial endocarditis. However, major reappraisals of evidence then led to recommendations by American dental, orthopedic, and cardiology societies (ADA, AAOS, and AHA, respectively) that the risks of bacterial infection triggered by dental procedures are low for most individuals. Furthermore, there is evidence that antibiotic prophylaxis before dental care does not reduce the risk of infection. The 2013 statement from AAOS-ADA instructed dentists that most patients with prosthetic joints do not need antibiotic prophylaxis for dental care, but there are case-by-case exceptions such as immunocompromised patients (with a list that did not mention SCD). The reasons for NOT giving antibiotic prophylaxis in low-risk scenarios include (1) increasing antibiotic-resistant bacteria, (2) opportunistic infection, (3) anaphylactic reactions to antibiotic, (4) adding barriers to dental care.

Therefore, the need for antibiotic prophylaxis for individuals with SCD and THA is left to be considered on a case-by-case basis.

Aims: This scoping review examined the risk of late infection of THA from dental procedures in individuals with SCD and THA. The hypothesis was that the risk is lower than the threshold for antibiotic prophylaxis for dental care.

Methods: Literature search was conducted for the period January 2013–June 2023 in PUBMED, GOOGLESCHOLAR, ScienceDirect, EMBASE, and SCIELO. Cochrane Reviews and PROSPERO registries were searched for systematic reviews. SCIELO was specifically searched to access publications from Brazil. These keywords were used: sickle cell disease, sickle cell anemia, total hip arthroplasty, hip joint prosthesis, bone infection, antibiotic prophylaxis, and dental. Two authors reviewed the papers and agreed upon the findings.

Results: Not enough published data were available to test the hypothesis (Figure). A systematic review of total hip arthroplasty in SCD (Fassihi 2020) reported the frequency of cases of late infected hip joint prostheses was 3.72% across 13 studies in SCD, with no link to dental procedures reported. No randomized controlled trials or case series reported whether antibiotic prophylaxis before dental procedures would reduce joint infection rate in SCD. AAOS (2016) does not mention that SCD with THA needs antibiotic prophylaxis before dental care.

Summary/Conclusion: This scoping review has limitations: (1) Limited reporting in THA in SCD about dental procedures were conducted, or whether antibiotic prophylaxis was given before that dental care. (2) Non-English publications could have been missed. Current guidelines suggest most individuals with SCD and THA might not need antibiotics but there is a data gap. AAOS and ADA guidelines highlight risk factors that might merit antibiotic prophylaxis: a history of prosthetic joint infection that required an operation, uncontrolled diabetes mellitus, or impaired cellular immunity. More study is needed.

Topics: 001–Basic and translational

K. Kuchenbaecker¹, M. Mackintosh², M. Silver², M. Nugent², S. Tallman², Y. Cho², W. Townley²

Genomics England; UCL¹, Genomics England²

Background: There are about 17,000 individuals with sickle cell disorder (SCD) in the UK and the prevalence is rising. Almost all clinical manifestations and complications are extremely variable between affected individuals. Understanding the causes of this variability has immense potential to help patients through personalised prognoses, targeted therapies, or the identification of novel drugs and therapies. Moreover, it will permit fine-grained characterisation of patient blood groups that can help eradicate transfusion reactions.

Aims: Diverse Data, a new programme at Genomics England, is developing the first national genomics research initiative for SCD. This initiative aims: 1) To drive improvements in health outcomes for people with sickle cell by building a world-leading sickle cell genomics research resource, 2) Research priorities for genomics set by people affected by sickle cell, 3) Raise awareness of Sickle cell and advocate for better patient-centred research, treatments and care.

Methods: This will be done in partnership with NIHR Bioresource and their Improving Black Health Outcomes study, and the Sickle Cell Society, as well as many other national and international partners. The aim is to offer enrolment to all affected individuals in England. The study will implement whole-genome sequencing of blood samples from all participants. The data will be made available to researchers internationally through the National Genomic Research Library.

Results: Here we present how this initiative was established, including how sickle cell was identified as a strategic priority for Diverse Data, insights from clinic visits, an Expert Dialogue, engagement with affected individuals and a literature review to map existing sickle cell and genomic datasets to inform the development of the phenotyping questionnaire. We will also present the future direction, priorities and key challenges for the initiative.

Conclusion: This initiative may help illuminate the causes of disease variability. Beyond the scientific significance, an initiative of this scale, implemented in partnership with key stakeholders and accompanied by excellent patient engagement, will support awareness and advocacy of this prevalent disease.

Topics: 001–Basic and translational

M. Adeturinmo¹, A. Hall², A. Wodjecka², K. Kandya², J. Makani¹, L.v. Keimpema¹, J. Ennis-Cole³, A. Hart²

Imperial College London¹, Royal College of Art², University College London³

Background: This study leverages the principles of design thinking and system thinking to investigate and visualise the impact of Sickle.

Cell. Sickle cell is a genetic disorder that affects millions of people worldwide and disproportionately affects people of African and Caribbean descent. Patients with this condition face a range of physical, emotional, and social challenges due to the unpredictable nature of the disease. The fundamental principle explored in this study is designing for empathy. Design for Sickle Cell (D4SC) initiative was developed to bridge the gap between art, design and science within the Sickle Cell landscape.

Aim: This design research project aims to investigate and visualise the condition's impact from a multi-stakeholder perspective by developing art and design prototypes that can inform an innovative Sickle Cell exhibition.

Methods: Techniques from social constructionism, phenomenological qualitative research and user-experience research were utilised to create a novel methodology for this small-scale study. The methodology involved a multi-step process combining the double diamond, system thinking, and action research frameworks to gather insights that guided the development of this design research practice. Semi-structured interviews were conducted with Sickle Cell experts consisting of patients, a healthcare practitioner and support staff. Common themes were generated from their experience of the condition's impact. D4SC collaborated with Imperial's Invisible Warrior Project, RCABlack, a PhD Archivist Researcher and Photographer at the Slade School of Fine Art, to develop visual prototypes for the exhibition.

Results: The findings from these interviews informed the development of a range of workshops and prototypes. The prototypes were tested by Sickle Cell experts and healthcare designers, who provided feedback on the concept. The results showed that the design outputs and exhibition were well-received and had the potential to improve education and awareness of the condition and promote empathy. Design research in healthcare has the potential to create innovative solutions. With the use of a multidisciplinary approach, it can yield a positive impact.

Conclusions: The project highlights the importance of design thinking, system thinking and collaboration in developing innovative healthcare solutions for this complex health condition. The study demonstrates the value of a multi-stakeholder approach to designing for empathy. It shows the potential of visualising the impact of Sickle Cell to promote understanding and awareness of the condition. To facilitate the further advancement of the concepts developed in this study, securing funding and undertaking additional research endeavours will be necessary, given this was a small-scale study to provide proof of concept.

Topics: 004–Clinical, public health and epidemiological studies

J.P. Pereira¹, E.C. Cunha², L.R. Relvas², P.S. Seabra³, E.R. Rocha⁴, C.B. Bento¹

Serviço de Hematologia Clínica, Centro Hospitalar e Universitário Coimbra; CIAS, Centro de Investigação em Antropologi a¹, Serviço de Hematologia Clínica, Centro Hospitalar e Universitário Coimbra², Serviço de Hematologia Clínica, Centro Hospitalar e U niversitário de Santo António³, Serviço de Pediatria, Hospital Distrital de Faro⁴

Here we report the case of 9 years old boy, presenting with a mild thalassemia intermedia phenotype, due to a compound heterozygozity for a β⁰ mutation and a δβ deletion, whose diagnosis was challenging because it seemed to contradict the facts.

Case report: We present the case of an 9-year-old Portuguese boy who was referred to our Hospital for diagnostic clarification: Sanger sequencing of HBB, showed a homozygosity for the β⁰ CD39 (HBB:c.118C>T; p.Gln40*) variant but hematological features were compatible with a thalassemia intermedia (Hb 8.4 g/dl) and HBA is present in the HPLC (Table I). His mother and brother were heterozygous for the same variant but his father had normal hematological parameters, normal HbA2 level and normal HBB gene. Short Tandem Repeats testing supported the paternity.

Due to high HbF value and family history, a search for large deletions was performed in our laboratory, by MLPA in the HBB cluster, and a 7.4 kb deletion was detected in heterozygosity. This deletion, encompassing the HBD and HBB, removes the δ-globin coding sequences, the δβ intergenic region as well as the β-globin gene promoter, causing a δβ thalassemia with 5.2% HBA.

Discussion/Conclusion: Delta beta-thalassemia is one of the causes of hereditary persistence of Hb F (HPFH). In this case, a genotype-phenotype correlation proved to be essential to make an accurate diagnosis in a predictable case of severe beta thalassemia.

The δβ deletion resulted in a hybrid gene, with the promoter region being δ and the coding region β. A normal β chain is synthesized, but in low amounts, and high HbF level is responsible for the good condition of this patient. This “Centaur” hemoglobin can be a good model to the genetic therapy when the main objective is to increase patients HbF level.

Topics: 004–Clinical, public health and epidemiological studies

V. Gutierrez Valle¹, P. Kountouris², S. Tamana², I. Labidi³, C. Diot Lefebvre¹, S. Reidel¹, F. Sophocleous², B. Gulbis⁴, M. Manu Pereira¹

Vall d'Hebron University Hospital, Group of Translational Research in Cancer and Blood disorders in Children¹, T he Cyprus Institute of Neurology and Genetics², Hôpital Universitaire de Bruxelles³, Hôpital Universitaire de Bruxelles, Univer sité Libre de Bruxelles, LHUB-ULB⁴

Background: Demographic and epidemiological data on rare anaemia disorders (RADs) are currently fragmented in different repositories. When national or local RAD registries exist, interoperability between them is not yet in place, the data pool doesn't reach a critical amount of data. The aim of this study was to provide an adequate and secure environment for data collection on RADs throughout the EU member states.

Methods: The Rare Anaemia Disorders European Epidemiological Platform (RADeep; radeepnetwork.eu) was implemented in the framework of the European Commission strategy on rare disease patient registries¹. RADeep is an initiative endorsed by the European Reference.

Network-EuroBloodNet. Main objectives² were 1) to promote the standards for patients’ registries interoperability, to collect and describe epidemiological data (i.e., haemoglobinopathies, enzymopathies, red blood cell membrane disorders, congenital dyserythropoietic anaemia, and iron related anaemia disorders), 2) to secure good standards and quality on data sharing, 3) to determine bias on patients' distribution on the clinical evolution and complications of the diseases.

Results: Ethics committee approval was obtained (N° PR (AMI) 427/202). A model of informed consent³ of transfer or re-use of pseudonymised data to RADeep, and a transfer agreement model between data providers and RADeep were developed. A consortium agreement documented the roles, rights, and responsibilities among parties. A data access committee was established as well as an application form for data request. Data elements, either mandatory or optional, are included in 15 subgroups with main topics: demographics, diagnosis, clinical manifestations, treatments, laboratory tests, disability, and offspring. Table 1 reports the set of mandatory data elements related to treatments. International codification schemes are used, i.e., Orpha-code for diagnosis. The platform developed has a modular architecture, is password protected and has encryption of sensitive data. A demo platform exists (demo.radeep.eu). Data entry can be done directly through RADeep or by batch transfer of data from local/national registry. A RADeep project developed in Research Electronic Data Capture can be provided to data contributors. Ongoing collaborations are with 13 countries of which four have national registries (Belgium, Spain, Germany and Sweden), two have national networks (Italy, The Netherlands) and seven with health care providers building national initiatives (Cyprus, Denmark, France, Greece, Portugal, Norway, and Ireland). A total of 1222 patients, 1067 (87%) with SCD and 155 (13%) with thalassemia, have already been included. Total number of patients expected to be included from current collaborations are 13,093 patients, 3713 (28%) with thalassemia and 9380 (72%) with SCD.

Conclusion: RADeep is an interoperable centralised web-based platform. The platform has been developed based on the strategy of the European Commission on rare diseases. It is already implemented and collaborations with data providers are ongoing. The collection of standardised and high-quality data expected through RADeep will enable data-driven healthcare planning and will allow large-scale, multi-centre research studies through data pooling across Europe.

Acknowledgement

RADeep has conducted this study with the support of EuroBloodNet Association through grants from Novartis Pharma AG, Agios Pharmaceuticals Inc and Bristol-Myers Squibb.

Topics: 007–Health services and outcomes research including psychology

S.R. Wilson¹, A.M. Yates², J. Moon², L. Lombard², L. Vinals³, J.A. Valbuena-Fajardo³, S. Harricharan³, M. Rizzo³

Division of Hematology, University of North Carolina at Chapel Hill¹, Agios Pharmaceuticals², Cytel Inc.³

Background: Despite decades of research, there is no standard biomarker in clinical use that accurately predicts vasoocclusive crises (VOC), end-organ damage, and mortality in sickle cell disease (SCD).

Aims: A systematic literature review (SLR) was performed to provide an overview of biomarkers reported in conjunction with clinical or health-related quality of life (HRQoL) outcomes in SCD and summarize evidence of their statistical association.

Methods: Searches (1 January 2017 to 11 April 2023) were conducted in Embase, MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews databases. Observational and interventional studies published in English reporting on biomarkers and clinical/HRQoL outcomes in patients with SCD were included. Records were screened by two independent reviewers. Data was extracted by one reviewer and validated by a second.

Results: In total, 237 studies reporting on biomarkers and clinical/HRQoL outcomes in patients with SCD were included (Figure 1). The most frequently reported biomarkers (>25 studies each) were hemoglobin (Hb), lactate dehydrogenase (LDH), white blood cell (WBC) count, total bilirubin, and reticulocyte count. These biomarkers were most often reported with the occurrence of VOC, acute chest syndrome, stroke, renal disease, priapism, leg ulcers, and death. Of the 237 included studies, 74 (31%) reported measures of statistical association between biomarkers and clinical/HRQoL outcomes; sample sizes ranged from 18 to 2,553. Except for one randomized controlled trial, all measures of statistical association came from observational studies. Most of these studies (45/74 [61%]) reported multivariable analyses with baseline age, sex, Hb, and SCD genotype as the most frequent covariates. Eighteen of 74 (24%) studies reported measures of association between biomarkers and the occurrence of VOC or composite endpoints including VOC. While the definition of VOC varied across studies, lower Hb, lower fetal Hb (HbF), and higher WBC were most frequently significantly associated with acute pain episodes requiring emergency room visits or hospitalizations. Twelve studies reported on biomarkers associated with mortality; lower Hb and higher alkaline phosphatase were significantly associated with mortality in 2 studies each; higher plasma free Hb, lower HbF, higher WBC count, higher total nucleated cell count, higher LDH, blood urea nitrogen >20 mg/dl, total bilirubin >103 μmol/L, and albumin <35 g/L were significantly associated with mortality in 1 study each. A single crosssectional study of 123 children with SCD from Oman provided statistical measures of associations between biomarkers and HRQoL outcomes. The study reported HbF levels and WBC counts were positively and negatively associated, respectively, with total HRQoL scores on the PedsQL when controlling for age, gender, spleen status, and hydroxyurea use.

Conclusion: Despite the multiple biomarkers measured in SCD, a clear consensus on their real-world utility to predict longterm morbidity and mortality is lacking. However, this SLR identified Hb and HbF as the biomarkers most frequently reported to be significantly associated with VOC and mortality. Additional studies are needed to better understand the role of biomarkers in SCD and their association with HRQoL.

Topics: 007–Health services and outcomes research including psychology

H.J. Joseph¹, L.C. Churande¹, R.M. Mutagonda¹, M.Y. Mbonea¹, E.B. Balandya¹, A.J. Jonathan¹, F.U. Florence Urio¹

MUHAS¹

Background: Sickle cell disease (SCD) is the most common hemoglobin disorder in the world. Africa has the highest burden of (SCD) accounting for up to 75% of the 300,000 SCD births worldwide each year. Despite treatment advancement most patients with SCD are still admitted for various reasons, pain being the leading cause of admission among adult patients with SCD. About 90% of hospital admissions of patients with SCD are attributed to painful events.

Aims: This study aimed to determine factors associated with inadequate pain control among patients with SCD presenting with a painful event at Mwananyamala Regional Referral Hospital (MRRH) and Muhimbili National Hospital (MNH) Dar es Salaam Tanzania.

Methods: This cross-sectional study was conducted at (MNH) and (MRRH) in Dar es Salaam Tanzania. A total of 390 patients with SCD who presented with painful events aged eight years and above were enrolled in the period of six months. A structured questionnaire was used to collect data on participants' socio-demographic characteristics and clinical parameters. The pain index score tool was used to assess the level of adequate pain control. Data was analyzed using software SPSS version 23. The results of the difference were considered statistically significant when the p-value was less than 0.05.

Results: A total of 390 patients with SCD, age 8 years and above were analyzed with a mean age (±SD) of 15 (±6) years. Male to female ratio was 1:1, majority of the patients (94.9%) were single about half (58.2%) had attained at least primary education. More than half of the patients (57.4%) come from Dar es Salaam. Majority of patients (91.0%) were within steady-state haemoglobin with more patients having less than three pain episodes per year (77.9%). Most patients presented to the hospital with mild pain (64.6%) and were on Hydroxyurea (62.3%). Most patients were recruited from outpatient clinics (88.2%). One third of patients had inadequate pain control while 61% attained adequate pain control. Factors that were associated with inadequate pain control included receiving initial pain management in other health centers aOR (95% CI) = 2.5 (1.5–4.5), P = 0.001, residing outside Dar-es-Salaam aOR (95% CI) = 1.74 (.1–2.9), p = 0.03. Other factors associated with inadequate pain control included presenting to the hospital with moderate pain aOR = 2.2, 95% CI (1.3–3.8), p = 0.006 and presenting to the hospital with a fever by aOR (95% CI) = 3.8 (1.1–13.9), p = 0.04.

Conclusion: One-third of patients received sub-optimal pain control. Factors significantly associated with inadequate pain control were residing outside Dar-es-Salaam, receiving initial pain management from other health care facility, presenting to the hospital with moderate pain, and having a fever.

Topics: 001–Basic and translational

M.L. Nugent¹

Genomics England¹

Background: There are about 17,000 individuals with sickle cell disorder (SCD) in the UK and the prevalence is rising. Almost all clinical manifestations and complications are extremely variable between affected individuals. Research is lacking to understanding the causes of this variability and help patients through personalised prognoses, targeted therapies, or the identification of novel drugs and therapies [1].

Aims: Diverse Data is a new programme at Genomics England that aims to reduce health inequalities and improve patient outcomes in genomic medicine for underrepresented communities. Through our national sickle cell genomics programme, we are working in close partnership with the Sickle Cell Society UK and James Lind Alliance to cocreate a top ten future research priorities set by those living with the condition and those that support them. The JLA has a published, trust-building methodology that cocreates future research priority areas with patients and healthcare professionals for health conditions. We will engage a range of healthcare professionals and people in communities living with sickle cell to support them to choose where future genomics research needs to focus in order to being maximum benefit to patients.

Methods: Through this process, we will 1) conduct desk research to identify evidence uncertainties, 2) engage patients and healthcare professionals, form an advisory group and refine these gaps 3) deliberate and agree patient-centred future priority areas 4) publish and rally future research. Throughout we will engage further patient groups in the community to refine what we expect to be large evidence gaps, and develop educational materials and resources to improve their awareness of genomics in research and healthcare.

Results: Here we present how this priority setting partnership was established and our process for building trust through research priority setting and engagement. We will also present the future direction, priorities and key challenges for building and sustaining trust.

Conclusion: As part of our wider sickle cell genomics programme, the priority setting partnership will publish a future top ten research priority areas set by patients and healthcare professionals. We aim to engage researchers and funders to be prepared to respond to these priorities in order to bring maximum benefit to patients through future research.

Topics: 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

H.M.H. Haji¹, F.U. Urio¹, E.B. Balandya¹, S.N. Nkya¹

SPARCO Tanzania/MUHAS¹

Background: Fetal hemoglobin (Hb F) is predominantly present in F cells, which are red blood cells containing measurable amounts of fetal hemoglobin. In sickle cell disease (SCD), the level of Hb F has a significant impact on the disease's clinical course. Individuals with higher Hb F levels generally experience a less severe course of the disease. However, some patients with high Hb F levels can still have severe symptoms. This diversity can be attributed to the concentration of Hb F distributed per F cell (Hb F/F cell). Therefore, it is hypothesized that the amount of Hb F /F cell is crucial in determining the clinical outcome of SCD rather than the overall level of Hb F and the number of F cells.

Broad objective: To determine the association between fetal hemoglobin parameters and disease severity in SCD patients in Tanzania.

Methodology: A retrospective cohort study involved secondary data analysis of 92 SCD individuals aged 6 years and above who were at their steady state and not on hydroxyurea, conducted at the Muhimbili University of Health and Allied Sciences between September 2022 and February 2023. This study was nested within the ongoing parental study, titled “Comparative study of Sickle Cell Disease (SCD) modifiers in Ghana, Nigeria and Tanzania; investigation of fetal hemoglobin parameters and clinical manifestation”.

Hematological and social demographic data were obtained from Sickle Pan-African Research Consortium (SPARCO) Tanzania registry and Hb F/F cell was calculated by the formula; Hb F /F cell = (Hb F% x MCH pg) /F cell%.

STATA version 15 was used for analysis, categorical variables were presented as proportion and continuous variables were presented as median and IQR. Mann Whitney test was used to compare Hb F parameters among age and sex, and the association of Hb F parameters and termination events and recurrent events was examined using univariable binary logistic regression and univariable ordinal logistic regression respectively. A p-value of <0.05 was considered statistically significant.

Results: Among the 92 SCD patients, 53 (57.4%) were below 18 years, the median age was 16 years (IQR: 10, 21) and male to female ratio was 1:1. The levels of Hb F parameters were generally low, below the cut of points of high levels used in this study with median levels of 4.45% (IQR: 2.33, 7.15), 21.60% (IQR: 13.20, 32.45), and 5.63 pg (IQR: 4.00, 7.98) respectively. Males had significantly higher levels of Hb F/F cell compared to females, with a median of 6.44 pg (IQR: 4.3, 9.5) and 5.34 pg (IQR: 3.5, 6.5) respectively (p = 0.004). Also, we observed that as the percentage of Hb F and F cells increased, there was a significant reduction in the risk of receiving multiple blood transfusions (p = 0.016, 95% CI: 0.802–0.969) and (p = 0.02, 95% CI: 0.947–0.995) respectively. However, Hb F/F cell level had no significant association with disease severity (termination events).

Conclusion: Hb F and F cells level remain a significant predictor of sickle cell events (blood transfusion) while Hb F/F cell showed no statistically significant association with disease severity in SCD patients in this cohort.

Recommendation: Larger sample size study to increase statistical power and enhance the ability to detect significant associations. Utilize a prospective study design to collect data over a specific period, allowing for the examination of continuous trends and assessment of connections between variables.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

M.Y. Yassin¹, N.E. Elenga²

Hamad Medical Corporation¹, CH Cayenne²

Background: Sickle cell disease (SCD) is a rare genetic blood disorder affecting millions of people around the world. Oxidative stress is one of the key contributors to the pathophysiology of SCD and related complications. L-glutamine (L-gln) has been shown to play an important role in the regulation of oxidative stress (1). In a Phase 3 clinical trial, L-gln demonstrated significant reduction in SCD acute complications with or without hydroxyurea (HU) use, over a 48-week period (2). Renal function (RF) impairment is a common complication of SCD and can have serious consequences for patients. Multiple studies have demonstrated a high prevalence of RF impairment in SCD patients and associated with an increased risk of mortality (3). A recent long-term real-world study demonstrated that l-gln reduced the acute complications and the hemolysis markers of 19 patients after 30 months of treatment (4). In this observational study, we are reporting the long-term RF evolution of 6 patients treated by L-gln for 30 months.

Aims: To explore the RF evolution of SCD patients treated with pharmaceutical-grade L-gln in pediatric and adult patients with SCD at follow-up time points of 12 and 30 months after initiation of treatment.

Methods: Six patients (1 pediatric and 5 adults), with confirmed diagnosis of SCD (HbSS genotype) were treated with L-gln oral powder (~0.3 g/kg) twice daily for 30 months. 4 patients were from Qatar with the Arab-Indian haplotype and 2 patients were from French Guiana with the African haplotype. Clinical events and laboratory parameters were collected or measured at baseline, 12 and at 30 months. Baseline measures for VOCs was collected for the 12 months prior to L-gln initiation.

Results: Four patients (all adults) were from Qatar, whereas two patients (one pediatric and one adult) were from French Guiana. 100% compliance was reported for all patients. The study demonstrated that all patients who ceased to show any VOCs, at both 12 and 30 months of treatment with L-gln, also showed significant improvements in blood parameters: the mean (SD) increase in hemoglobin concentrations was 0.48 (0.64) g/dL from baseline to 12 months while the mean (SD) from baseline to 30 months was 1.47 (0.77) g/dL. Mean (SD) reticulocyte counts and LDH levels decreased from baseline to 120 weeks (mean [SD] change from baseline to 120 weeks, reticulocyte counts: −88.83 [181.70] x 10⁹ cells/L; LDH levels: −408.00 [344.65] U/L). Regarding the RF, the eGFR levels reduced from baseline to 12 and 30 months (mean (SD) change from baseline to 12 months: −5.33 [15.32] mL/min/1.73 m²; 30 months: −12.17 [22.08] mL/min/1.73 m²). There were improvements observed in albumin creatinine ratio (ACR) from baseline to 12 months (mean [SD] ACR: −7.63 [11.33] mg/g) and 30 months (mean [SD]

ACR: −17.62 [26.44] mg/g) consistent with an improvement in albuminuria from baseline to 12 and 30 months (mean (SD) change from baseline to 12 months (−3.53 [2.88] mg/L; 30 months: −8.03 [7.15] mg/L). Improvements were also seen in both serum creatinine and urine creatinine levels from baseline to 12 months (mean [SD] serum creatinine: −0.50 [3.39] micromol/L; urine creatinine: −0.35 [0.62] micromol/L).

Summary/Conclusion: This real-world study showed that, along with significant improvement in clinical outcomes and hemolysis, Lgln improved RF of six SCD patients after 30 months of treatment. Moreover, this study highlighted that treating SCD patients for 30 months with L-gln was safe and did not alter patient RF.

Topics: 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

A.R.C. Cole¹, Y. Carroll¹

St. Jude Children's Research Hospital¹

Background: Sickle cell trait (SCT) is part of newborn screening (NBS) in all fifty states in the United States. SCT is the carrier status for sickle cell disease (SCD). In the United States, there are 3 million individuals with SCT. SCT has been linked to chronic renal disease, splenic infarction, venous thromboembolism, exertion related injury, and death. Counseling on the inheritance risk for SCD is imperative for parents of infants screened positive for SCT on NBS. However, there is a scarcity of qualified nurses to provide trait education. St. Jude Children's Research Hospital (SJCRH) is the sickle cell center for Western Tennessee (W TN) with a catchment area of 21 rural counties. SJCRH partners with W TN rural health departments (RHD) for trait counseling. SJCRH has provided in person training to RHD nurses in W TN for 20 years. Due to COVID, in person training was no longer viable. Therefore, SJCRH conducted an educational landscape assessment with RHD nurses to determine methods to increase knowledge and counseling rates. This assessment and literature search revealed nurses wanted an easily accessible training leading to the development of e-learning strategies. This e-learning program has implications beyond Tennessee and will provide a standardized evidence-based program for all nurses providing trait education after the pilot program.

Aim: The purpose of this project is to develop an e-learning training resource for nurses counseling parents of newborns with sickle cell trait and other hemoglobin traits.

Methods: SJCRH conducted a landscape assessment with RHD nurses. A confidence survey was given to RHD nurses to assess their confidence level counseling families of newborns screened positive for hemoglobin traits. A literature review was conducted to determine the most efficacious way to provide trait counseling. Data was analyzed to determine current RHD nurse trait counseling completion rates in W TN.

Results: Eleven of the 21 RHD nurses responded to the landscape assessment. The average confidence rate for hemoglobin trait counseling among RHD nurses was 2.7 out of 5. Assessment of documented counseling from July 2021 to December 2021 revealed 49.1% of families with newborns identified with hemoglobin traits were counseled by RHD nurses.

Conclusion: Based on the results and literature search, interactive e-learning modules were identified as an alternative to in-person training. This led to the development of trait counseling e-learning modules in an interactive format that nurses can complete in 15-20 minutes. Module topics include an overview of trait counseling, the inheritance risk of sickle cell, and hemoglobin C, E, and alpha thalassemia traits, and possible complications. Each module will include a pre and a post-test assessment.

Documentation of hemoglobin counseling will be compared with pre-program rates.

Topics: 007–Health services and outcomes research including psychology

B.A. Poku¹, K.M. Atkin², J. Grainger³, I. Thomas⁴, S. Kirk⁵

University of Nottingham¹, University of York², Royal Manchester Children's Hospital³, Sickle Cell Society⁴, Unive rsity of Manchester⁵

Background: Studies identify fatigue as the most frequently experienced symptom of sickle cell disease (SCD), with fatiguerelated concerns expressed more often than those associated with vaso-occlusive crises. In children/young people (CYP) with SCD, chronic or persistent fatigue is experienced as having limited energy capacity for activities of daily living. It is significantly associated with poorer quality of life, increased pain crises, hospital admissions, missed school days and depressive symptoms. Fatigue also impacts family, social, and educational participation and limits CYP's educational, career and biographical pursuits. Fatigue is stigmatising and a major threat to ‘normalcy’ too. It is identified as the most restrictive, disruptive, and disabling aspect of growing up with SCD, threatening CYP's capacity to build the personal and social capital necessary for independence. Yet, there is limited understanding of how this symptom is managed.

Aim: To explore how fatigue is managed in CYP with SCD in England.

Methods: This exploratory qualitative research interviewed 12 CYP with SCD aged 12–23 years, five parents and ten healthcare professionals. Eligible participants were recruited using convenience sampling from an NHS Trust and through SCD-focused charities and social media. Data were collected using audio-recorded semi-structured or art-elicitation interviews. Interviews were transcribed and analysed using coding, constant comparison, and thematic categorisation.

Results: The research identified four main themes relating to fatigue management: clinical management, self-management, management challenges and management recommendations. Clinically, there was no defined provision for fatigue in SCD services. It was not considered in health assessments/reviews, health consultations, patient and parent education or transition services. This invisibility of fatigue constrained CYP and caregivers in raising the symptom with care providers, and they were left to rely on their own experience to manage fatigue. They employed various strategies to manage energy (e.g., frequent rest, activity pacing, hydration, healthy diets, multivitamin supplementation, adequate ventilation, solitary activities and social withdrawal). Strategies seemed to come from everyday experience and ‘common sense’. Their ‘effectiveness’ was unclear. Self-managing fatigue meant making daily decisions on how best to use limited energy, strict prioritisation of energy use and considerable self-discipline. Several challenges constrained fatigue management. At the clinical level, health professionals' lack of understanding of SCD fatigue and how to help CYP and the absence of assessment tools explained the lack of attention. At the patient level, fatigue self-management seemed constrained by knowledge and financial limitations, unsupportive social networks/environments, and poor housing. Fatigue management recommendations highlighted (1) incorporating fatigue impact in SCD public education, service provision and professionals' education/training; (2) developing care pathways for fatigue that involve fatigue assessment and self-management interventions; and (3) measuring fatigue as an outcome in evaluating current and future therapies/treatments.

Conclusion: There needs to be more recognition given to fatigue in SCD management. Fatigue management approaches are urgently needed to improve the quality of life and support the development of CYP with SCD.

Topics: 001–Basic and translational

K. Benmoussa¹, M. Beraud¹, H. Fabre¹, A. Bah¹

Terumo BCT Europe¹

Background: In France, Sickle Cell Disease (SCD) is the first rare disease and the most important genetic disease, with 19 800–32 400 patients diagnosed in 2016 and 1:714 SCD newborn in 2019.i SCD is caused by a single mutation on the β-globin gene, resulting in abnormal falciform hemoglobin, called Hemoglobin S (HbS). SCD patients face several severe acute and chronic complications, including stroke, acute chest syndrome (ACS), painful vaso-occlusive crisis (VOC), organ failures and a high risk of infections.ii

Transfusion remains a reference treatment for SCD patients worldwide. In France, 1,500 patients were transfused at least once in 2010,iii with the objective to treat symptoms and to prevent complications. There are three types of transfusion: simple transfusion (ST), manual red blood cell exchange (mRBCX) and automated red blood cell exchange (aRBCX). Over the world, several studies regarding aRBCX reveal a its better efficacy, especially in chronic indications, to achieve a percentage of HbS of 30% or less, and control blood viscosity, but also to treat the main SCD complications and manage iron overload.^4,5 However, its use is limited by vascular access and some contraindications, but also from a logistics aspect, including blood bags availability, cost of the device, staff training, and medical personnel availability.^6,7,8

In France, SCD patients' pathway remains unclear. Furthermore, we observe a certain disparity between French HAS (Haute Autorité de Santé) guidelines and clinical practice. These guidelines differ from guidelines from other countries, like ASFA in US and NICE in UK, in some aspects, especially regarding the categories of recommendation for some acute (acute stroke, severe ACS) and chronic (stroke prophylaxis, repetitive painful VOC, pregnancy) complications.

Aim: We, Terumo BCT, organized an Ad Board in France, in the presence of 9 medical and scientific experts in SCD. This meeting occurred in February 2023, and aimed to have a better understanding of SCD Key Opinion leaders (KOLs) clinical practice, the alignment with guidelines and explain the disparities we can observe in SCD management between centers and regions.

Methods: The advisory group was composed of SCD expert, and Terumo BCT Medical Affairs representants to discuss clinical practice and the impact of guidelines on aRBCX treatment.

Results: Based on their clinical experience, all the experts highlighted the higher efficacy of aRBCX in the management of several symptoms of the disease. The experts and Terumo BCT agreed on the need to generate strong data to prove aRBCX benefits compared to other transfusion techniques and the need to update guidelines.

Summary/Conclusion: This meeting allowed us to collect the feedback and clinical experience of 9 KOLs regarding options currently available for patients with sickle cell disease (SCD) in France, especially transfusion therapies and aRBCX. Terumo BCT and the nine KOLs agreed on the need to generate strong data on aRBCX efficacy in comparison with other transfusion technics. This data generation seems to be crucial to allow French guidelines reevaluation and to determine in which complications aRBCX could be more beneficial than mRBCX or ST.

All the experts concluded by agreeing that transfusion programs should remain the most clinically appropriate treatment for SCD patients in the coming years.

Topics: 004–Clinical, public health and epidemiological studies

M. Brito¹, C. Ginete¹, C. Cruz¹, M. Mendes², F. Simão³, F. Fernandes¹, J.N. Vasconcelos⁴

H&TRC, ESTeSL, IPL¹, Hospital Materno Infantil Dr Manuel Pedro Azancot de Menezes², Maternidade Lucrécia Paim³, Centro de Investigação em Saúde de Angola, Caxito⁴

Background: Pregnancy in Sickle Cell Disease (SCD) poses a heightened risk of severe complications, including eclampsia, pre-eclampsia, strokes, and even mortality. Therefore, it is of utmost importance to maintain continuous medical surveillance throughout pregnancy.

Aims: The study aimed to identify pregnancy complications in women with SCD, with a particular focus on factors contributing to maternal mortality at Lucrecia Paim Maternity Hospital, Luanda, Angola. Moreover, we support the obstetric consultations contributing to the reduction of both mortality and morbidity rates associated with SCD.

Methods: Pregnancy monitoring includes analysis of clinical history and incidents (number of hospitalizations, blood transfusions, occlusive painful crisis, and other clinical complications), hematological and biochemical analysis, transcranial doppler to assess cerebral hemodynamics and genetic analysis (confirmation of the diagnosis, genotyping of four SNPs in the β-cluster to assess the haplotype, and evaluation of the presence of the 3.7 kb deletion of the α-globin gene).

Results: As of now, 125 women undergone obstetric consultations, ranging in age from 17 to 40 years old (with a mean age of 26.1 ± 5.7). Among the patients, 76.5% have previously received blood transfusions (75 out of 98), 95.9% have been hospitalized (94 out of 98) due to complications from sickle cell disease (SCD), and 19.1% (19 out of 99) have experienced at least one miscarriage. Regarding the genetics, the most prevalent haplotype in this population is the CAR/CAR haplotype (68.2%), which is typically associated with a more severe prognosis. The CAR/Atypical haplotype follows in prevalence at 14%. Additionally, 10.3% of the population is homozygous for the 3.7 kb thalassemia deletion, while 42.2% are carriers. This deletion has an impact on the hematological and clinical characteristics of sickle cell disease patients, resulting in less severe phenotypes. Preliminary results reveal significant effects of both alpha thalassemia co-inheritance and haplotypes on hematological values (Table 1). In the case of alpha thalassemia, individuals homozygous for the deletion exhibited the highest red blood cell count (RBC) (3.13 ± 0.44 × 106/µL) and hematocrit (HCT) values (23.60 ± 3.39%), along with lower mean corpuscular hemoglobin concentration values (33.48 ± 1.76 pg) compared to individuals without the deletion, indicating a potential attenuation of anemia in those with the deletion. Moreover, homozygous individuals for the deletion showed significantly higher eosinophil levels (3.11 ± 2.26 × 106/µL) when compared to individuals heterozygous for the deletion and those with the 4 alpha copies. Regarding haplotypes, the “CAR/CAR” group displayed higher HCT (20.20 ± 3.51%) and hemoglobin (HGB) (7.00 ± 1.08) levels compared to the other haplotypes considered.

TCD time-averaged mean of the maximum velocity at the middle cerebral arteries ranged between 41 to 132 cm/s (mean 84 cm/s) and peak systolic velocity from 61 to 180 cm/s (mean 129 cm/s). At the basilar artery level, TAMMx obtained were between 29 to 102 cm/s (mean 52 cm/s) and PSV ranged from 43 to 141 cm/s (mean 78 cm/s).

Conclusion: These findings have the potential to positively impact medical care for this vulnerable population, reducing risks and improving obstetric outcomes in pregnant women with SCD, not only in Angola but also in other resource-limited settings.

Table 1. Variables significantly associated (ANOVA).

Topics: 007–Health services and outcomes research including psychology

I. Kanyoke¹, F. Hayford Blankson², D. Dwuma-Badu¹, A. Peprah¹, I. Odoom-Brown¹, N. Harith¹, E. Nkansah¹, M. Ampadu¹, B. Goka³, J. Welbeck³, I. Odame⁴, C. Segbefia³

Korle Bu Teaching Hospital¹, School of Public Health, College of Health Sciences, University of Ghana², Korle Bu Teaching Hospital /University of Ghana Medical School³, Centre for Global Child Health, SickKids⁴

Background: The goal of newborn screening for sickle cell disease (NBS for SCD) is to ensure that infants with the disease begin comprehensive follow-up care within the first few months of life. However, barriers to care include parents refusing to accept the initial positive diagnosis or failing to attend the clinic after the initial visit.¹ This has dire implications, particularly in sub-Saharan Africa, where under-5 mortality rates for SCD are very high.

Aim: To explore parents' experiences following receipt of positive NBS for SCD test results at a teaching hospital in Ghana.

Methods: Approval for the study was obtained from the Korle Bu Teaching Hospital (KBTH) Institutional Review Board. Using purposive sampling, data were collected using semi-structured individual guides to interview parents of children identified through newborn screening, and attending the pediatric SCD clinic at KBTH, the major referral health facility in Ghana. Questions were categorized into 3 main areas: parents’ reactions to initial positive results, parents’ responses to in-clinic counselling, and parents’ attitudes towards follow-up clinic care. Interviews were conducted face to face either in English or a local dialect (Twi) after which they were transcribed verbatim. Data were analyzed using NVivo software to identify relevant codes which were organized into themes and sub-themes.

Results: Twenty four mothers and one father were interviewed between November 2021 and January 2022. The ages of their children ranged from 7 months to 3 years 9 months. Seventeen (68%) of the parents were married, 5 (20%) had more than one child enrolled in the clinic, and 10 (40%) reported that they or their partners had SCD. The 5 themes identified were: (i) emotional response after disclosure, (ii) decision to share results, (iii) care and management of newborns at home, (iv) knowledge of genetics of SCD, and (v) adherence to routine follow-up. Positive test results elicited worry, surprise, or shock in majority, especially those with no previous knowledge of or experience with SCD. Most parents had received counselling and educational information on home care of their screen-positive newborns and danger signs of SCD. The decision to share test results with others was influenced by fear of stigmatization. While desiring to see their babies remain healthy, parents defaulted on clinic visits due to financial difficulties and the COVID-19 pandemic.

Conclusion: Knowledge of SCD and personal experience influenced parents’ reactions to initial positive NBS for SCD test results. There is need for more education about SCD among the general population and strengthening measures which provide psychological and socioeconomic support for families attending the KBTH clinic. Promoting a community-based model for SCD care through training of primary healthcare workers would help reduce geographic and financial barriers to healthcare access.

Topics: 007–Health services and outcomes research including psychology

R.H. Lawrence¹, A. Griffin², J. Cornette³, M. Robinson³, P. McManus⁴, P.H. White⁴, C. Courtland⁵, L. Noonan⁵, S. Mabus⁵, L. Starnes⁶, A. Coleman³, J. Nu'Man⁷, E. Saah⁸, W. Smith⁹, I. Sisler⁹, R. Seavers¹⁰, I. Osunkwo¹¹, P.C. Desai³

Jiann Ping Hsu College of Public Health, Georgia Southern University¹, Children's Hospital Los Angeles, Keck School of Medicine at the University of Southern California², Levine Cancer Institute, Atrium Health³, The National Alliance to Advance Adolescent Health/Got Transition⁴, Center for Advancing Pediatric Excellence, The Levine Children's Hospital, Atrium Health⁵, Office of Children's Medical Services Care Plan and Specialty Programs, Florida Department of Health⁶, Sickle Cell Foundation of Georgia⁷, Emory University⁸, Virginia Commonwealth University⁹, Sickle Cell Association of Kentuckiana¹⁰, Novo Nordisk A/S, Rare Disease Division,¹¹

Background: The Sickle Cell Trevor Thompson Transition Project (ST3P-UP) is a 14-site study comparing a structured education-based transition program with/without peer mentoring to improve acute care utilization during sickle cell disease (SCD) transition. Each site was required to engage a community-based organization (CBO) as an equal partner on the research team. We established the concept of “the Site Triad” comprised of the adult and pediatric provider teams, the CBO, and a patient. The primary focus of the Triad was to improve access to and enhance the quality of care during transition.

The ST3P-UP quality improvement (QI) collaborative was formed to engage all 14 site Triads in using the Got Transition® Six Core Elements of Health Care Transition¹ (6CE) and QI methods to implement, locally, a standard transition process. QI meetings occurred monthly (Nov 2018-Dec 2022); participants received a change package with resources, coaching on QI methods and discussed practical ideas for continuous transition program improvement.

Realizing Triad engagement was key to the sustainability of site-specific QI strategies, an engagement QI project was developed to quantify and improve engagement within each Triad.

Aim: The aim for the Engagement/QI study was, "Fully collaborative relationships between providers, patients and CBOs have demonstrated improved clinical outcomes for SCD patients. We aim to improve the transition outcomes of EA-SCDs by strengthening the collaborative relationships between each segment of the Triad by Dec 2022".

Methods: We administered a baseline Engagement QI survey to gauge perceived levels of engagement within the Triad on a Likert scale (1–5, 5 = strongly agree) based on three primary drivers of engagement (DE) (psychological safety, psychological meaningfulness, and psychological availability) and on triad inclusion (TI; fairly implemented practices and collective commitment to learning). The Engagement QI project was launched in July 2022 with a series of didactic sessions focusing on engagement topics during monthly QI collaborative meetings. A post engagement QI survey was administered in Dec. 2022. Means and standard deviations summarize the survey scores. Pre- vs. post-survey results were compared with Wilcoxon signed rank tests.

Results: Complete pre- and post-survey scores were available from 44 respondents (30% CBO, 39% w PIs, 32% transition coordinators). The overall Triad engagement score increased over time (mean 7.8 + 1.2 vs. 8.2 + 1.0, p = 0.004).

The DE subscale scores also improved significantly over time (mean 3.9 + 0.6 vs. 4.1 + 0.5; p = 0.032). Increased psychological meaningfulness scores contributed the most to the improvements in the DE score (mean 4.0 + 0.6 vs. 4.2 + 0.4; p = 0.025). Psychological safety was also notably improved (mean 4.1 + 0.6 vs. 4.3 + 0.6; p = 0.051). Lastly, the TI global scale as well as TI subscales all showed significant improvement (global TI 3.9 + 0.7 vs. 4.1 + 0.6 p = 0.001; fairly implemented practices: 3.7 vs. 4.0, p = 0.001; collective commitment to learning: 3.9 vs. 4.2, p = 0.001).

Summary/Conclusion: In conclusion, the QI intervention significantly improved DE, highlighting the effectiveness of combining engagement and QI methods in enhancing stakeholder engagement for community-based projects. The data emphasizes the essential role of intentional collaboration within the Triad, with a need for longer follow-up to confirm the sustainability of engagement.

Topics: 007–Health services and outcomes research including psychology

C. Jaja¹, R.W. Gibson², J. Eden-Hotah³, S. Ibemere⁴, S. Abazu¹

University of South Florida¹, Medical College of Georgia- Augusta University², Faculty of Nursing, College of Medi cine and Allied Health Sciences³, Duke University⁴

Background: Sickle cell disease (SCD) is a chronic disorder of growing global significance. Early SCD diagnosis in neonates demonstrably decreases morbidity and mortality rates considerably in the first 5 years of life through linkage to prevention and treatment for disease comorbidities. Universal newborn screening (NBS), an evidence-based practice, is the initial step for comprehensive care for SCD. However, the high costs of conventional laboratory methods have hampered sub-Saharan African (SSA) nations’ ability to implement NBS programs. Emergent point-of-care tests (POCTs) for SCD address many of the structural and cost barriers to NBS as noted in recent feasibility studies. The objective of this study is to provide an inventory of key considerations for the implementation of SCD-POCT NBS programs based on current evidence.

Methods: A systematic literature search of online databases, namely PubMed, CINAHL, Scopus, Embase, and Web of Science was performed in June 2023. Inclusion criteria were established, which included original studies that addressed the following questions: (1) what is the analytic, clinical validity, and utility of SCD-POCTs, and (2) what are the ethical, legal, and social implication (ELSI) issues associated with the results of screening and initiation and implementation of SCD-POCT NBS program in sub-Saharan Africa? Data were extracted in standard form from all studies according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Recorded information included first author, year of publication, location, study design, sample size, study population, scope and method of testing, outcome measures, key results, and strengths and limitations of the study.

Results: The fourteen articles identified explored the diagnostic accuracy and clinical utility of two commercially available POCTs, with all studies showing excellent performance for the HemoTypeSC™ and Sickle SCAN™ tests evidenced by high sensitivity and specificity even in the presence of fetal hemoglobin when compared to gold standard laboratory-based assays. Assessment of readiness for adoption of POCTs for SCD NBS was made against the background of fragile and economically stressed healthcare systems. Key ELSI findings centered on distributive justice issues such as the availability and accessibility of short-term and long-term follow-up services. Knowledge about SCD and NBS was generally low among parents, necessitating public engagement, community awareness and education about NBS, and designing appropriate informed consent to minimize psychosocial harms and instill trust in program implementation.

Conclusions: SCD-POCT NBS may optimize the health and well-being of Africa's children. The findings of this systematic review suggest that implementing SCD-POCT NBS will require a nuanced approach with key considerations regarding the capabilities of state health systems, associated health economic implications, and broader familial and community issues associated with screening for a genetic condition and the ethical values of African communities. It will be essential to rigorously evaluate these considerations to ensure that programs evolve to maximize benefits. Therefore, POCT programs must be evidencebased, acceptable, and beneficial.

Topics: 004–Clinical, public health and epidemiological studies

P.P. Patil¹, P. Immanuel¹, G.B. Rathod¹, G.N. Kusneniwar¹, A.K. Pyati¹, S.A. Prabhala¹

All India Institute of Medical Sciences¹

Background: Thalassemia and Sickle Cell anemia show an autosomal recessive inheritance; hence, the incidence is high in communities where consanguineous marriages are common, like the tribal population (1) and in population residing in the subHimalayan belt and in central parts of India (2). The prevalence of other haemolytic disorders like HbE and HbC may also be high, but because of the limited healthcare access these communities have, many patients could be undiagnosed.

Aims: The study aims at finding prevalence of these disorders in tribal population.

Methods: Whole blood was obtained with aseptic venepuncture technique from adult tribal people residing in Yadadri district of Telangana state in Central India. Haemoglobin, red cell count and Mean Corpuscular Volume (MCV) were evaluated. Mentzer's index (MI) was calculated for all patients; cut-off of 13 was used, values lesser than 13 to be suggestive of thalassemia trait. Screening for haemoglobin variants was done for anaemic individuals (HB males < 13 gm% and females < 12 gm%) and those with MI less than 13. Analysis for haemoglobin variants was done using ‘ARKRAY ADAM's 8180T HPLC automated analyser’.

Results: A total of 480 individuals were screened (Figure 1), which included 155 males and 325 females. 26.87% individuals (n = 129), which included 15.48% males (n = 24) and 32.30% females (n = 105), were found anemic. Thalassemia trait, as diagnosed by HbA2 levels of more than 3.5%, was present in 6.45% individuals (n = 31), of which 19.37% also had low hemoglobin (n = 25). MI was lesser than 13 in 7% individuals (n = 34) of which 47.05% tested positive for thalassemia trait (n = 16); however, it was interesting to observe that 13 among them had normal hemoglobin and 3 were found to be thalassemia trait. Sickle cell trait was observed in 4 individuals and one case of HbE disease was identified.

Conclusion: The prevalence of anemia was found to be as high as one-fourth of the total population (26.87%); and anemia was found to be more in females (32.30%) as compared to males (15.48%). Although consanguinity is a common practice in this population, it could not be documented objectively; mainly due to the lack of literacy and reluctance of the people to open up regarding their customs. The prevalence of thalassemia trait was found to be high (6.45%); however only 19.37% among them had anemia and 6 individuals had a normal hemoglobin level. MI, although lacks sensitivity in screening for thalassemia trait (50% as compared to 80% for hemoglobin), should not be ignored completely as it does help in mopping up cases which could have been easily missed owing to their normal hemoglobin. Sickle cell anemia and HbE disease was found to be present, but not as common as thalassemia trait in this population. Surprising as it may sound that no case of thalassemia major was diagnosed despite the consanguinity, it could be due to the fact that the infant mortality rate and under-five mortality rate are still high, 41.6% and 50.3% respectively (3), in this population, and many of those lost lives could have been probably due to thalassemia major and lost to diagnosis. In conclusion, the tribal population living in central parts of India has a high prevalence of thalassemia trait (6.45%); however, owing to lack of accessible, reliable and affordable medical infrastructure, most of the cases go undiagnosed. Better programs for screening, counseling and management of this underserved population is need of the hour.

Topics: 004–Clinical, public health and epidemiological studies

S. Okoli¹, N.E. Igbineweka², O. Ojewunmi³, C. Oke¹, R. Brown¹, M. Sohal¹, A. Luqmani¹, J. Makani², M. Layton¹

Department of Haematology, Imperial College Healthcare NHS Trust, Du Cane Road¹, Imperial College London, Ce ntre for Haematology, Department of Immunology & Inflammation, Commonwealth Building, Du Cane Road², Red Cell Haemat ology, King's College London³

Background: Sickle cell disease (SCD) is an inherited anaemia caused by a point mutation in the β globin gene that results in vasoocclusion and haemolysis. It can lead to numerous acute and chronic complications, and although mortality has improved dramatically over the last 50 years, with limited interventions, SCD remains a life-limiting condition. Even for those patients treated in high-income countries, life expectancy remains >20 years behind that of their ethnically matched peers.

Aim: To describe the epidemiology of a west London sickle cell cohort, in the United Kingdom. This will focus on the complications, disease modifiers, interventions, and interactions with secondary care.

Method: A retrospective review of adult patients treated at a single centre in United Kingdom. The Imperial College NHS Trust is one of the sickle cell specialist centres in the West London Sickle Cell haemoglobinopathy coordinating centre. We investigated patient outcomes between 2018–2022 for all sickle cell syndromes. Data collection included demographics, diseasemodification, steady state parameters and sickle genotype variation. In addition, the study evaluated disease complications such as incidence of stroke, acute chest syndrome, liver and renal dysfunction, transfusion reactions, maternity outcomes and overall mortality.

Results (Preliminary): This single centre study identified 402 individuals who were seen between 2018 and 2022, over five years, (approximately 2,010 patient years of observation). The age range was 18 to 77 years with median of 39 years (SD = 14.94) and gender ratio was 1:2.3 (43%), male. A preliminary review of the data indicated that most, 286 patients (71%), had the HbSS genotype. 83% of eligible patients were treated with hydroxycarbamide and 85% were enrolled on a regular red cell exchange programme. The mortality rates for the cohort were significantly lower than those reported in previous analyses, and there was no maternal mortality. The majority died from SCD-related chronic multiorgan impairment despite maximal medical therapy. The incidence of severe complications was observed most frequently in the HbSS and HbSβ0 genotypes, although significant complications were also seen in other genotypes such as HbSC.

Conclusions: This single centre study aims to present a comprehensive and renewed perspective of the treatment of SCD in UK. As a centre in a high-income setting, this study will provide greater insight into the natural history of SCD and the impact current therapies, available at specialist centres in high-income settings, have on mortality and morbidity.

Topics: 004–Clinical, public health and epidemiological studies

M.A. Carter¹, R. Auturally¹, E. Bearblock², P. Boraks¹, L. Besser³, M. Besser³, C. Campbell⁴, A. Chang², A. Ddungu⁵, E. Dickens¹, I. Evans³, J. Fawehimni⁶, V. Garcia¹, P. Horrobin³, R. Jolley¹, J. Li², H. Lin², B. Lubwama¹, J. Martin⁴, R. Mathews⁷, M. Mcfarlane⁸, T. Milano³, F. Natukunda⁵, S. Narinian⁹, A. Pentland³, A. Quarrell², R. Scheiiling³, T. See⁹, O. Sharmadina⁴, A. Stafford¹⁰, G. Stafford¹¹, T. Stafford¹⁰, E. Taktashova³, W. Tan¹², V. Veprek³, L. von Neree¹³, T. Walker³, O. Wilkey¹⁴, H. Wilson³, E. Young¹, Y. Zhou¹, S. Fahle², S. Trompeter⁴, M. Besser¹

Cambridge University Hospitals¹, University of Cambridge², Impington Village College³, NHS Blood and Transplant⁴,

Makerere School of Medicine⁵, Colchester County Highway School for Girls⁶, University of Debrecen⁷, Sickle Society⁸, Perse Upper School⁹, Meldreth Primary School¹⁰, Hinchinbrooke School¹¹, Hills Road College¹², Blood and Transplant Research Unit, University of Oxford¹³, Department of Paediatrics, North Middlesex University Hospital¹⁴

Background: Increased awareness of the challenges of sickle cell disease could help improve patient care and experience. There have been a number of awareness campaigns to try to improve the public knowledge of sickle cell disease in recent years¹, and the effect of these campaigns is yet to be fully assessed. Education and increased patient involvement should also be part of the care of patients with sickle cell disease².

Aims: We held a public outreach event to highlight sickle cell disease and increase awareness within our region. This day included a series of dance performances by a dance troupe (SIN Cru), presentations from NHS Blood and Transplant, local research groups, haematologists, an apheresis team and sickle cell charity groups.

Methods: The outreach day was advertised as part of a University Science Festival, on social media and to patients registered at our centre. Attendance was free and was open to all. The day was centred around a series of dance performances which told the story of a patient with sickle cell disease and their experiences. In between dance performances, attendees circulated between a series of stations on different aspects of sickle cell disease.

Sponsorship was obtained from Terumo® and Agios® for the dance troupe budget and the printing of t-shirts and other consumables.

The clinicians involved reached out to local schools and did a presentation as part of the Gropius Lecture programme at Impington village college where most of the volunteers were based. All elective medical students and work experience students from our department of the last 12 months were approached to volunteer.

Results: 37 attendees responded to our post-event survey. 87% of respondents found the event to be ‘very helpful’ in raising awareness and knowledge of sickle cell disease. 78% (29/37) either identified themselves as having sickle cell disease, knowing or caring for someone with sickle cell disease (Fig. 1). Formal education relating to sickle cell disease was only reported in a minority of attendees (40% (15/37), Fig. 2).

All attendees strongly agreed (65%) or agreed (35%) that sickle cell disease is poorly understood by the general public. Knowledge of available treatments for sickle cell disease was variable ranging from 16% (voxelotor) to 73% (bone marrow transplant) (Fig. 3).

An estimate was made by survey respondents of the pain that a sickle cell crisis causes on a scale of 1 to 10, and the mean estimated score was 9.4.

Summary/Conclusion: This single timepoint survey showed the event was very well received and felt to be a helpful educational event in increasing awareness of sickle cell disease. It highlights a lack of formal education into sickle cell disease at all levels, and further inclusion in the national curriculum could be useful.

There was variation in the knowledge of the treatments for sickle cell disease, with fewer respondents knowing about newer treatments such as voxelotor, as may be expected. Interestingly, knowledge of bone marrow transplant appeared higher than the more commonly used treatment of hydroxycarbmide.

Recognition of the severe pain that a sickle cell crisis can cause was high. This event was well attended by those personally affected by sickle cell disease and their families. Similar events in schools, other centres and workplaces, such as GP surgeries, to increase understanding amongst the general population and healthcare workers could be a useful future step.

Topics: 005–Clinical, infection and nutritional deficiencies

L.D. Rahmartani¹, T.T. Sari¹, P.A. Wahidiyat¹

Pediatric Hematology Oncology Division, Department of Child Health, Universitas Indonesia - Cipto Mangunkusu mo National Hospital¹

Background: Children with transfusion-dependent thalassemia (TDT) are at risk of bone-related issues due to chronic anemia, iron overload, vitamin D deficiency, malnutrition, and other risk factors. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA) serves as a reference standard for assessing osteoporosis, but diagnosing osteoporosis in children involves complex considerations and limited availability. Vertebral compression fractures (VCFs) are the most common fractures in patients with reduced bone mineral density (BMD). The ISCD Pediatric Positions Task Forces stated that pediatric osteoporosis diagnosis included nontraumatic VCFs without needing BMD criteria.

Aims: This study aims to describe the prevalence of osteoporosis in children with TDT using vertebral X-Ray and associated factors.

Methods: A cross-sectional study design using secondary data on a population of children with thalassemia major aged 7–18 years was conducted at the Thalassemia Center at Cipto Mangunkusumo National Hospital.

Result: This study obtained 115 subjects (54% male, 66% homozygous -β thalassemia). The prevalence of vertebral compression fractures was 54.8%, with 71.4% at the lumbar region. There were no subjects with fractures who had complaints of pain or a history of previous trauma. Hypovitaminosis D occurred in 82.6% (33.9% deficiency, 48.7% insufficiency) subjects with the median vitamin D level [25(OH)D] was 15.1 (8–36.2) ng/mL. The mean pre-transfusion hemoglobin level was 8.79 ± 0.81 g/dL. The median serum ferritin level was 5018.8 (798.5–38750.3) ng/mL. Severe malnourishment occurred in 12.2% of subjects, and moderate malnourishment in 49.6% of subjects. There was no significant relationship between pre-transfusion Hb levels, mean serum ferritin, vitamin D levels, blood calcium, calcium ions, length of illness, gender, and type of iron chelation on the incidence of vertebral compression fractures. There is a significant relationship between nutritional status and the incidence of vertebral compression fractures. In severe malnutrition aOR = 21.44, 95% CI = 1.03–443.44, p value = 0.047 and in moderate malnutrition aOR = 0.81, 95% CI = 0.22–2.98, p value = 0.008.

Conclusion: Plain radiographs of the vertebrae can be used to detect osteoporosis in children with thalassemia major. In this study, nutritional status was associated with the incidence of vertebral compression fractures. Further research is needed to consider the other risk factors.

Topics: 007–Health services and outcomes research including psychology

C. Udeze¹, N.F. Ly², F.C. Ingleby², S.D. Fleming², S. Conner¹, J. Howard¹, N. Li¹, F. Shah³

Vertex Pharmaceuticals¹, IQVIA Ltd², Whittington Hospital³

Objectives/Aims: Patients with transfusion-dependent β-thalassemia (TDT) have reduced or absent β-globin production and require regular red blood cell transfusions (RBCTs) for survival. This study aimed to describe the healthcare resource utilization (HCRU) associated with TDT in England.

Methods: This longitudinal, retrospective cohort study utilized the Clinical Practice Research Datalink (linked with secondary care data [Hospital Episode Statistics]) in England to identify patients with a primary or secondary diagnosis for βthalassemia between July 1, 2008, and June 30, 2018. Eligible patients with TDT were required to have ≥8 RBCTs per year in ≥2 consecutive years. Patients were required to have ≥1 year of follow-up data after their index date (eighth transfusion in the second year of 2 consecutive years). Patients were followed from the index date until censoring, defined as death, deregistration due to patient leaving the practice, practice discontinuing its contribution to the database, or end of study period (June 30, 2019). Demographics were assessed at the index date, and RBCTs and HCRU were summarized during the follow-up period.

Results: A total of 237 patients met the inclusion criteria for TDT. The mean age of patients at the index date was 24.8 years, 52.3% were female, and 53.6% were South Asian. Patients with TDT averaged 13.6 RBCTs per-patient-per-year (PPPY) in the follow-up period. Patients averaged 34.78 secondary care visits PPPY. Of these (all PPPY), 0.67 were accident and emergency hospitalizations, 16.69 were outpatient visits, and 17.41 were inpatient hospitalizations. Of the 17.41 inpatient hospitalizations PPPY, 16.62 were hospitalizations that lasted <1 day. Patients averaged 24.09 prescriptions PPPY and 6.98 primary care visits PPPY in the follow-up period.

Conclusion: There is a substantial HCRU associated with the care of patients with TDT in England driven by RBCTs and secondary care visits.

Topics: 007–Health services and outcomes research including psychology

C. Udeze¹, N.F. Ly², F.C. Ingleby², S.D. Fleming², S. Conner¹, J. Howard¹, N. Li¹, F. Shah³

Vertex Pharmaceuticals¹, IQVIA Ltd², Whittington Hospital³

Objectives/Aims: Sickle cell disease (SCD) is an inherited red blood cell disease leading to hemolysis, vaso-occlusive crises (VOCs), and significant morbidity. This study aimed to describe the healthcare resource utilization (HCRU) of patients with SCD with recurrent VOCs in England.

Methods: This longitudinal, retrospective cohort study utilized the Clinical Practice Research Datalink (linked with secondary care data [Hospital Episode Statistics]) in England to identify patients with a primary or secondary diagnosis for SCD between July 1, 2008, and June 30, 2018. Eligible patients with SCD were required to have ≥2 VOCs per year in any 2 consecutive years. A VOC was defined as any of the following: SCD with crisis, priapism, or acute chest syndrome. Patients were required to have ≥1 year of follow-up data after their index date (second VOC in the second year of 2 consecutive years). Patients were followed from the index date until censoring, defined as death, patient deregistration, practice discontinuing its contribution to the database, or end of study period (June 30, 2019). Demographics were assessed at the index date, and VOCs and HCRU were summarized during the follow-up period.

Results: A total of 1,117 patients met the inclusion criteria for SCD with recurrent VOCs. The mean age of patients at the index date was 25.0 years, 51.4% were female, and 91.6% were Black. Patients experienced an average of 5.8 VOCs perpatient-per-year (PPPY) during the follow-up period. Patients averaged 22.17 secondary care visits PPPY. Of these (all PPPY), 4.97 were accident and emergency hospitalizations, 9.60 were outpatient visits, and 7.59 were inpatient hospitalizations. Patients averaged 2.98 inpatient hospitalizations PPPY that lasted ≥1 day. Patients averaged 31.06 prescriptions PPPY and 6.98 primary care visits PPPY.

Conclusion: There is substantial HCRU associated with the care of patients with SCD driven by VOCs and hospitalizations.

Topics: 004–Clinical, public health and epidemiological studies

M.Y. Mohd Yasin¹, R. Raman¹, Z. Zamri¹, M.P. Mohd Pauzy¹, A.H. Abdul Hamid¹, A. Aziz¹, H. Hassan¹, M.S. Mohd Sahid¹, M.Y. Mat Yusoff¹, E. Esa¹

Institute for Medical Research¹

Introduction: The identification of the β-thalassaemia carrier relies on the elevated Hb A2 level (HbA2). HbA2 level of (>4.0%) is considered the most reliable hematologic finding for the presumptive diagnosis of β-thalassemia carriers. The ‘grey zone’ of borderline haemoglobin A2 (HbA2) levels may pose a diagnostic challenge as their HbA2 levels are below cut off point could be due to coinheritance of α- or δ-thalassaemia that might affect the levels. Currently, limited data is available describing the molecular basis of borderline HbA2 in the Malaysian population particularly.

Aims: This study aimed to characterise and delineate the common genotypes involved in borderline HbA2 thalassaemia and to determine the significant cut-off HbA2 level that required further molecular analysis to rule out β-thalassaemia.

Methods: A retrospective analysis of 2886 cases from January 2017 to December 2020 with borderline HbA2 ranges from 3.0% to 3.9% based on either capillary electrophoresis (CE) or High-Performance Liquid Chromatography (HPLC) was collected. The samples were further divided into two groups. The first group with HbA2 level of 3.0–3.4% and the second group with HbA2 level of 3.5–3.9%. Samples with borderline HbA2 levels and normochromic normocytic red cell indices were analysed separately. Results of haematological parameters and Hb analysis were reviewed. All the samples were analysed with conventional multiplex amplification refractory mutation system (β-MARMS) and HBB gene sequencing. Selected cases will proceed with α-GAP and ARMS-PCR, alpha triplication and HBD gene sequencing based on their haematological parameters and Hb analysis. Statistical analysis was conducted using SPSS version 26. A Receiver Operating Characteristic (ROC) analysis was performed to determine the sensitivity and specificity of HbA2 in genotype determination within the 3.0 to 3.9% interval.

Results: Among 589 subjects in 1st group with HbA2 level of 3.0–3.4%, 203 (35%) were positive for a molecular defect in the α-, β- and δ-globin genes, with a majority of the samples (62.7%, n = 370) have no abnormality detected in both genes. For 2nd group with HbA2 level of 3.5–3.9% (n = 1142), the majority of the samples have a significant beta mutation (52.23%, n = 596), 54 cases (4.73%) with βmutation co-inherited with alpha and α-mutation (37.51%, n = 428). As expected, different mutation spectrums of borderline βthalassaemia were found in this study as compared to the genotype spectrum of classical β-thalassaemia and surprisingly, αthalassaemia alone involved in significant numbers of samples with raised HbA2 levels. The data also showed the cut-off HbA2 level that is currently used for the definition of borderline HbA2 beta thalassaemia (HbA2 of 3.3%) will give 94% sensitivity with 30% sensitivity while lowering the cut-off value to 3.2% will increase the sensitivity to 96% with 20% specificity.

Summary: The borderline HbA2 β-thalassaemia is not a rare event in our country. Based on our findings, the prevalence of borderline HbA2 β-thalassaemia in our population is around 40%. The chosen cut-off value will affect the sensitivity and specificity of the molecular test. Our findings showed according to the evaluation of both MCV/MCH and HbA2 levels, it is possible to differentiate mild mutations from more severe β-globin gene defects.

Topics: 007–Health services and outcomes research including psychology

M.A.A. Ampomah¹, A. Anum², A.M. Hood³, F.J. Kirkham⁴

Universiity of Health and Allied Sciences, Ho, Volta region, Ghana¹, University of Ghana², University of Manchester³, UCL GOSH Institute of Child Health⁴

Background: Sickle cell disease (SCD) is recognized as the predominant hereditary haemoglobinopathy with significant public health impact¹. Over 240,000 total annual conceptions are affected by SCD in Africa². Although Africa is home to many individuals living with SCD, most of the advances in SCD have occurred outside the continent³. Currently, owing to early detection through newborn screening, advances in medicine, and patient education, people living with SCD are now living longer into adulthood⁴. Yet, people living with SCD have significant psychiatric and Quality of life (QOL) concerns⁵ which remain poorly defined in adults. Most of the literature has focused on children^5,6 and cross-sectional studies^7,8 using nondisease-specific QOL measures^9,10.

Aims: This longitudinal study of adults living with SCD aimed to investigate QOL and psychiatric symptoms and their relationship with each other and patients’ demographic and illness severity markers at baseline and after 7 years.

Methods: QOL and psychiatric symptoms were investigated in 34 adult Ghanaian SCD patients, with a Symptom Checklist90Revised¹¹ and a Sickle Cell Illness Impact Measurement (SIMS)¹² at baseline and after 7 years.

Results: Generally, at the 7-year follow-up, there were significant changes in QOL rather than psychiatric symptoms.

Overall quality of life declined but not significantly (Mean difference, MD −40.41 (standard error, SE 21.55), p = 0.07).

Significant declines were observed in QOL in General Health Perception (MD −14.00 (SE 2.63), p < 0.01), Arm Functioning (MD −2.53 (SE 0.93), p < 0.01), Emotional Functioning (MD −41.48 (SE 19.72), p = 0.048), and Mood (MD -1.77 (SE 0.83), p = 0.042), after 7 years. However, significant improvement was observed in the patient's Pain Report (MD 17.22 (SE 2.01), p < 0.01), Overall Impact (MD 1.58 (SE 1.57), p < 0.01), and Health Perception (MD 2.18 (SE 1.57), p = 0.034) with no difference in Mobility, Walking and Bending, Household Tasks, Tension, Life Satisfaction, Life Improvement, General Feelings, Social Activities, Support from Family and Friends, Work Status, Relationship with Significant others, Social Services, Access to Care or Perception of Health Personnel at the clinic. Overall, the patient's psychiatric symptoms after 7 years showed improvement with experiences of somatization significantly better (0.41 (0.17), p = 0.027). Patient's experiences of pain negatively correlated with follow-up Obsessive Compulsive Disorder (r = −0.515, p = .002), Anxiety (r = −0.388, p = .028), Hostility (r = −0.353, p = .044), Psychoticism (r = −0.377, p = 0.031), and Global Severity Index (r = −0.428, p = 0.013) after 7 years. Follow-up White Blood Count (WBC) positively correlated significantly with follow-up Somatization (r = .406, p = .021), Obsessive Compulsive Disorder (r = .571, p < 0.01), Interpersonal Sensitivity (r = .494, p = .004), Depression (r = .445, p = .011), Anxiety (r = .676, p < 0.01), Phobic Anxiety (r = .551, p < .001), Hostility (r = .733, p < 0.01), Paranoid Ideation (r = .407, p = .021), Psychotism (r = .596, p < 0.01), and Global Severity Score (r = .655, p < 0.01), and while baseline WBC negatively correlated significantly with Pain (r = −.412, p = 0.024), and General Health Perception (r = −.378, p = 0.039). Baseline Frequency of Crisis significantly correlated positively with baseline mobility (r = .520, p = 0.02), Social Activity (r = .491, p = 0.003), Social Service (r = .424, p = 0.013), Household Task (r = .370, p = 0.031), Work Status (r = .365, p = 0.034), Physical Function (r = .388, p = 0.024), and Quality of Care (r = .404, p = 0.018). The number of SCD complications during follow-up in patients significantly correlated with Current and Future Health (r = .387, p = 0.024), Access to Care (r = −.418, p = 0.014), and Work Status (r = −.370, p = 0.031). Patient's Age of SCD Diagnosis at follow-up significantly correlated positively with Interpersonal Sensitivity (r = .496, p = 0.003), Depression (r = .361, p = 0.039) and Hostility (r = .467, p = 0.006), paranoid ideation (r = .562, p < 0.01), and Global Severity Index (r = .458, p = 0.007).

Discussion: The findings observed showed significant changes in QOL and Psychiatric symptoms in people living with SCD. Thus, assessing and addressing QOL and psychiatric symptoms concerns should be a priority. The effects of chronic infection and/or inflammation alongside the anaemia could be investigated. Early QOL and psychiatric symptoms surveillance, assessment, evaluations and appropriate management will provide avenues to improve the quality of life of adult sickle cell patients in Ghana.

Topics: 005–Clinical, infection and nutritional deficiencies

N.P. Udechukwu¹, U.C. Ukoh², I. Nwokoye³, K.Y. Okiche³, U.C. Iloduba³

Alex Ekwueme Federal University Teaching Hospital Abakaliki Hospital Abakaliki¹, Alex Ekwu Eme Federal University Teaching Hospital Hospital Abakaliki², Alex Ekwueme Federal University Teachi Ng Hospital Abakaliki³

Background: Sickle cell anaemia (SCA) constitutes a real public health issue especially in sub Saharan Africa¹. Bacterial infections are one of the serious complications of SCA and can occur either as an acute or a chronic condition thus they constitute a major cause of morbidity and mortality among children and adults with sickle cell anaemia². Invasive bacterial infections (IBI) are infections occurring at a site where bacteria are not normally present such as bloodstream, soft tissue and meninges. The incidence of bacterial infection among children with SCA varies from one country to another and the bacterial organism that causes infections in SCA patients depend on the environment³. Knowledge of the most common pathogens infecting patients with SCA could be used to improve antimicrobial prophylaxis and empirical treatment of infections.

Methods: We conducted a retrospective review of Paediatric patients with SCA admitted and managed for bacterial infections in the Paediatric unit of Sickle Cell Centre, Alex Ekwueme-Federal University Teaching Hospital Abakaliki between January 2015 and December 2020, aged 17 years and below. The medical records of those with a suspicion of IBI and presented a positive result after culture of a body specimen (blood, cerebrospinal fluid, synovial fluid or surgical specimen) were selected and reviewd. Data was collected with a questionaire and presented as charts and tables.

Results: We evaluated 52 children with SCA and suspected IBI who had culture done during the study period and 13 (25%) came out positive and 39 (75%) was negative image 1. There were 34 (65.4%) males and 18 (34.6%) females. All patients had fever with temperature ranging from 38°C to 40°C.

Patients in the age groups 5 to 10 (34.6%) and 11 to 15 (30.8%) had the most IBI, Most cases of IBI were diagnosed in the age range of 1 to 15 and non at above 15 years. Most patients affected belonged to the middle (42.4%) and low (44.2%) socioeconomic class.

Staphylococcus aureus is the most frequent pathogen isolated image 03 and antimicrobial susceptibility is shoWn in image 02.

The pattern of sensitivity of different bacterial pathogens encountered in the study showed the cell wall inhibitors – predominantly; the cephalosporins, then the penicillins and imipenem – featured prominently among the antibiotics to which the organisms displayed sensitivity to, however resistance was also prominent among cell wall inhibitors of the penicillin class.

The major types of infection were septicaemia (59.6%) with infective endocarditis in 2 cases and pericardial abscess in 1 case as complications and osteoarticular infections (15.3%) image 04. The mortality rate was 7.7% table 11 (image 04).

Summary: The more frequently encountered bacterial pathogen seen in this study were staphylococcus and Escherichia Coli. This is in keeping with more recent studies that isolated a greater prevalence of staphylococcus aureus and non typhi salmonella in their report as against the encapsulated organisms earlier reported in SCA patients^4,5 Septiceamia was the most common clinical type of infection and mortality occurred in those with multi focal involvement affecting vital organs like pericardial abscess and empyema.

This study also demonstrated good susceptibility of the organisms to the quinolones.

Conclusion: It is therefore necessary to review antibiotic use and their sensitivity in our environment. Prompt and aggressive management of infections in children with SCA will prevent overwhelming septiceamia and subsequent mortality.

Topics: 007–Health services and outcomes research including psychology

S.A. Afridi¹, R.K.A. Kesse-Adu¹, D.S. Seviar¹, S.S.S. Stuart-Smith², A.D.K. De-Kreuk³, M.A. Awogbade³, M.P. Player⁴, K.G. Gardner⁵

Guys & St Thomas' NHS Trust¹, King's College NHS Trust & Nottingham University Hospitals NHS Trust², King's College Hospital NHS Trust³, King's College London⁴, Guys & St Thomas' NHS Trust and Nottingham University Hospitals NH S Trust⁵

Background: The Sickle Cell Natural History Study has established a research database of adults with sickle cell disease currently based in three UK sickle centers: Guy's and St Thomas’ NHS trust, King's College Hospital NHS Trust, Nottingham University Hospitals NHS Trust. This includes patient reported outcomes based on quality of life metrics using (1) Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) survey tool and (2) the Patient Reported Outcomes Measurement Information System (PROMIS).

Metrics used in the quality-of-life questionnaire

All the ASCQ-Me and PROMIS metrics are created from standardized t-scores using a sickle cell cohort, where, for each measure, 50 is the average point and 1 standard deviation is 10. A higher t score on Pain Impact, Emotional Impact, Social Impact, Sleep Impact and Cognitive Functioning measures mean that a participant is experiencing less difficulties in this area. A higher t score on the Fatigue measure means that a participant is experiencing more difficulties in this area.

Methods: Patients have been consented to take part in a five-year research study using standard of care data, collecting clinical, laboratory, treatment, hospitalization data, as well as quality of life metrics as above.

Conclusions: Our data confirms a large variability in Quality of life experienced by all patients with sickle cell. There were some differences suggesting that HbSS patients, and Females, have poorer quality of life in some spheres than HbSC and males. Notably, pain was reported as less problematic in older patients: whether this is because older patients have less pain (possibly with milder disease for a very long-lived patients), or have more experience of how to manage pain, is not clear.

Quality of life data remains a crucial outcome to measure in sickle cell to better understand how we can serve patients’ health needs, as well as a crucial tool against which to measure new treatments.

Measurement Information System (PROMIS)(Keller et al., 2017)

Topics: 007–Health services and outcomes research including psychology

J.P. Libago¹, M. Player², J. Port³, M. Copple⁴, A. Webster¹

University of Hospitals Leicester¹, Nottingham University Hospitals², EMSTN Network Manager³, EMSTN Lead Nurse⁴

Background and Aims: Sickle cell disease (SCD) is a lifelong condition affecting 14,000 people in the UK. It can present with non-specific symptoms, and patients often feel healthcare staff struggle to understand it. Feedback is therefore important to identify deficiencies in care. The East Midlands Sickle Cell and Thalassaemia Network (EMSTN) was formed in 2009 to support SCD patients within the region.

Data is collected annually on patient experiences. As of 2022/23, two different methods are used: an EMSTN questionnaire (EQ) and a more thorough Picker questionnaire (PQ), which has been introduced in line with Peer Review standards. The main aim of this study was to compare both and consider if PQs gather better feedback. A secondary aim was to highlight any flaws in care to allow for appropriate changes to be implemented.

Method: SCD patients in East Midlands were invited to complete a questionnaire regarding experiences of care. These were completed at face to face hospital appointments. Both adults and children were involved, with carers or support workers answering on behalf of/assisting patients where applicable. Leicester used the newer PQs; all other sites used EQs.

Results: A total of 222 responses were collected. Responses from the different sites were as follows: Leicester (67, 30.1%); Nottingham (102, 45.9%); Derby (19, 8.6%); Northampton (15, 6.8%); and Kettering (19, 8.6%).

Both asked for feedback on inpatient management and emergency care, and also provided ample opportunity to provide subjective comments. However, PQs continue by further breaking down each aspect of care. One such example is asking if sufficient analgesia was given in emergency admissions. In contrast, EQs only ask patients to rate overall emergency care on a scale ranging from Very Poor to Excellent. The level of detail in PQs make it more time consuming to complete, and this may discourage patients from participating, as seen in the level of participation between Leicester and Nottingham.

Emphasis has been placed on improving emergency care for SCD patients in EMSTN. Of the 79 total responses on this, most were positive, but 13 patients rated their experience as ‘Poor’ and 6 as ‘Very Poor’. Feedback on other areas continues to largely be reassuring, with fantastic comments on our excellent sickle cell specialist nurses. 16% of SCD patients mentioned wanting to be offered psychological support and some felt the opportunity to meet other people with SCD to share their experiences could be facilitated.

Conclusion: Feedback gained from PQs is very valuable, with information about a certain aspect of a patient's overall care being easier to gain and highlighted for review. Feedback from EQs continue to be beneficial, but with other trusts within East Midlands following Leicester's footsteps and transitioning to PQs, more thorough feedback can be gained. Patient participation for the new feedback forms will be monitored for any differences between EQs and PQs.

Responses have been encouraging, but emergency care experience continues to be a concern. Staff training to improve healthcare staff awareness of SCD has been emphasised. A sickle cell support group for the Midlands may be established for the psycho-social aspect of the management of SCD. These recommendations have been presented in an EMSTN meeting, and patient feedback will continue to be collected to see if any suggested changes, if implemented, have improved patient care.

Topics: 002–Novel therapies, gene therapies and bone marrow transplant

G.B. Brugnera¹, M.A. Abboud², D.N. Noun², H.H. Haidar², F.R. Rodigari¹, R.C. Colombatti¹

Dipartimento della Salute della Donna e del Bambino, Clinica di Pediatria¹, American University of Beirut Medical Center, Department of Pediatrics and Adolescent Medicine²

Background: Sickle cell disease (SCD) and beta-thalassemia major (beta-TM) are hematological chronic disorders associated to acute complications, severe morbidity, premature mortality, leading to impaired quality of life. In the era of evolving new drugs and gene therapy, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only available curative therapy for hemoglobinopathies.

Aim: This study aims to summarize HSCT experience in SCD and beta-TM pediatric patients in Lebanon, where the main struggle isn't the availability of a suitable donor but limited resources and financial constraints.

Methods and materials: This retrospective study was conducted at the American University of Beirut Medical Center, Department of Pediatrics and Adolescent Medicine, Beirut. SCD and beta-TM patients who underwent HSCT at any age, from July 2012 to July 2022, were included. Charts were reviewed for patients’ demographics, pre-transplant iron assessment, hepatomegaly and splenomegaly, conditioning regimen, GVHD prophylaxis, histocompatibility, source of SC, engraftment and chimerism follow up.

Results: 20 patients were included, with a mean age at transplant of 7.74 years. Serum ferritin (SF) levels were available for all patients: 3 patients reported SF > 2000 ng/ml. LIC was assessed by T2-MRI in 17 patients: 14 reported abnormal LIC (4 insignificant siderosis, 5 mild siderosis, 1 moderate siderosis, 4 severe siderosis). MIC was assessed by T2-MRI in 16 patients, 9 patients had abnormal MIC. All patients received HLA fully matched related donors transplant (17 MSD, 3 MFD). The sources of stem cells were BMSC and PBSC. Bu-Cy-ATG was the main selected conditioning regimen. CsA-MTX was the main administered GVHD prophylaxis. 1 patient required the administration of MMF combined to CsA after having a mild gradual drop in hemoglobin. CsA, MTX and MPN regimen was used in 1 patient. Neutrophil and platelet engraftment occurred at a median of 19, 5 days post-HSCT. Platelet engraftment occurred at a median of 18, 2 days in 18 patients: 1 patient delayed platelets recovery due to a severe VOD/SOS, 1 patient remained PLT transfusion dependent. At a median follow-up of 42, 1 months, OS and DFS were 95%. No graft rejections (GR) was observed. Acute GVHD occurred in 1 patient (5%). No chronic GVHD was noted. 4patients developed VOD (20%). All infectious complications occurred in 12 patients (60%), but only 3 developed severe infections. Overall bacterial infections rate was 30%, CMV reactivation 20%, fungal infections 5%. Mucositis and/or hypertension were reported in 5 patients (50% of non-infectious complications). Chimerism analysis was performed in 19 patients. At a median follow up of 27, 9 months, 7 patients (35%) had a full donor chimerism, 12 patients (60%) had a mixed donor chimerism.

Conclusion: At a medium follow-up was 42,1 months, the OS and DFS were both 95%, no GR was observed. Low incidence of acute and chronic GVHD has been reported. VOD incidence in our study is relatively higher, Bu pharmacokinetics and eventual prophylactic therapy with Defibrotide should be considered. Although overall infectious complications’ prevalence was high, only 15% of patients developed severe infections. Our experience showed satisfactory outcome of HSCT in hemoglobinopathies in Lebanon, where the main obstacle to HSCT is financial burden rather than the unavailability of a matched family donor, due to relative marriages.

The ARISE project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 824021.

Topics: 004–Clinical, public health and epidemiological studies

F.R. Rodigari¹, G.B. Brugnera¹, T.A.N. Abi Nassif², G.R. Reggiani³, M.P.B. Boaro³, M.A. Abboud², R.C. Colombatti³

ARISE Secondee, Dipartimento della salute della donna e del bambino, Università degli Studi di Padova¹, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center², UOC Oncoematologia pediatrica, Dipartimento della salute della donna e del bambino, Università degli Studi di Padova³

Background: Sickle cell disease (SCD) represents a hypercoagulable state which predisposes to venous thromboembolism (VTE) as a consequence of endothelial dysfunction, platelet activation and inflammatory state associated with chronic hemolysis. Pulmonary embolism (PE) is a described complication of SCD, however, its exact incidence in pediatric patients is unknown. Moreover, there is a lack of pediatric-specific data to guide recommendations for prevention and management of PE in SCD. We describe a case of recurrent PE in a patient with SCD and multiple thrombotic risk factors, which raises the question of the best clinical management.

Case Report: A 20-months Lebanese male was diagnosed with HbSS SCD following check-up for chronic anemia. At 29 months he underwent splenectomy after splenic sequestration. Following splenectomy he developed progressive thrombocytosis and started taking aspirin. At 3 years he contracted a rhino/enterovirus infection, followed by acute chest syndrome (ACS) with infiltration of the right lobe and PE at the level of the left lower lobar segmental pulmonary artery, without any sign of deep vein thrombosis. Echocardiogram was normal. CBC showed Hb 11 g/dL, PLT 760 × 10^3/μL, reticulocytes 3%, D-dimer 1946 ng/mL. He was treated with intravenous (IV) antibiotics with clinical improvement. Manual exchange transfusion was done and enoxaparin was initiated at 1 mg/kg every 12 hours. Extended anticoagulant therapy with enoxaparin was continued for a total duration of 3 months with follow up on factor Xa level. After discharge he started hydroxyurea and vitamin B12. Blood exams showed persistent thrombocytosis. Thrombophilia screening revealed MTHFR (c677T) homozygous mutation with normal homocysteine levels. He followed regular follow up at the outpatient department. When he was 6-year-old he developed a new episode of ACS with infiltration of the right lobe and homolateral PE at the level of the upper and middle lobe pulmonary arteries.

Blood exams showed Hb 8,3 g/dL, PLT 1625 × 10^3/μL, CRP 57,2 mg/L, D-dimer 1704 ng/mL. Deep vein thrombosis of the extremities was excluded through Doppler ultrasound. Echocardiogram was normal. Homocysteine level was normal. He was treated with IV antibiotics and enoxaparin with improvement. He was maintained on enoxaparin monitoring factor Xa level. At follow-up his blood exams showed persistent thrombocytosis (PLT 1040 × 10^3/μL). Given the progressive thrombocytosis, a search for myeloproliferative disorders has been done. The search for BCR-ABL translocation was negative, the search for JAK2 mutation has not been performed yet for financial reasons.

Discussion: This case represents, to our knowledge and literature review, the first reported case of pediatric SCD patient presenting recurrent PE associated with multiple thrombosis risk factors other than SCD. The patient developed PE in the context of ACS precipitated by upper respiratory tract infection and pulmonary infection. Despite appropriate acute and chronic management and anticoagulation therapy, the patient's clinical condition precipitated on two different occasions. The role of anticoagulation therapy for prevention and management of VTE in pediatric SCD patients is currently debated. Moreover, there is significant variability in the management of the acute VTE disease and uncertainty regarding prophylaxis strategies. Multicentric studies on VTE management in pediatric SCD patients are needed to generate evidence for future guidelines.

Topics: 004–Clinical, public health and epidemiological studies

L.A. Osayi¹, A.O.D. Ofakunrin², E.S. Okpe², C.S. Yilgwan², F. Bode-Thomas²

Department of Pediatrics, Jos University Teaching Hospital¹, Department of Pediatrics, University of Jos/Jos University Teaching Hospital²

Background: Pulmonary hypertension is an important cause of morbidity in children with sickle cell anaemia (SCA), and has no known definitive treatment. Hydroxyurea (HU) has been used to modify the pathophysiological mechanisms implicated in pulmonary hypertension but very few authors have reports on its effect on the occurrence of pulmonary hypertension.

The present study aimed to compare the occurrence of pulmonary hypertension and some of its known risk factors, among children with SCA receiving HU and those who were not, in Jos University Teaching Hospital (JUTH).

Methods: This was a cross-sectional comparative study of 121 children with SCA receiving HU (for at least 6 months prior to enrolment) and 121 others who were not. Relevant clinical history, physical examination, full blood count, lactate dehydrogenase assay, and Doppler echocardiography (for evidence of pulmonary hypertension) were performed on all participants. Data collected were compared via bivariate and logistic regression analyses using the IBM SPSS® statistical software version 26, and p values <0.05 were considered statistically significant.

Results: Of the 242 children, 122 (50.4%) were females and the ages of the children ranged from 2–17 years with a median age of 9 years (IQR 5–12). Overall, 95 (39%) of the 242 children had pulmonary hypertension (TRV values ≥ 2.5 m/s). More females 50 (52.6%) than males 45 (47.4%) were affected, this was however not statistically significant (p = 0.579). The occurrence of pulmonary hypertension in subjects receiving HU was 26.4% (32/121) compared to 52.1% (63/121) in those not receiving HU (p < 0.0001). The non-hydroxyurea users had a higher median total white blood cell count (13.5 vs. 9.3 (x109/l) (p < 0.0001), serum lactate dehydrogenase (363 vs. 323 (IU/l) (p = 0.001), but lower median haematocrit (23.2% vs. 25.8%) (p < 0.0001) than the hydroxyurea users.

History of acute chest syndrome and blood transfusion were associated with increased odds of pulmonary hypertension in subjects receiving HU (p = 0.017 and p = 0.009 respectively). Blood transfusion was the only significant factor associated with pulmonary hypertension in those not receiving HU (p = 0.003).

Regarding laboratory parameters, an elevated WBC and lower haematocrit were seen to be significantly associated with PH (p = 0.03 and p = 0.01 respectively) among hydroxyurea users while a lower haematocrit was the only significant factor associated with PH (p = 0.006) among non-hydroxyurea users.

Conclusion: Hydroxyurea was associated with a significant decrease in the occurrence of pulmonary hypertension; therefore it is recommended for use in children with SCA to prevent pulmonary hypertension.

Topics: 004–Clinical, public health and epidemiological studies

O.A. Agrippa¹, K.Z. Summers¹, K.A. Anie², P. Telfer³, S. Lugthart⁴

Sanius Health¹, London North West University Healthcare NHS Trust², Barts Health NHS Trust³, University Hospitals Bristol and Weston NHS Foundation Trust⁴

Background: Current standards of care in Sickle Cell Disease (SCD) are limited to hydroxyurea (HU) and blood transfusion therapy, with new disease-modifying and curative treatments emerging to potentially enrich the therapeutic landscape. A critical part of ensuring new therapies reach the patients who need them is a strong understanding of current treatment lines. As such, a deeper granularity of insights across treatment lines, supported by real-world evidence, is crucial in better understanding care pathways and where the greatest impact may be when initiating a novel therapy – supporting the integration of new therapies for SCD in the UK.

Aim: This work aimed to better describe the use of transfusion therapy in the treatment of patients with SCD, both as a whole and as a second-line treatment to HU, from NHS site-reported data and through a real-world SCD data ecosystem.

Methods: Data surrounding transfusion therapy rates and positioning in relation to HU usage was obtained from two key sources. Firstly, data was integrated into a real-world SCD data ecosystem through digitisation and transcribing of medical records, obtained at the point of informed consent through participant completion of a Subject Access Request form. This was enriched with patient-reported data from their onboarding questionnaires and follow-up survey.

The proportion of patients on each treatment was calculated and compared to that seen in clinical settings. This was provided to the project team as a snapshot number and proportion of patients by clinical leads at 4 secondary care sites, through internal patient counts. Additional deidentified data was obtained and analysed from a primary care network and combined at each treatment level with NHS site figures, as an external real-world position across care providers for comparison to ecosystem figures. As not all centres reported all lines of treatment, the total patient volume for each breakdown is given.

Results: Treatment patterns were analysed for a total of 1,303 patients, 434 enrolled with the ecosystem and 869 registered to a primary or secondary care centre. 37% (159/434) of ecosystem patients had recorded HU use at some point in their treatment pathway, in line with 36% (315/869) of patients reported by clinical teams. 3% (11/434) and 6% (32/495) of patients were reported to be intolerant of/ineligible for HU within the ecosystem and provider cohorts, respectively.

While the proportion of patients in the ecosystem with any recorded transfusion therapy was higher (55% [239/434] vs. 24% [70/295]), the rate of patients receiving both HU and regular transfusion therapy (defined as every ≤6 weeks) was similar, at 3% (12/434) within the ecosystem and 5% (16/295) at provider sites. More detailed examination of treatment lines found that 3% (11/434) of ecosystem patients and 6% (36/574) of the provider cohort had received regular transfusion therapy after receiving HU treatment.

Conclusion: This work provides an important real-world insight into treatment lines across current standards of care for SCD in a UK patient cohort, for whom few treatment options are available. Our data found 36–37% of patients had received HU at some point in their care pathway and 3-6% received regular transfusions after their first dose of HU, in line with HU intolerance/ineligibility rates. Similar proportions of patients at each treatment level were seen both through reporting from provider patient counts and data captured by the data ecosystem.

Critically, this highlights a proportion of patients who have not received HU as the current standard of care, potentially due to factors such as stigma around medications or anxiety around complications. Future work will focus on exploring treatment pathways with deeper granularity, to develop a more detailed understanding of the treatment landscape, proportion of patients who have not received any treatment, underlying causes, and resulting impact on healthcare admissions and costs. This may further support the understanding of the optimal positioning of novel interventions in the real world as they emerge.

Topics: 004–Clinical, public health and epidemiological studies

J.M. Marco Sanchez¹, E.J. Bardon Cancho², D. Benéitez³, A.C. Gimbert⁴, A. Ruiz-Llobet⁵, E. Rodríguez⁶, J.A. Salinas⁷, M.L. Rubio⁸, A. Cervera⁹, M.J. Ortega¹⁰, M.T. Coll¹¹, J.J. Uriz¹², V. Recasens¹³, B. Argilés¹⁴, S. Payán¹⁵, M. Bermúdez¹⁶, M. Morado¹, A. Gondra¹⁷, P. González¹, E. Cela¹

Hospital Gregorio Marañon¹, Hospital Gregorio Marañón², Hospital Vall d'Hebron³, Hospita Vall d'Hebron⁴, Hospital Sant Joan de Déu⁵, Hospital Niño Jesus⁶, Hospital Son Espases⁷, Hospital Principe de Asturias⁸, Hospital Mostoles⁹, Hospi tal Virgen de las Nieves¹⁰, Hospital Granollers¹¹, Hospital Universitario Donostia¹², Hospital Miguel Servet¹³, Hospital la Fe¹⁴, Hospital Virgen del Rocío¹⁵, Hospital Virgen de la Arrixaca¹⁶, Hospital Basurto¹⁷

Background: Since the creation in 2013 of the Spanish Registry of Rare Hemoglobinopathies and Anaemias (REHem-AR- SEHOP), the collection data of demographic characteristics of sickle cell disease (SCD) continues. The last publication in this regard dates from 2019. The recent implementation of neonatal screening for hemoglobinopathies in all of our communities that did not yet have it, as well as the addition of new centers during these years, has considerably increased our sample of patients. This justifies updating the latest publication on the matter, with a follow-up of more than 5 years than the previous one.

Methods: Observational, descriptive, multicenter and ambispective study, including adult and pediatric patients with sickle cell disease registered in REHem. Data presented corresponds to the cross-sectional analysis of June 1, 2023. Epidemiological and clinical variables were entered by each of the physicians, and are expressed as median and interquartile range. Duplicate records were excluded by the patient identification code (CIPA) of the national health system.

Results: 1,317 patients with SCD were registered nationwide, male/female ratio of 1.09 (52.2% male, 47.6% female). The most frequent phenotype was SS (77.8%), followed by SC (13.5%), Sβ0 (4%), Sβ+ (3.7%) and SD (0.3%). Spain was the country of birth for most of the children (62.4%), followed by Equatorial Guinea (8.7%). 67% were under 18 years of age, 33% adult patients. 36.7% were diagnosed by neonatal screening, 24.3% due to clinical anemia, 15% due to pain crises and 8% due to family screening. The mean age at diagnosis was 2.5 years (0.0–3.0). 8.2% had glucose-6-phosphate dehydrogenase deficiency and 3.1% had positive congenital thrombotic diathesis studies.

The centers with the highest load of patients were Gregorio Marañón, Vall d'Hebrón and Sant Joan de Déu hospitals with 25.6, 5.4 and 8.9%, respectively, placing Madrid and Catalonia as the communities with the largest population of this disease.

Since 2017, 100 patients presented some alteration in the magnetic resonance imaging (MRI) of the brain, most frequent being lacunar infarcts (60%). 19% of the patients presented a secondary cerebrovascular accident (CVA).

82.4% of the patients started penicillin prophylaxis. 52.3% received vitamin D osteopenia prophylaxis at some point. Treatment with hydroxyurea was started in 686 patients (62.1%), with a median age of onset of 5 years (2.0–9.0) and a median duration of 2 years (0.0–4.75). 12.4% (133) of the cases entered a chronic transfusion regime program, with a median age of onset of 7 years (4.0–11.0) and a median duration of 1 year (0.0–2.0).

Chelation treatment had to be started in 7.5% of the patients, with deferasirox being the most frequently used drug (93.7%). The median age of initiation of chelation treatment was 9 years (6.0-14.0) with a median duration of 1 year (0.0–2.0). A total of 51 patients (4.7%) underwent splenectomy, with a median age at the procedure of 4 years (2.0–8.0). Hematopoietic stem cell transplantation (HSCT) was performed in 83 patients (7.7%), with a median age of 7 years (4.0–10.0). 27 patients (5.9%) of the sample have died.

39.2% of the patients in the sample have lost follow-up.

Conclusion: Since 2019, the REHem-AR has increased by more than 500 cases. Vaso-occlusive crisis and acute chest syndrome continue to be the most important complications in sickle cell.

Topics: 004–Clinical, public health and epidemiological studies

C. Stephanou¹, P. Kountouris¹, C. Bento², C.L. Hartveld³, J. Traeger-Synodinos⁴, J.S. Waye⁵, Z. Peng⁶, I. Fylaktou⁴, H. Halim-Fikri⁷, T. Koopmann³, L. Nfonsam⁵, J. Sun⁶, K. Michailidou¹, T. Papasavva¹, C. Lederer¹, Z.B. Alwi⁷, M. Kleanthous¹, ClinGen Hemoglobinopathy Variant Curation Expert Panel⁸

The Cyprus Institute of Neurology & Genetics¹, Centro Hospitalar e Universitário de Coimbra², Leiden University Medical Center³, National and Kapodistrian University of Athens⁴, Hamilton Health Sciences; McMaster University⁵, BGI Genomics⁶, Universiti Sains Malaysia⁷, ClinGen Hemoglobinopathy Variant Curation Expert Panel⁸

Background: The increasing use of sequence-based diagnosis emphasizes the need for accurate and consistent classification of sequence variants. The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guideline provides a structured approach, utilizing diverse lines of evidence for classifying variants related to monogenic diseases. The generality of this guideline requires the application of expert judgment when evaluating and weighing evidence for variant interpretation. To address this, the Hemoglobinopathy Variant Curation Expert Panel (VCEP), formed under the auspices of the Clinical Genome Resource (ClinGen), performed gene- and disease-specific modifications of the ACMG/AMP guideline for the annotation of all variants related to hemoglobinopathies.

Aim: To conduct a pilot test of the Hemoglobinopathy VCEP-specified ACMG/AMP guideline.

Methods: Rule specifications were piloted on 48 globin variants in the genes HBB (β-globin locus, NG_000007), HBA2 and HBA1 (αglobin locus, NG_000006), previously submitted to ClinVar. The pilot variants represented different types of variants relevant to hemoglobinopathies (null, missense, synonymous, intronic) and different variant classifications (likely benign (LB), benign (B), likely pathogenic (LP), pathogenic (P), uncertain significance (VUS)). The curation process involved the collection of published and unpublished data for each variant and a preliminary variant pathogenicity classification on the ClinGen Variant Curation Interface by trained biocurators, followed by monthly meetings with a VCEP expert sub-group for review and final classification. Disease selection for each variant followed the recommendations by the Hemoglobinopathy VCEP, prepared under the guidance of the ClinGen Lumping and Splitting Working Group.

Results: The Hemoglobinopathy VCEP developed disease-specific rules for sequence variant classification with a final set of 31 unique evidence codes, some of which have different levels of strength based on the amount of evidence available. The pilot study tested 84% (26/31) of the rules with good coverage of pathogenic (95%, 20/21) and benign (60%, 6/10) criteria, and most were used more than once. After applying the VCEP-specified ACMG/AMP criteria, 26 variants had unambiguous classifications. An equal number of reclassified variants underwent an upgrade (LP to P, 4/22) and downgrade (P to LP, 4/22) in pathogenicity, while others, mainly benign variants, were reclassified as VUS with insufficient (9%, 2/22) or conflicting (23%, 5/22) evidence of pathogenicity. In addition, 67% of the discordant variants (6/9) were resolved into LB (17%, 1/6) or VUS with insufficient evidence (83%, 5/6). Furthermore, three VUS with conflicting evidence under the standard ACMG/AMP classification framework were reclassified as P by application of the Bayesian framework.

Summary/Conclusion: The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation for additional known globin gene variants in a pilot study (toward Step 3 approval). This pilot study demonstrates the requirement and utility of expert specifications of the ACMG/AMP guideline for globin gene variant interpretation, as a key step toward comprehensive globin variant classification.

Topics: 004–Clinical, public health and epidemiological studies

S. Azouji-Benjamin¹, R. Kesse-Adu¹, S. Stuart-Smith², D. Seviar¹, A. de Kreuk², M. Awogbade², K. Gardner¹

Guy's and St Thomas' NHS Trust¹, King's College Hospital NHS Trust²

Background: The UK Sickle Cell Natural History Study has established a research cohort of adults with sickle cell disease to collect and analyse detailed clinical outcomes. The redcap database is aligned with the US-based GRNDaD consortium to facilitate future between-country comparisons. It is an investigator-led, commercially funded (bluebirdbio) study.

Results: After 12 months, 241 individuals were recruited: mean age 40.5 (std dev 13.9, range 8–79) with 149 (61.8%) female, and with sickle genotype: 156 HbSS (64.7%), 73 (30.3%) HbSC, 11 (4.6%) HbSB+ thal and 1 (0.4%) HbSHPFH. 232/241 (96.2%) have black heritage (black African/black African-Caribbean/black British), with the remainder having either mixed ethnic background (black/white), Middle Eastern or South Asian background, per UK ethnicity definitions.

Clinical characteristics: The burden of end organ damage is summarised in table 1. There has been one death in a 35 year old male with HbSS.

Disease modifying treatment: 92/153 (60.1%) of HbSS patients are on either hydroxycarbamide or a transfusion programme as disease modifying therapy for sickle cell disease, significantly more than 14/72 (19.4%) with HbSC (p < 0.001), see table 2 for a breakdown of treatment.

Cancer: There were four patients with malignancies currently at baseline: skin cancer, breast cancer, neuro-endocrine tumour, haematological malignancy.

Resource utilisation: 64/236 had been hospitalised at least once, and 172/236 had no hospital admissions (5 had no data). Median hospitalisation rate for sickle complications was 0/year (range 0–20/year, IQR: 0–1).

Summary: This new research database presents detailed and curated real-world data on individuals with sickle cell. This enables researchers and to understand the characteristics of a well-managed cohort in an high-income setting, and will now start providing longitudinal data to work towards delineating the different natural histories of patients with SCD.

Topics: 004–Clinical, public health and epidemiological studies

L.G. Dogara¹, H. Isah², I.P. Ijei-Enesi¹, C. Biya³, H. Saleh³, J.Y. Waje², M.S. Shuaibu¹, L. Hsu⁴, P.D.B. Inusa⁵

Barau Dikko Teaching Hospital (BDTH) - Kaduna State University (KASU)¹, Sickle Cell Cohort Research Foundation (SCORE) Nigeria, BDTH Office², Kaduna State Primary Healthcare Development Board³, University of Illinois⁴, Evelina Children's Hospital, Guys' and St. Thomas' NHS Trust⁵

Background: Nigeria has the highest incidence of sickle cell disease (SCD) cases in the world, with an estimated 150,000 babies born annually and under 5 years mortality estimated at 50%.^1,4 However, Nigeria still lacks a sustainable programme to care for the SCD population.^1–3 Effective management of SCD should incorporate newborn screening (NBS) and early diagnosis so that babies have access to lifesaving preventive care like antibiotics and modern medical care for sickle cell complications.^5,6 However, Nigeria's SCD burden is in orders of magnitude larger than clinical series in North America or Europe,^7,8 and Kaduna with a population of 10.4 million, an estimated 4000–7000 babies born each year with SCD is faced with the challenge in implementing effective management. In a 2009–2011 pilot NBS in Kaduna State, (Ref)an incidence of 1.7% highlighted the degree of the problem. This was followed with stakeholder engagements and focussed group activities which emphasized the importance of leveraging on the existing healthcare infrastructure such as primary health care system, and in 2019 under American Society of Hematology (ASH) Consortium for Newborn screening of SCD for Africa (CONSA), Kaduna state was selected to screening 10,000 babies annually.

Key project goals- Implement a sustainable routine NBS program for sickle cell disease in Kaduna state as a backbone for public health and clinical care.

Methodology: Screening activity began in 2019 by collecting dried blood samples from birth to three months based at the three tertiary institutions across the three zones of the state, Ahmadu Bello University Teaching Hospital, Barau Dikko Teaching Hospital, and Sir Patrick Yakowa Hospitals. In order to increase access, the Primary Health Centres (PHC) staff were trained to collect samples for subsequent transportation to the central laboratories. (See chart for activity flow). Successful implementation of NBS at the PHC level required a number of stepsfew of which are; existing infrastructure and collaboration between stakeholders, government commitment through legal framework, policy backing, and budget; working with PHC practitioners to come up with a sustainability model for SCD primary care management, including protocols development for community health extension and community officer's work, guidelines on chemoprophylaxis for SCD to minimum age of 5 years.

Results: Sample Collection and Trend to show Key Role and Capacity for a Public Health NBS within PHC system in Kaduna, Nigeria (Collection Year Cycle May-April).

Summary/conclusion: Although newborn screening and follow-up have been implemented for SCD in many countries, the sheer numbers of babies with SCD in Nigeria is a “scale up problem“. Tackling this scale up problem has required selection of tools like train the trainer, implementation science, adapting existing Nigerian health system, and capacity building.

The economic benefit of reducing hospitalizations for SCD can be estimated from improving family work absences by 2 weeks per year at $406/yea and 27.9% labour force in Kaduna.^9,10

Overall, the SCD NBS pilot program in Kaduna is beginning to demonstrate benefits of reduction of burden of care and to return a healthy and sustainable model of care. Implementing SCD care is associated with 30% reduction in hospitalization due to SCD complications and a 35% reduction in those with more than 3 hospitalizations in a year.

Utility of implementation science approaches cannot be overemphasized, looking at the pilot NBS program in the areas of planning, implementation, and for sustainability, monitoring and evaluation. With these, the sample collection rate for NBS in Kaduna state which began with an average of 150 infants screened per month in 2019, dramatically grew when the program was introduced to primary healthcare facilities in August 2022, to an average of 547 newborns checked per month.

Topics: 001–Basic and translational

M. Yasin¹, R. Raman¹, K. Kosnan¹, S. Sulaiman², M. Ibrahim³, M. Sahid¹, M. Yusoff¹, E. Esa¹

Haematology Unit, Institute for Medical Research¹, 2UKM Medical Molecular Biology Institute (UMBI)², Paediatric Department, Women and Children Hospital, Tunku Azizah Hospital (HTA)³

Background: A lncRNA–miRNA–mRNA networks have revealed a mode of RNA interaction and are essential for many biological processes. They could be used as therapeutic targets, prognostic, and diagnostic indicators. This study aimed to identify the lncRNA– miRNA–mRNA network in Beta Thalassaemia patients.

Aims: RNA was extracted from the serum samples of Beta-thalassemia patients (major and traits, n = 6 each) and healthy controls (n = 6). LncRNA expression analysis was performed using Human SurePrint Microarray v3 (Agilent Technologies), and data analysis was performed using the Genespring software v14 (Agilent Technologies). Differentially expressed genes (DEGs) and lncRNAs with p value < 0.05 from three comparisons were selected: 1) Beta thalassemia major vs. controls, 2) Beta thalassemia trait vs. controls, and 3) Beta thalassemia major vs. trait. Then, lncRNA-miRNA and mRNA-miRNA interactions were predicted using the lncRNA-miRNAmRNA database LncBook, RNAcentral,LncBase, LNCipedia, miRNet) and the network was constructed using Cytoscape software.

Results: A total of 1053, 452, and 349 circulating DEGs and lncRNAs were identified in the three comparisons consecutively. Nineteen lncRNAs were significantly different in Traits compared to controls, 34 lncRNAs were different in Major compared to controls, and 94 lncRNAs were different in Major compared to Traits. LncRNA–miRNA–mRNA network was constructed by combining these DEGS and lncRNAs that were shared between the three comparisons consisting of 31 lncRNAs, eight miRNAs, and five mRNAs. A specific analysis identified 21 lncRNAs significantly different in beta-thalassemia individuals with 41/42 beta zero mutation, and one lncRNA, lnc-DNAJC8-1, was significantly reduced in all major patients regardless of mutation profiles.

Summary: To conclude, we constructed a network of lncRNA-miRNA-mRNA in both beta-thalassemia major and traits and found that the lnc-DNAJC8-1 was present in all major patients. This lncRNA could be a biomarker for beta-thalassemia major, and further research on the molecular mechanism is needed to confirm this.

Topics: 005–Clinical, infection and nutritional deficiencies

C. Adams-Mitchell¹, S. Cohen¹, M. Prosperi¹

University of Florida¹

Introduction: Sickle Cell Disease (SCD) is a deadly, painful set of genetic abnormalities primarily affecting patients of African and Mediterranean descent.

Although the hallmark symptom of SCD is pain, it is a multi-system disease that results in an amalgam of severe and lifethreatening health consequences including increased susceptibility to bacterial, viral, and fungal infections. Infection remains the leading cause of morbidity and mortality in individuals diagnosed with SCD.

We identified no research focused on the treatment patterns of antibiotic utilization in adults with SCD. This dearth of literature specific to SCD is surprising since the first 24 hours of antibiotic treatment in patients with SCD, especially those at risk for recurrent infection could reduce life threatening complications, length of hospital stay, and overall healthcare expenditures. A standardized protocol for treatment of infections in SCD does not exist and the first 24 hours of treatment varies among physicians and institutions. Treatment plans are determined by consensus guidelines, clinical experience and modifying treatment practices that have have shown promise in other diseases. The purpose of this study is to analyze treatment patterns within the first 24 hours of hospitalization in patients with SCD and infection to identify major factors influencing outcomes and clinical management.

Methods: We conducted a retrospective cohort study using electronic health records from hospitalizations with a documented infection in North-Central Florida. Encounters from patients with sickle cell disease (SCD) were identified using ICD codes (ICD-9 codes: 282.41, 282.42, 282.61, 282.62, 282.63, 282.64, 282.68, 282.69). Demographics, comorbid conditions, empiric antibiotic use, causative infectious organism, and the presenting infectious syndrome were extracted from EHR for each hospitalization. Outcomes of interest were length of hospitalization and 90-day all-cause mortality. Patients with no listed comorbid conditions at the time of hospital admission were excluded. Patient characteristics and clinical factors between groups were summarized descriptively and compared between SCD encounters.

Results: Among approximately 140,000 eligible encounters, 988 (0.71%) encounters were from those with SCD and of those 837 were included in the analysis:

Median Age: 47 y/o.

Sex: Female 583 (69.7%) Male: 254 (30.3%).

209 (0.25%) had an infection from E. coli and (12.4%) had an infection from staphylococcus aureus.

332 (39.7%) of hospital admissions were secondary to genitourinary infections.

Vancomycin (28.7) was the most frequently used antibiotic within the first 24 hours of admission.

More than half (67.4%) of patients had chronic pulmonary disease.

The median length of stay during our study period was 7 days.

12.1% of encounters required intensive care unit hospitalization.

90 Day All-Cause Mortality was 5.5%.

Summary: We examined the key comorbid conditions and factors that influence the hospitalization and their outcomes in SCD Future studies are needed to examine the key factors resulting in an increased risk of infection among SCD genotypes and the treatment patterns within the first 24 hours of treatment in patients with SCD and non-SCD to identify major factors influencing differences in outcomes and clinical management. Machine learning approaches could aid in stratifying patients to direct more intensive interventions towards.

Topics: 001–Basic and translational

A.K. Orolu¹, B.I. Osikomaiya², O.I. Adeyemi³, T.O. Ogunlade¹

Alimosho General Hospital, Igando¹, Lagos State Blood Transfusion Services², Lagos State University Teaching Hospital³

Background: The highest incidence of sickle cell disease (SCD) is seen in sub-Saharan Africa with the burden of the disease highest in Nigeria¹. About 2–3% of the population have SCD². In women with SCD, pregnancy is associated a high risk of maternal and fetal morbidity and mortality worldwide. To reduce the disease burden in pregnancy, several studies in the western world have indicated that 30% and 70% of women with SCD require at least one blood transfusion during pregnancy^3,4,5. It is important to explore this outcome in the Nigerian SCD population.

Aim: To determine transfusion rates among pregnant women with SCD.

Method: A retrospective observational study, which enrolled pregnant women with SCD who attended the obstetrics clinic as well as the heamatology clinic at Alimosho general hospital (ALGH), Igando, over a one-year period. Data was collected from patients' clinical notes using a study proforma. Data included antenatal, intrapartum and postnatal events. All pregnancies were managed according to the department's standard guidelines.

Results: The study enrolled 23 pregnant women, 16 (69.6%) were haemoglobin (Hb) SS while 7 (30.4%) were Hb SC phenotype. All patients were booked at the antenatal care (ANC) clinic and mean gestational age (GA) at booking was 18 weeks (8–28). The mean maternal age was 29.6 years (22–34) and mean GA at birth was 30 weeks (34–40). The mean booking packed cell volume (PCV) and stable PCV were 25.8% (21–35%) and 27.6% (21–35) respectively.

Prior to pregnancy only 3 women had 3 or more vaso-occlusive episodes per year, and were all of HbSS phenotype – 2 were on hydroxyurea.

A total of 20 (87%) women were transfused during pregnancy and postpartum. The mean trigger for blood transfusion was a PCV of 20.6% (15–26).

In the antepartum period 11 (47.8%) women required emergency transfusion of packed cells. Of these only one woman was HbSC. Most transfusions occurred in the 3rd trimester (63.6%). At post-partum, 18 (78. 3%) women were transfused due to symptomatic anaemia (6 HbSC and 12 HbSS).

The reasons observed for transfusion antepartum were malaria in pregnancy (n = 7), acute chest syndrome (n = 1), hyperhaemolytic crisis (n = 1), symptomatic anaemia (n = 11) and septicaemia (n = 5). At postpartum, other reported indications for transfusion were hyperhaemolytic crisis (n = 1), puerperal sepsis (n = 1), post-partum haemorrhage (n = 4) and acute chest syndrome (n = 1).

The women who received blood transfusions had significantly lower mean stable PCV (25.8 vs. 28.3%; p < 0.001) and significantly longer mean length of stay in the hospital postpartum (10.3 vs. 6 days; p < 0.001) when compared with the nontransfused cases.

Conclusion: In line with multidisciplinary care, heamatologists and obstetricians employ the use of blood transfusion therapy either prophylactically or during an acute event such as acute chest syndrome (ACS), to reduce the high disease burden of SCD in pregnancy. This study finds high rates of selective blood transfusion requirements among pregnant women with SCD. A larger prospective study of pregnant women with SCD will be needed to clarify the benefit of blood transfusion during pregnancy in SCD.

Topics: 005–Clinical, infection and nutritional deficiencies

M.G.B. Garcia Bernal¹, R.G.P. Garcia Puig², M.L.L. Lopez Liñan³

Hospital Universitari Mutua Terrassa /Consorci Sanitari de Terrassa¹, Hospital Universitari Mutua Terrassa², Cons orci Sanitari de Terrassa³

Background: Sickle cell disease (SCD) is an hemoglobinopathy characterized by sickle shape and rigidity of its red blood cells, leading to severe multi-organ effects by occlusion of blood vessels. Pain is the most common symptom in these patients. The abdominal Vaso occlusive crisis might be difficult to distinguish from other causes of abdominal pain.

Aim: We report three cases of coexisting diagnoses of SCD and autoimmune digestive disorders in paediatric patients from two hospitals of our geographical area around Barcelona.

Results: Case 1: an 8-year-old boy born from non-consanguineous Senegal parents and with HbSS SCD presents with a history of chronic diarrhoea and poor weight gain for the last 2 years. Although his symptoms were reported before, visits and exams were delayed due to Covid19 pandemic.

Faecal calprotectin levels were elevated, upper endoscopy was normal, and colonoscopy found active inflammation. Colonic biopsies showed features consistent with Ulcerative Colitis (UC).

Initially oral mesalazine was started. Due to poor response, other treatments had to be started: oral steroids, azathioprine, intravenous infliximab and finally intravenous ustekinumab. With this last treatment he achieved remission that he maintains today. Hydroxyurea treatment was not discontinued during this time.

Case 2: a 14-year-old girl, daughter of two consanguineous Moroccan parents and with HbSS SCD presents with intermittent abdominal pain, bloody stools, hyporexia for the last 4 years. Previous exams were always normal until faecal calprotectin level was high. Upper endoscopy, colonoscopy, magnetic resonance enterography and endoscopic capsule were performed, obtaining biopsies. She was diagnosed with Crohn Disease (CD) affecting ileum and rectum.

Oral budesonide was started followed by oral azathioprine, obtaining remission in a few weeks. Hydroxyurea treatment was also maintained during these months.

Case 3: a 9-year-old girl, daughter of two non-consanguineous parents from Senegal and with HbSS SCD presents with intermittent abdominal pain and persistent elevated liver enzymes for the last 4 years. Abdominal ultrasounds and viral serologies were normal, celiac disease and food allergies had been ruled out. A mild elevation of immunoglobulin G and positivity of anti-smooth muscle antibody were found. Finally, a liver biopsy showed features consistent with autoimmune hepatitis. Magnetic cholangioresonance wass normal, ruling out sclerous cholangitis. Oral steroids were started and after normalization of liver enzymes, she received oral azathioprine. The treatment was maintained until April 2022, when a bone marrow transplant from her HLA-matched sister was performed, resulting in the cure of both her hemoglobinopathy and the autoimmune hepatitis. She has had normal cell blood count and liver enzymes with no treatment required since then.

Summary/Conclusion: The co-existence of sickle cell disease and inflammatory bowel disease, as well as with autoimmune hepatitis, has been previously described although is not very common.

Symptoms may mimic those of the underlying hemoglobinopathy, causing delay in getting to the diagnosis. Therefore, the co-existence of IBD and AIH in patients with SCD represent a true challenge and physicians should be alert in the presence of digestive disorders non explained by SCD or the treatment received. A multidisciplinary approach in expert centres is encouraged.

Topics: 001 –Basic and translational

N.A. Al Allawi¹, S.D.M. Atroshi², C. Oberkanins³, R.K. Sadullah⁴, A.A. Eissa⁵, G. Kriegshauser⁶, S.M.S. Al-Zebari⁷, S.M.A. Qadir⁸, D.J. Khalil⁹

College of Medicine, University of Duhok¹, College of Medicine, University of Duhok², ViennaLab Diagnostics³, College of Health and Medical Techniques, Ploytechnic University⁴, College of Medicine, Iniversity of Duhok⁵, IHR Labor Medical Diagnostic Laboratories⁶, College of Scinece, University of Duhok⁷, Hematology, Azadi Teaching Hospital⁸, College of Science, University of Duhok⁹

Background: The heterogeneity of β-thalassemia phenotype has been attributed to several genetic modifiers, which may vary in different populations.

Aims: We aimed to study the roles of various genetic modifiers in Iraqi patients with β-thalassemia, and assess whether a population oriented genetic scoring system could be used to predict phenotype.

Methods: A total of 224 Iraqi patients with homozygous or compound heterozygous β-thalassemia were assessed for αthalassemia deletions and five polymorphisms at hemoglobin F QTLs namely: rs7482144 C>T at HBG2, rs1427407 G>T and rs10189857 A>G at BCL11A, and rs28384513 A>C and rs9399137 T>C at HMIP. The predictive ability of β-genotype, concomitant α-thalassemia and the aforementioned five polymorphisms, as they relate to phenotype were subsequently analyzed.

Results: The enrolled patients had a median age of 14 years, with 96 males and 128 females. They included 144 thalassemia major, and 80 thalassemia intermedia patients. Multivariate logistic regression revealed that a model including four out of the seven presumed genetic modifiers namely: β+alleles, HBG2rs7482144, α-thalassemia deletions, and BCL11Ars1427407 could significantly predict phenotype (Intermedia versus Major) with an overall prediction accuracy of 83.9%. A cumulative favorable allele score based on these significant predictors had an area under curve of 0.875 (95% CI: 0.830–0.919), which was highly significant (P = 1.594E–20).

Conclusion: Multivariate analysis identified four significant genetic predictors of phenotype in Iraqi β-thalassemia patients. Furthermore, a population-oriented cumulative favorable allele scoring system based on these four predictors had a good ability to discriminate between thalassemia major and intermedia. The study underscores the variable impact of genetic modifiers in different populations, and may pave the way to personalized medicine for β-thalassemia in this part of the world.

Topics 001–Basic and translational

R.D.A. Almabadi¹, L. Doi², C. Chandler²

University of Edinburgh/King Saud University¹, University of Edinburgh²

Background: The lack of evidence-based self-management programs for young adults (18–25 years old) with sickle cell disease (SCD) leads to high mortality and morbidity in this population. Therefore, developing a comprehensive, personcentered, and evidence-based self-management program that draws on different tools and strategies is crucial to improve quality of life and prevent disease complications among young adults with SCD.

Aim: To develop a toolbox of self-management interventions that help young adults with SCD live an efficient and normal life.

Methods: The research will be guided by the 2021 MRC Framework for Complex Interventions, in addition to co-production and personbased frameworks. Intervention development will take a phased approach, which includes:

Phase 1: Conducting a scoping review to synthesis the evidence related to the effective approaches, components, and characteristics of self-management interventions in young adults with chronic conditions that exhibit similar characteristics to SCD.

Phase 2: Conducting workshops with SCD young adults to define the concept of self-management and its components in SCD.

Phase 3: Carrying out focus groups with SCD young adults to learn more about their needs and preferences for the intervention's content, mechanisms of change, and delivery. This process will also identify self-management facilitators and barriers to further inform the development of the intervention.

Phase 4: Co-production of the self-management toolbox of interventions with SCD young adults.

Conclusion: The self-management toolbox would allow young adults with SCD to manage their lives by tailoring their actions to their needs to control their illness, enhance their health, and lower the risk of poor health outcomes and early mortality.

Topics: 007–Health services and outcomes research including psychology

K.L. Powell-Roach¹, U.O. Ogu¹, E.V. Culp¹, X. Cao², D.L. Clayton-Jones³, Y. Cruz-Almeida⁴, M.R. Wallace⁴, D.J. Wilkie⁴

University of Tennessee Health Science Center¹, The University of Tennessee Health Science Center (MEMPHIS)², Marquette University³, University of Florida⁴

Background: Pain is a widespread experience that can vary significantly between younger and older adults. In the context of sickle cell disease (SCD), that pathophysiology of pain is multifaceted, encompassing biological factors, stress, and vaso-occlusive processes. Whereas some patients manage their pain crisis at home, others require hospitalization for proper management. Despite the significance of pain and stress in SCD, a major obstacle is the limited understanding of the underlying mechanisms that contribute to pain and stress experienced by individuals in this population. Both young and older adult groups confront stressors related to discrimination, societal expectations, career challenges, financial strains, and agerelated health complications. Comprehending the multifaceted nature of pain and stress in this patient population is necessary to address the unique needs and challenges of each age group.

Aims: The primary aim of this study was to investigate the experiences of pain and stress in both younger and older adults living with SCD. By comparing these two groups, we seek to understand how pain and stress manifest in these age groups.

Methods: In this cross-sectional study, we examine perceived stress and pain experiences in a cohort of 50 adults living with SCD. The sample mean age was 39.8 ± 8.5 years and grouped as young adults (n = 25; age 29–39 years) and older adults (n = 25; age 40–59 years). Ninety-six percent of the participants were of African ancestry, and 62% were female. Participants had the following hemoglobin genotypes: 34 (68%) had SS, 12 (24%) had SC, and 4 (8%) had other Hgb genotypes. PAINReportIt was used to assess the Average Pain Intensity (API, average of current, least, and worst pain experienced within a 24-hour period, measured on a scale from 0 to 10). The Adult Sickle Cell Quality of Life Measure (ASCQ-Me) was used to measure the number of vaso-occlusive crisis at home and at the hospital. The individual's subjective perception of stress in their lives was measured using the Perceived Stress Scale (PSS). Descriptive statistics, independent t tests (continuous variables), and Chisquare tests (categorical variables) were conducted using R statistical software. The study received approval from the Institutional Review Board at the University of Tennessee Health Science Center.

Results: Age groups were not significantly different by sex, SCD type, weight, tobacco use, or alcohol use. Mean API scores among young adults (5.07 ± 2.18) and older adults (5.37 ± 2.36) were not significantly different (p = 0.63). Similarly, the number of pain crisis at home of young adults (4.2 ± 1.59) and older adults (4.2 ± 1.04) were not significantly different (p = 0.92) or respectively for the number of hospitalizations (1.84 ± 1.57 vs. 1.84 ± 1.49). The mean PSS scores approached significance (young adults 18.5 ± 4.52 vs. older adults 15.56 ± 7.14, p = 0.09).

Conclusion: We investigated the interplay between pain and perceived stress among individuals living with sickle cell disease across the age groups. Our analysis revealed none of the associations between the pain indicator, perceived stress, and demographic variables in younger and older adults were significant. Further research is needed with a larger sample size to examine the stress levels of young adults and older adults with SCD.

Topics: 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

A. Inati¹, N. Sbeiti², E. Khoriaty³, S. Koussa⁴, A. Taher⁵, T.A. Nasr⁴, T.G. St Pierre⁶

Lebanese American University¹, Rafic Hariri University Hospital², Clemenceau Medical Center³, Chronic Care Center⁴, American University of Beirut Medical Center⁵, The University of Western Australia⁶

Background: Measurement of liver iron concentration (LIC) by MRI is recommended in several guidelines on the management of iron overload in patients with thalassemia. However, a key barrier to adoption of such methods in resource poor countries is access to expertise and training in the associated image data analysis [1]. A new software system, DLA R2-MRI [2], based on deep-learning trained neural networks, has become available that automatically carries out both input data quality assurance and data analysis of suitable MR images increasing the possibility of more widespread adoption of reliable MRI based LIC measurement.

Aims: Our aim was to assess the diagnostic accuracy of the index DLA R2-MRI method on MR images acquired as part of a previous study comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation [3]. LIC values from MR scans obtained with the spin-density-projection-assisted (SDPA) R2 MRI method [4] were to be used as the reference values.

Methods: Archived MR data from the previous study were retrieved and analysed using the DLA R2-MRI software to generate LIC values. No human input was required in the analysis process and results were generated in seconds. The bias and 95% limits of agreement between the index and reference method were calculated. The sensitivities and specificities (with 95% CIs) of the index method for predicting LIC values by the reference method above clinically relevant thresholds were calculated using the Wilson-Brown method [5].

Results: 68 datasets were retrieved from archives and analysed by the DLA R2-MRI software. Six were rejected by the input quality control module owing to an absent date of birth in the DICOM images. The remaining 62 datasets yielded an LIC value. The 62 successful analyses represented evaluations on 32 patients with 8 patients being scanned 3 times, 14 patients being scanned twice, and 10 patients being scanned once. Patients (18/32 male) ranged in age from 3.2 to 19.7 years at first scan (mean 13.1 SD 4.1 years). 26 patients underwent iron reduction therapy during the study (14 phlebotomy and 12 chelation); 5 patients did not receive iron reduction therapy (4 not meeting eligibility criteria, and one not treated due to parental refusal); one patient withdrew from the study after only 2 months of iron reduction therapy. A plot of the 62 LIC values by the index method plotted against the reference method is shown in Figure 1. The bias between the index and reference results represented as the geometric mean ratio of the index LIC to the reference LIC was statistically insignificant being 1.00 [95% CI: 0.96–1.05]. The sensitivities and specificities of the index method for predicting reference LIC values above clinically relevant thresholds are shown in Table 1.

Summary/Conclusion: The data show a negligible bias between the fully automated index DLA R2-MRI method and the manual expert-dependent reference SDPA R2-MRI. The diagnostic accuracy is sufficient to guide iron reduction therapy in thalassemia major patients. The ability of the software to both provide input data quality assessment and LIC results within seconds without the need for data analyst training or outsourced analysis offers the opportunity for lower cost and more widespread availability of reliable LIC measurement by MRI for thalassemia major patients in Lebanon and beyond.

Topics: 004–Clinical, public health and epidemiological studies

G.Q. Queiroz¹, C.M. Monteiro², L.M. Manco¹, L.R. Relvas³, M.J.T. Trovoada⁴, A.L. Leita⁵, C.B. Bento³

Centro de Investigação em Antropologia e Saúde da Universidade de Coimbra (CIAS-UC), Coimbra, Portugal¹, Hospital Dr. Ayres de Menezes, São Tomé, República Democrática de São Tomé e Príncipe², Unidade Funcional Hematologia Molecular, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal³, Centro Nacional de Endemias da República Democrática de São Tomé e Príncipe, São Tomé, República Democrática de São Tomé e Prínc⁴, NOVA National School of Public Health, Public Health Research Centre, Comprehensive Health Research Center, CHRC, NOVA Universit⁵

Background: Although Sickle Cell Disorder (SCD) is Africa's most prevalent genetic disease, it remains a neglected condition, with high mortality under five and a lack of population-based studies in the region. Indeed, the newly-published Lancet Haematology Special Commission defies countries to publish epidemiological data on SCD until 2025 (1). DrepaComunidade is a community-driven platform that aims to improve knowledge and care around SCD in lusophone countries, starting precisely by studying its prevalence.

Aims: Pretending to launch a pilot study on nationwide SCD surveys, we started with the smallest Portuguese-speaking country, São Tomé e Príncipe, believing it could be an example to follow in a future scale-up. We kept it to women of reproductive age to improve the benefits from the results and point-of-care to better inform and capacitate local resources. Besides, based on our Drepacomunidade vision, we added a literacy assessment to inform public policies.

Methods: We conducted a cluster survey in 35 neighbourhoods. Haemoglobin was assessed through point-of-care capillary electrophoresis or high-performance liquid chromatography, and sociodemographic data through questionnaires. The weighted prevalence of sickle cell trait and HbC was estimated with a 95% confidence interval (95% CI). For its association with age and individual and collective genetic heritage, we calculated weighted prevalence ratios (95% CI) through robust Poisson regression.

Results: The prevalence of sickle cell trait in women of reproductive age in São Tomé e Príncipe (n = 376) was 13.45% (95% CI: 9.05–19.00). The prevalence of HbC carriers was 8.00% (95% CI: 4.71–12.00). Older age and speaking Forro or Angolar were positively associated with having sickle cell trait.

Conclusion: The prevalence of sickle cell trait in São Tomé e Príncipe ranks high in the West African region.

DrepaComunidade, through São Tome e Principe SCD patients association, Filhos da meia Lua Vermelha, is working with local stakeholders to translate and adapt international guidelines, in a way to implement neonatal screening and comprehensive healthcare management. We hope this is the first step to raising awareness of Drepanocitose (SCD in Portuguese) patients in Africa.

Funding: CIAS-UC (FCT: UIDB/00283/2020), DrepaComunidade and Forum Haematologico de Coimbra.

Topics: 007–Health services and outcomes research including psychology

A. Rylatt¹, J. James¹

Sickle Cell Society¹

Background: One of the clear findings of the ‘sickle cell care in England’ inquiry conducted by the Sickle Cell Society and the APPG on Sickle Cell and Thalassaemia, as detailed in the ‘No One's Listening’ report, was that inadequate staffing levels for sickle cell care are a key factor in the care failings sickle cell patients encounter. This research project set out to gain a more detailed understanding of the current level of nurse staffing for sickle cell, the impact this has on patients and clinicians, and what needs to happen to ensure there are sufficient numbers of nurses to deliver a good standard of care to sickle cell patients.

Methods: We launched a call for written evidence, which led to the receipt of 28 submissions from organisations and individuals from across England, including nurses, other healthcare professionals, patients and patient carers/relatives. We conducted nine one-to-one interviews with relevant experts – including nurses, consultant haematologists and patient relatives – and a focus group with the Sickle Cell & Thalassaemia Association of Nurses, Midwives and Allied Professionals (STANMAP). We also submitted Freedom of Information requests to Haemoglobinopathy Coordinating Centres and NHS Trusts to gain quantitative data.

Results: The overwhelming consensus among experts is that there is an insufficient number of specialist sickle cell nurses to deliver a good standard of care to patients. This is supported by the data, which shows that there is a higher sickle cell patient to nurse ratio in many areas of the country than recommended by experts as the level required to enable routine delivery of a good standard of care. The data we attained also showed that there is generally a higher number of patients per nurse across the country for sickle cell than for cystic fibrosis, a similar condition. There is a high degree of regional variation in the sickle cell nursing workforce level across the country, and particularly in the commissioning and availability of community-based sickle cell nursing support. In addition to insufficient funding, other factors identified as affecting specialist sickle cell nursing workforce levels included: insufficient training and lack of exposure to sickle cell patients for nurses in the early years of their career; a lack of leadership positions and fewer options for career progression for sickle cell nurses; and perceived lack of job satisfaction due to overwork and low pay. Those who provided evidence reported significant impacts on the standard of care patients receive and on nurses’ own wellbeing due to the insufficient number of specialist sickle cell nurses.

Conclusions: Our report shows the need for action to increase the specialist sickle cell nursing workforce and ensure existing specialist sickle cell nurses are being utilised as effectively as possible. Funding for more positions is part of the answer, but not the entirety. Other important measures include increased training and practical experience in delivering sickle cell care for nurses during training and the early years of their career; more leadership positions and clear pathways for development; better succession planning; and additional administrative support and utilisation of technology to reduce nurses’ non-patient-facing duties. We conclude that commissioning service specifications should contain a requirement for a minimum of one specialist sickle cell nurse per 100 registered sickle cell patients.

Topics: 004–Clinical, public health and epidemiological studies

S.F. Odoom¹, A. Osei-Akoto¹, D. Ansong¹, S.B. Nguah¹, E.K. Nakua², R. Asampong¹, K. Boakye², E.O. Acheampong², M.M. Beru², N.A.S. Eyeson², E.X. Amuzu¹, I. Nyanor¹, F.A. Osei², E. Amanor², A.A. Aidoo², V. Paintsil¹

Komfo Anokye Teaching Hospital¹, Kwame Nkrumah University of Science and Technology²

Background: Sickle Cell Disease (SCD) remains a significant issue in public health, particularly in Africa where over 200,000 newborns are affected yearly. Annually, approximately 2.0% of all live births in Ghana are diagnosed with SCD. Majority of patients with SCD still suffer from complications which necessitate hospitalisation.

Aims: The aim of this study was to determine the frequency, causes, and factors contributing to hospitalisation and rehospitalisation among children with SCD in Kumasi-Ghana.

Method: The study was an analytical cross-sectional study of 421 children with SCD between the ages of 2 to 17 years accessing care from the outpatient hematology clinic at the Komfo Anokye Teaching Hospital between October 2021 to January 2022. The 421 SCD patients were randomly selected from the Sickle Pan-African Research Consortium Ghana Database. The outcome variables (Hospitalisation and Rehospitalisation) measured in this study was assessed self-reportedly by the SCD patients and/or caregivers. Logistic regression analysis was used to determine the key factors contributing to hospitalisation and rehospitalisation among children with SCD. Statistical significance was set at 0.05.

Results: Hospitalisation was observed in 160 (38.00%) of the patients. Among these patients hospitalised, 57 (35.63%) had at least 2 episodes of hospitalisation in the past 12 months. The most common causes of hospitalisation were Vaso-occlusive Pain Episodes (VOPE) 78 (18.53%), Severe anemia 42 (9.98%), and malaria 18 (4.28%). Key factors contributing to hospitalisation in this study were age at diagnosis of SCD (aOR = 0.89, CI = 0.84–0.95), and taking home-made medication for the treatment of SCD (aOR = 2.70, CI = 1.6–24.49). Also, presence of comorbidity (aOR = 4.31, CI = 1.05–17.72) and VOPE (aOR = 2.07, 1.00–4.36) significantly increased the odds of rehospitalisation.

Conclusion: The study reports a relatively high prevalence of hospitalisation among children with SCD. The findings point to the urgent need to address VOPE, anemia and malaria among children with SCD, and intensify health education against the use of ineffective homemade medication for the treatment of SCD.

Topics: 002–Novel therapies, gene therapies and bone marrow transplant

N. Igbineweka¹, S. Okoli¹, M. Sohal¹, A. Luqmani¹, C. Lee¹, S. Mackie¹, C. Vladescu¹, A. Cull², E. Bennett², J. Milek², J. Quinton², D. Bukini³, F. Urio³, R. Christopher³, J. Manongi³, C. Kanza³, M. Chapman⁴, H. Vincon⁵, F. Ciuculescu⁵, M. Armant⁵, E. Esrick⁵, P. Campbell⁴, D. Williams⁶, D.M. Layton¹, J. Makani⁷, D. Kent²

Imperial College London¹, University of York², Muhimbili University of Health and Allied Sciences (MUHAS)³, Well come Sanger Institute⁴, Boston Children's Hospital, Harvard Medical School⁵, Dana-Farber/Boston Children's Cancer⁶, Imperial College London UK/Muhimbili University of Health and Allied Sciences (MUHAS), Dar-es-Salaam, Tanzania⁷

Background: Recent advances in gene therapy as a curative therapeutic strategy is revolutionising sickle cell disease (SCD). Nonetheless, concerns remain regarding the potential for developing gene-therapy related haematological malignancies. Substantial recent progress has been made in technologies to permit whole genome sequencing (WGS) and high-depth duplex sequencing to chart mutational burden in patient cohorts. These tools set the stage for in-depth characterisation of genome integrity in patients with SCD.

Aim: To evaluate SCD genomic integrity from multiple international locations using high-depth duplex sequencing to track acquisition of driver mutations and overall mutational burden.

Methods: This is a cross-sectional, multi-centre study, investigating SCD mutational burdens using high-depth duplex sequencing. Including the UK, this is undertaken at three other sites: two African (Tanzania and Uganda), and one site in the USA, to compare genetic variation amongst cohorts. Minimum number for UK recruitment is 50 participants (25 SCD and 25 non-SCD controls) both adult and children for age and ethnically matched controls with an overall total of 200 participants across the 4 sites. UK patients with SCD are recruited from SCD clinics and healthy controls, from general haematology clinics. For each consented patient, peripheral blood samples are collected. To maintain cell viability, samples are processed in the laboratory within 2 hours of blood collection with density gradient centrifugation to isolate the granulocytes from mononuclear cells. Following red blood cell lysis, DNA is then extracted and stored at −20°C/−80°C before being sent for sequencing. Individual mutational burden will be correlated with predictor variables such as SCD genotype and mutation rates across genes associated with clonal haematopoiesis. The study start and end date are 1st November 2022 to 1st November 2024.

Results: In the UK, sample recruitment number have been met with 25 adult SCD participants consented and recruited. These samples have been stored and we now plan to recruit 25 age and ethnically matched adult controls. This presents logistical challenges sourcing this patient group. As such, these participant controls will be identified and recruited from general haematology clinics with assistance from local haematology consultants and a clinical research coordinator. Other challenges include paediatric SCD recruitment in an adult haematology department so collaboration with paediatric colleagues’ is needed.

Conclusion: This study aims to provide key information around SCD mutagenesis and clonal haematopoiesis with application of findings expected within the year.

Topics: 007–Health services and outcomes research including psychology

R.M.K. Awadzi¹, A.A. Anwer², L. Allawi¹, M. Abdi¹, J. Setsoafia³, S. Kalu⁴, D. Reddiar⁵, S. Kazi¹, A. Odulaja⁶, A. Awadzi⁷, H. Attua⁸, D. Saad El-Din¹, K. Anie⁹

London Northwest University Healthcare NHS Trust, London¹, University Hospital of Wales, Cardiff², Worcester A cute Hospitals NHS Trust³, Causeway Hospital, Northern Ireland⁴, Health Data Research UK⁵, Whittington Health NHS Trust, London⁶, Dundee University⁷, Anglia Ruskin University⁸, Imperial College London⁹

Background: Sickle cell disease (SCD) is a multifaceted condition that poses significant challenges to healthcare professionals (HCPs) and patients worldwide. Access to accurate, up-to-date information is crucial for providing optimal care and enhancing the quality of life for those living with SCD. However, the limited availability of educational resources on this condition often hampers HCPs' ability to deliver effective care and restricts patients from proactively managing their condition.

Methods: This systematic literature review highlights the critical role of online medical education teaching platforms in addressing knowledge gaps in sickle cell education for patients and HCPs. Through a systematic literature search, three relevant studies were identified, with one being particularly pertinent to the clinical question. In response to the pressing need for comprehensive education on SCD, a cutting-edge online teaching platform, known as the Sickle Cell Education Series, was developed by a team of HCPs. This retrospective cohort review examines a single-centre study featuring a series of four online sessions targeting HCPs and patients for managing sickle cell disease. The teaching framework, adapted from the “Head, Heart, and Hands" model, was advertised on social media, Eventbrite, and by word of mouth, attracting an initial cohort of 60, which grew to 350 participants by the fourth session.

Results: The novel platform aims to bridge the educational gap by delivering evidence-based, engaging, and interactive learning experiences tailored to both HCPs and patients. Its curriculum offers a comprehensive understanding of SCD, encompassing epidemiology, pathophysiology, diagnosis, management, and research. The modules integrate multimedia elements, case studies, and interactive simulations to enhance learning retention and clinical application. To assess the platform's impact, evaluation strategies employed include: pre- and post-assessments, participant feedback, and performance metrics. These refine the platform's content and delivery methods, ensuring its relevance and effectiveness over time.

Summary: The platform empowers patients with valuable insights into their condition, fostering informed self-advocacy and promoting adherence to treatment plans. Patient-centred modules address essential aspects of SCD, including symptom recognition, pain management, lifestyle adjustments, and psychosocial support, all designed to enhance patients' autonomy in managing their health. The SCE platform includes live webinars, discussion forums, and virtual conferences, facilitating real-time interactions among healthcare professionals, patients, and experts from diverse backgrounds. Furthermore, the platform's user-friendly interface and accessibility across multiple devices ensure seamless integration into busy healthcare schedules and patients' daily lives.

Conclusion: The Sickle Cell Education online teaching platform represents a pioneering effort in bridging the knowledge gap in SCD among healthcare professionals and patients. By providing evidence-based, interactive, and patient-centric learning experiences, this platform holds immense potential to improve healthcare outcomes, promote informed decision-making, and foster collaborative patientprovider relationships in the management of SCD. As the series continues to evolve, its contribution to improving the care of SCD patients is poised to leave a lasting impact on global healthcare communities.

Topics: 004–Clinical, public health and epidemiological studies

S. Al Kindi¹, S. Raniga¹, E. Al-Ajmi¹, F. Al Azri¹, A. Al Asmi¹, A.V. Pathare¹

Sultan Qaboos University¹

Background: Sickle cell disease (SCD) is a major public health problem in Oman with a high morbidity and mortality. Fat embolism syndrome (FES) is a rare but serious complication following bone marrow necrosis in SCD patients with vasooclusive crisis (VOC).

Methods: The aim was to study the underlying factors associated with SCD patients who develop FES during VOCs in Oman. The electronic medical records of 24 consecutive SCD patients who were diagnosed with FES between 2006 to 2022 were analysed. The study was approved by the local medical research and ethics committee. The data captured included SCD clinical and laboratory manifestations during VOC episodes leading to FES. Specifically, we analysed the cardiovascular, haematological, biochemical and radiological parameters as well as the use of antibiotics, simple and exchange blood transfusions.

Results: 24 patients (15 males, 9 females) who formed this cohort showed a median age of 24.5 years with an interquartile range (IQR) of 21.25–34 years. The median length of hospital stay was 23.5 days with IQR between 16.5 to 43.25 days. During their hospital stay, patients had fever, chest/back pain, cough and crepitation in 100%, 96%, 50% and 100% respectively, with reduced O2 saturation in 96% and neurological manifestations in 71%. Further, abnormal chest x-rays and CT scans (n = 7) were observed in 96%, 100% respectively. Amongst the haematology parameters, there was a significant drop in the median hemoglobin and platelet counts from baseline, along with a significant rise in the median WBC count (p < 0.05, Wilcoxon Signed Ranks test). The biochemical parameters showed a significant rise in the median serum lactic dehydrogenase and median C-reactive protein levels (p < 0.05). In this cohort, 15 patients had culture proven sepsis, with 8 (53%) patients showing multiple microorganisms. Amongst the 20 microorganisms isolated, 10 (50%) each respectively, were bacterial and fungal isolates. All patients (100%) received antibiotics, along with simple and exchange blood transfusions, whereas, 27%, 32% and 41% respectively, required non-invasive ventilation (NIV) alone, NIV with ventilation and ventilation alone. Four patients (17%) died, whereas, 20 (83%) made a complete recovery.

Conclusion: Although FES historically, has a significantly high morbidity and mortality, a high index of suspicion, coupled with rapid institution of supportive measures including broad spectrum antibiotics, top-up simple and exchange blood transfusions and multidisciplinary approach, were critical in reducing the mortality in FES.

Topics: 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

A.P. Piehler¹, C. Creatore², H.T. Mevik², E.C. Langsjøen², H. Cario³, G. Hoermann¹, E.W. Axelsen²

MLL Munich Leukemia Laboratory¹, Fürst Medical Laboratroy², Universitätsklinikum Ulm, Klinik für Kinder- und J ugendmedizin, Labor für Spezielle Hämatologische Diagnostik³

Background: Hemoglobinopathies are mainly caused by mutations in the alpha- and beta-globin gene clusters which are located on chromosomes 11 and 16, respectively, and therefore inherited independently. Thus, alpha-thalassemia can be coinherited with other hemoglobinopathies caused by mutations in the beta-globin gene.

Aim: In the current study, we sought to determine (1) the frequency of co-inheritance of alpha-thalassemia and other hemoglobinopathies caused by mutations in the beta-globin gene in a population from a European country of immigration and (2) whether this co-inheritance can be detected based on erythrocyte indices and hemoglobin capillary electrophoresis without genetic testing.

Methods: In the period 2013–2023, consecutive samples (n = 18493) from patients sent for hemoglobinopathy work-up at a large European laboratory were included. Beta-thalassemia trait was defined by HbA2 levels ≥3.6% as measured by capillary electrophoresis on Sebia Capillarys 2 and the absence of a structural hemoglobin variant. Beta-thalassemia intermedia and major were excluded. Hemoglobin S and E were confirmed by HPLC (BioRad). Common α-globin gene deletions (-a3.7, -a4.2, -SEA, --MED, --FIL, --THAI,-(a)20.5) were detected by multiplex gap-PCR. Erythrocyte parameters were measured on a Sysmex XN-1000. Further biochemical tests were performed on Siemens Advia instruments.

Results: Alpha-thalassemia, beta-thalassemia, HbS, and HbE were detected in 3994 (21.5%), 2646 (14.3%), 553 (3%) and 646 (3.5%) samples, respectively. Within the beta-thalassemia, HbS and HbE cohorts, alpha-thalassemia was simultaneously diagnosed in 271 (10.2%), 208 (37.6%) and 168 (26.0%) cases, respectively. Samples with co-inherited alpha-thalassemia showed significantly lower levels of HbS (mean 32.1% vs. 38.7%) or HbE (mean 19.1% vs. 25.2%) in capillary electrophoresis than heterozygous HbS or HbE carriers without additional alpha-thalassemia, and higher levels of hemoglobin, MCH and MCV (mean 12.37 g/dl, 20.85 pg and 68.34 fl) than isolated β-thalassemia trait (11.70 g/dl, 19.9 pg and 65.2 fl) (all p < 0.0001).

Applying machine learning, detection of co-inherited alpha-thalassemia depends on the investigated subgroup. Using treebased algorithms, machine learning was able to distinguish co-inheritance of alpha-thalassemia from HbE trait alone with an F1-score of 88% (accuracy 94%, PPV 85%, NPV 97%). HbE fraction with a cut-off of 23.3% as the single best discriminator performed with an F1-score of 86% (accuracy 92%, PPV 81%, NPV 97%). Similarly, co-inheritance of alpha-thalassemia and HbS can be separated from HbS trait alone with an F1-score of 95% (accuracy 96%, PPV 93%, NPV 98%) using machine learning. An HbS fraction cut-off of 36.0% as a single discriminator showed an F1-score of 94% (accuracy 95%, PPV 90%, NPV 98%). These results demonstrate that machine learning presents a slight competitive advantage compared to fixed cut-off thresholds.

In contrast, co-inheritance of alpha- and beta-thalassemia was not sufficiently distinguishable from beta-thalassemia alone. This finding was further supported by visualising case distributions. Neither MCH alone as the single best discriminative parameter nor dimensionality reduction on multiple erythrocyte indices were able to achieve significant separation between the two groups.

Conclusion: Co-inheritance of alpha-thalassemia with other hemoglobinopathies caused by mutations in the beta-globin gene is frequent. Machine learning indicates a promising potential for improving detection of co-inheritance of alpha-thalassemia in HbE and HbS trait cases, respectively, but has no clinically significant impact on identification of co-inherited alphathalassemia in betathalassemia trait samples. So far, genetic testing is required to rule out co-inherited alpha-thalassemia definitely e.g. for the purpose of genetic counseling of couples at risk for severe alpha-thalassemia.

Topics: 004–Clinical, public health and epidemiological studies

Z.E. Gbedemah¹, M.S. Fuseini¹, L. Mowatt², A. Adenekan³, A. Ahmed⁴, N. Osuji⁵, R. Bourkiza⁶, E. Mensah⁶, S. Sivaprasad⁷, W.M.K. Amoaku⁸, K.N. Amissah-Arthur⁹

Korle-bu Teaching Hospital¹, University of the West Indies and the University Hospital of the West Indies², Lagos University Teaching Hospital and College of Medicine University of Lagos³, Komfo Anokye Teaching Hospital⁴, North Middles ex University Hospital NHS Trust⁵, London North West University Healthcare NHS Trust⁶, Moorfields Eye Hospital NHS Foundation Trust and Moorfields NIHR Clinical Research Facility⁷, University of Nottingham and Nottingham University Hospitals Trust⁸, Korle Bu Teaching Hospital and University of Ghana School of Medicine and Dentistry⁹

Background: Enhancing patients' comprehension of their medical conditions through accessible information is of utmost importance. Online resources play a crucial role in patient education, underscoring the significance of assessing their quality and readability is important to empower individuals effectively.

Aims: This study aims to evaluate the readabilty and quality of internet-based health information on sickle cell retinopathy.

Methods: The study conducted a simulated online search representative of a patient's perspective utilising the top three search engines (Google, Bing and Yahoo). The search queries “sickle cell retinopathy” and “sickle cell disease in the eye” were entered yielding the initial 20 results from each search. Subsequently, a meticulous examination of quality and readability was undertaken. To gauge the quality of information employed, the DISCERN questionnaire, the Journal of the American Medical Association (JAMA) standards and the Health on the Net (HON) criteria were employed. The readability of each website was assessed utilising Flesch-Kincaid Grade Level (FKGL), Flesch Reading Ease (FRES) and Automated Readability Index (ARI).

Results: The results revealed a mean DISCERN score of 40.91 (SD 10.39, maximum possible, 80). Among the analysed online sources, 12 out of 16 (75%) scored moderately on the DISCERN tool. Only three (18.75%) of the websites were certified by the HON code, and none of the sites satisfied all JAMA benchmarks. The mean FRES was 57.76 (±4.61), falling short of the recommended range of 80–90. On both the FKGL and the ARI, all the websites surpassed the American Medical Association target grade level of six.

Summary/Conclusion: This study presents a thorough evaluation of the internet's information pertaining to sickle cell retinopathy for patients. The findings underscore two key insights: firstly, scarcity of comprehensive content addressing sickle cell retinopathy exists. Secondly, the available information poses challenges in terms of readability and expected quality. By channelling collective expertise, knowledge, and resources, the research outputs stemming from the sickle cell retinopathy network (SCR.net) hold the key to potentially addressing these existing disparities.

Topics: 004–Clinical, public health and epidemiological studies

A.G.M. Ismail¹, G.S.M. Ahmed¹, S.F.M. Bushara², A.J. Abdi³, O.S.M. Suliman⁴

Sudanese Medical Specialization Board¹, Khartoum University², Federal Ministry of Health³, International African University⁴

Background: Sickle-cell disease is a multisystem disease, associated with episodes of acute illness and progressive organ damage, and is one of the most common severe monogenic disorders worldwide. The most devastating neurologic manifestation of SCD is stroke. In thanks to advancements in early detection, prevention and management of SCD-related complications such as stroke, the quality of life and survival have been improved. However, less knowledge about SCDrelated stroke types, risk factors, presenting symptoms and outcomes of patients.

Objectives: To study risk factors and outcomes of stroke among sickle cell disease children at Ibrahim Malik Hospital and Jaafar Ibn Ouf Hospital.

Methods: This is a cross-sectional hospital-based study conducted from May 2022 to November 2022 in two large hospitals in Khartoum, Sudan. The study population was all SCD children with stroke who are aged below 18 years. Data was collected using a data collection sheet filled from an interview, clinical evaluation and reviewing of tests after the obtainment of verbal consent from the caregivers. Analysis was conducted using SPSS version 26, and p-values less than 0.05 were considered significant.

Results: A total of 93 SCD stroke patients were enrolled on the study, of those, most participants (64.2%) were aged more than 10 years old with male predominance (54.8%). Family history of SCD was present among (75.3%) of participants, while consanguinity between parents was present in (69.9%).

The majority of (38.7%) children were diagnosed with SCD at ages between 6 months and one year, while (52.7%) of participants had experienced a first stroke at the age of more than 5 years. (36.6%) had a past history of stroke. The majority of the patients 92 and few of them received a pneumococcal vaccine, influenza vaccine and phenoxy benzylpenicillin, 23, 4 and 1 respectively. The most frequent neurological symptoms among the study group were speech disorders (68.8%) and convulsions (60.2%). Sensory symptoms were observed in (4.3%), weakness in (89.2%), hemiplegia in (74.2%) and cranial involvement in (53.8%). The vast majority of participants (88.2%) had infarction stroke and (5.4%) had hemorrhagic stroke type.

Most of the patients (63.4%) had a residual disability, (17.2%) of patients expressed partial recovery and (19.4%) of patients recovered fully. A significant association was found between adherence to prophylactic measures and the onset of disease (p = 0.04).

Conclusion: This study revealed several potential risk factors for stroke among SCD children, particularly irregular preventive medications. Furthermore, the study documented slightly high unfavourable outcomes of SCD stroke patients.

Topics: 004–Clinical, public health and epidemiological studies

D. Bukini¹, C. Kanza¹, A. Rifai¹, J. Mashaka¹, E.P. Kisali¹, D. Maingu¹, F. Luoga¹, S. Karim¹, M.Z. Alimohamed¹, G. Moshi², L. Luzzatto¹, J. Makani¹

Muhimbili University of Health and Allied Sciences¹, KK Women's and Children's Hospital²

Background: There are considerable efforts in improving comprehensive care services for Sickle Cell Disease in Africa. However, there are gaps in knowledge, training and clinical capacity to provide advanced care for patients with SCD in Africa. Tanzania is in the process of setting up an advanced therapy program for SCD. The program aims to develop and strengthen s Exchange Blood Transfusion (ExBT) and stem cell transplantation services for SCD. This paper highlights the steps taken to establish the Sickle- ARx program by looking at four main areas; Clinical, Research, Patient Engagement, Training and Capacity Building Component, spotlight the successes attained and share the challenges faced and how to navigate them in a low resourced SCD center in Africa.

Progress: Patient Engagement: Advanced therapy patient engagement camp was conducted between March - June 2021 to raise awareness on various advance therapy options increasingly available to SCD patients globally and specifically provide information on the ExBT services that were established in Dar es Salaam. 50 patients participated in the camps. Advanced Therapy for SCD Symposia was done on 11 June 2022. The symposium brought together 135 patients, caregivers and healthcare providers. The focus was to understand general perspectives of patients on advanced therapy for SCD in Tanzania.

Clinical Approach (i) Screening Stage: In total 700 patients were screened between September 2021 to August 2022 which 120 patients fit the inclusion criteria to be part of the advanced therapy registry. (ii) Referral for Exchange transfusion and HLA typing: In total 15 patients received EBT at since August 2021. On average three number of cycles were done per patient at the interval of four to six weeks depending on HbSS levels and based on patients' clinical presentations. HLA Typing to determine the availability of HLAmatched sibling donor.

Research Approach: There is ongoing work on (i) the establishment of a cord blood collection pipeline, the cord blood serving as a rich source of stem cells that can be cryopreserved and utilized when needed either for allogeneic bone marrow transplants (BMT), or in gene-editing workflows. (ii) The development of Target Product Profile (TPP) for both in vivo and ex vivo gene therapy products will help guide researchers, clinicians and patients to agree on the acceptable target endpoints that will define the pathway for the in vivo and ex vivo gene therapy product at both minimal and optimal conditions (iii) Potential enablers and barriers to in vivo gene therapy for Sickle Cell Disease is investigated by means of desktop review and qualitative research with specific attention being paid to the ethical, legal, and social issues which may arise.

Conclusion: Tanzania has demonstrated that there is progress in developing a strategy for curative therapies for SCD in Africa. A key component of these strategies for care and cure is partnerships at the local and global levels. Muhimbili University of Health and Allied Sciences has been keen in forming partnerships both locally and globally in order to find a suitable and appropriate curative option for SCD patients in Africa that would also be beneficial and cost effective.

Topics: 004–Clinical, public health and epidemiological studies

F. Jamil¹, N. Capaldi¹, J. Kennedy¹, N. Priddee², J. Laird², L. McIlwaine¹

Glasgow Royal Infirmary¹, Scottish National Blood Transfusion Service²

Background: Numbers of patients with haemoglobinopathies treated in Scotland are rising, predominantly as a result of migration from Africa. Just over 50% of adult patients are managed in Greater Glasgow and Clyde (GGC) Healthboard. Red cell transfusion remains a mainstay of treatment in emergency and long-term care for patients and for prevention of complications. Patients with sickle cell disorder (SCD) must be given units that are ABO, extended Rh and Kell compatible¹. The British Society of Haematology recommends patients with R₀ phenotype are transfused R₀ blood.

Aim: To identify patients’ transfusion requirements within our population based on extended red cell phenotype, particular Rh phenotypes, antibodies present, and compare to the donor population in Scotland.

Methods: Patients managed in GGC were identified. We obtained laboratory information to collate phenotype and antibody status. Donor information was obtained from the Scottish National Blood Transfusion Service.

Results: 98 patients are currently being or have been managed in the last two years with 36 requiring transfusion – either top up or exchange. 84 patients have extended red cell phenotypes including Rh phenotype available. The most common Rh phenotype was R₀R₀/R₀r, found in 48 patients (49%). 11 patients were found to have antibodies.

Only 2% of UK blood donors have R₀ blood. It is more common in people of Black African or Black Carribean descent². In Scotland,

0.15% of blood donors are of “Black African” and 0.18% from “Mixed African or Caribbean” descent.

Conclusion: We anticipate that our data sample of just over 50% of adult SCD patients in Scotland will be representative of demographics of SCD patients nationally. Results highlight the need to identify R₀ donors and improve matching with SCD recipients. The data also underlines a mismatch between the ethnicity of the Scottish blood donor and SCD populations. Current strategies to address this include phenotyping of all suitable donors and engagement with ethnic minority communities to improve donor recruitment and retention.

Topics: 002–Novel therapies, gene therapies and bone marrow transplant

H.R. Reikvam¹, S.K.A. Almeland², F.E. Ezligini³, K.D. Dorsch⁴, J.N.H. Hourani⁴, L.A.O. Omert⁴

University of Bergen¹, University of Bergen; Haukeland University Hospital², Oslo University Hospital³, Hemanext Inc⁴

Background: Red blood cell transfusion provides life-saving oxygen delivery for patients with acquired bleeding in trauma and burns as well as being an integral part of supportive care in benign hematologic disorders and hematologic malignancies. Despite the advantages of RBCs, adverse events (AEs) occur in both acute and chronically transfused patients. Hemanext Inc. (Lexington, MA, United States) has developed a CE mark certified device to process and store RBCs hypoxically–CPD/PAGGSM leukocytes-reduced (LR), O2/CO2 reduced–which may potentially reduce transfusion burden in transfusiondependent patients (e.g., sickle cell disease, thalassemia, and cancer) and attenuate the oxidative stress associated with acute major bleeding.

Aims: The objective of this observational pilot study is to investigate the safety and tolerance of transfusing hypoxic red blood cells in 20 patients requiring acute or chronic RBC transfusions. The hypoxic RBC should have a similar safety profile to the standard of care¹.

Methods: Patients aged ≥18 years with hemoglobin (Hb) ≤9 g/dL and requiring ≥2 units of RBCs in a single transfusion event (hematologic patients) or who require ≥2 units RBCs due to perioperative bleeding (burn patients) are being enrolled. The full study protocol will include 10 patients with hematological malignancies and 10 patients with burns; this interim report describes the first 12 patients to receive hypoxic RBCs. All patients received one 2-hour transfusion episode of two units of hypoxic RBCs produced using the CPD/PAGGSM LR, O2/CO2 reduced system instead of conventionally stored RBCs. The primary objective is the number of AEs up to 24 hours following transfusion initiation and up to 7 days (±1 day) posttransfusion in comparison with historical controls (including but not limited to infection, deep vein thrombosis, acute respiratory distress syndrome, transfusion-related acute lung injury, transfusion associated circulatory overload, anaphylactic shock, acute hemolytic transfusion reaction).

Secondary objectives include assessment of AEs up to the subsequent transfusion episode or 28 days (±1 day) posttransfusion, whichever occurred first. Additionally, changes in Hb levels post-transfusion are assessed.

Results: At the time of this report, 8 hematological malignancy and 4 burn patients have been enrolled. Hematologic malignancy patients had been receiving conventional RBC transfusions every two weeks prior to study initiation, and all patients received the hypoxic RBCs without complication. Individual patient characteristics are shown in Table 1.

Sixteen adverse events occurred in 8 patients, and none were deemed related to the blood product or device. There were no severe adverse events. Two infections (rhinovirus) were reported, there were no reports of deep vein thrombosis, acute respiratory distress syndrome, transfusion-related acute lung injury, transfusion associated circulatory overload, anaphylactic shock, or acute hemolytic transfusion reaction.

Hb levels increased by 13% following the administration of hypoxic RBCs from a pre-transfusion mean [±SD] of 8.7 ± 1.5 g/dL to 9.8 ± 1.5 g/dL post-transfusion.

Summary/Conclusion: This interim report showed that transfusion with hypoxic RBCs processed with the CPD/PAGGSM LR, O2/CO2 reduced system are safe and well-tolerated in patients with hematologic malignancies and burns. Additionally, Hb levels were within the target range at follow-up, suggesting that hypoxically stored RBCs function appropriately. The overall clinical program will assess the benefits of hypoxic RBCs versus conventional RBCs in sickle cell disease, thalassemia, MDS, and trauma patients requiring chronic or acute transfusions.

Topics: 007–Health services and outcomes research including psychology

L. Mowatt¹, A. Adenekan², K.N. Amissah-Arthur³, A. Ahmed⁴, M.S. Fuseini⁵, Z.E. Gbedemah⁵, N. Osuji⁶, R. Bourkiza⁷, S. Sivaprasad⁸, W.M.K. Amoaku⁹, E. Mensah¹⁰

University of the West Indies, University Hospital of the West Indies¹, Lagos University Teaching Hospital and College of Medicine University of Lagos², Korle Bu Teaching Hospital and University of Ghana School of Medicine and Dentistry³, Komfo Anokye Teaching Hospital⁴, Korle Bu Teaching Hospital⁵, North Middlesex University Hospital NHS Trust⁶, London North West University Healthcare NHS Trust⁷, 7. Moorfields Eye Hospital NHS Foundation Trust and Moorfields NIHR Clinical Research Facility⁸, University of Nottingham and Nottingham University Hospitals Trust⁹, London North West University Healthcare NHS Trust, UK¹⁰

Background: Sickle cell retinopathy (SCR) is a potentially blinding condition that affects young people. There is a scarcity and imbalance in research and clinical trials concerning SCR, particularly when juxtaposed with other retinovascular diseases that pose similar risks to vision. The underlying reasons for this inequity are diverse, encompassing factors such as racial disparities, funding discrepancies, and geographical distribution. Visual loss from SCR can be prevented with timely screening and treatment. There are many unanswered questions with regard to management and appropriate treatment protocols¹.

Aim: We describe the design and initiation of the sickle cell retinopathy network (SCR.net) with the following vision and mission declarations:

Vision Statement: To reduce the prevalence of vision-threatening complications in people with any sickle cell genotype.

Mission Statement: To highlight the importance of and conduct research to reduce vision-threatening complications in people with any sickle cell genotype, through global collaboration with multidisciplinary teams in countries and populations where this disease is present. To produce robust multicenter research to determine the diagnosis and risk factors affecting visual loss in this population. To develop evidence-based screening and management protocols to reduce preventable blindness in the population with the sickle cell genotype.

Conclusion: The SCR.net establishment marks a pivotal step towards addressing the significant paucity of research and clinical gaps in SCR. The multifaceted implications of SCR extend beyond the healthcare realm, encompassing socioeconomic ramifications. By uniting a global community of multidisciplinary experts, SCR.net is poised to revolutionise the approach to SCR, by working collaboratively to reduce vision-threatening complications in individuals with sickle cell genotypes. Through a commitment to rigorous research, evidence-based protocols, and enhanced ophthalmic care, SCR.net's transformative goals can reshape the landscape of SCR management, reducing visual loss and mitigating socioeconomic consequences.

Topics: 007–Health services and outcomes research including psychology

S. AlNuaimi¹, N. Singh¹, F.A. Azeez¹, M. Khaseif¹, F. AlMutairy¹, N. Hussein¹, A. Gopakumar², M. Naveed¹

Fujairah Hospital Emirates Health Services¹, Emirates Health Services²

Background: Beta-Thalassemia is among the most common inherited blood diseases of public health importance in the Arab World. It is a chronic illness that affects the production of hemoglobin and red blood cells. The gene carrier frequency and incidence of Beta-Thalassemia are high in the indigenous Emirati population in the United Arab Emirates (UAE).

Aims: Chronic diseases significantly contribute to mortality, morbidity, and socioeconomic costs globally, and Quality of life (QoL) is an essential patient-centered outcome for chronic disease. This study investigated the quality of life among patients with Transfusion Dependent Thalassemia (TDT) in the UAE.

Methods: Using the World Health Organization's Quality of Life Brief Questionnaire (WHOQOL-BREF) instrument, this descriptive cross-sectional survey assessed the physical, psychological, social relationship, and environmental quality of life of 54 patients with TDT. We obtained ethical approval for this study from our institutional review board. Medical Social Worker did a face-to-face interview to get written informed consent from participants or their legally authorized representatives. We collected the patient responses and performed descriptive statistics (frequencies and percentages) on the data of all consenting patients and their families.

Results: Domain scores of 54 patients were tested for normality (by Shapiro–Wilk test). The mean (standard deviation) physical (score 7-35), psychological (score 6-30), social relationship (score 3-15), and environmental health-related (score 5-25) quality of life domain scores were 27.1 (3.3), 23.1 (2.2), 11.7 (1.5) and 17.8 (2.4) respectively out of 54 respondents. A score of overall QoL ranges from 26130, with an average score of 79.8 ± 6.9. QoL was classified into three groups, Poor, Average, and Good. Based on the scoring system, good QoL among the patients was observed for the domains such as physical (96.3%, n-52), psychological (98.1%, n-53), social relationship (94.4%, n-51), and environmental (85.2%, n-46). No patients were found to be under the poor QoL category. Overall, 78% (n-42) patients had Good QoL in all four domains, 19% (n-10) found under the Good QoL category in 3 domains, and two patients (4%) had Good QoL in 2 domains.

Conclusions: The quality of life of most persons living with TDT managed at our Thalassemia Center was satisfactory in all four domains of the WHOQOL-BREF instrument. This was possible due to a federal initiative advocating holistic care to all patients with TDT. For the minority of the patients, strategies that identify and address any deterioration in the quality of life in specific domains are required throughout their care plan at our Center.

Topics: 004–Clinical, public health and epidemiological studies

A.S. Seenivasan¹, F.K. Kagalwala²

Lister Hospital¹, Lister Hospital²

Aims: To analyze the incidence of Ceftriaxone Induced Immune Hemolytic Anemia (CIIHA) in pediatric population and its significance among various genotypes of Sickle cell Disease (SCD).

Methods: We performed a single-centered retrospective study for 5 years on ceftriaxone induced hemolysis in SCD population who were in our data base. Pre and post hemoglobin levels following intravenous Ceftriaxone was analyzed. In addition, the duration of antibiotics and its effect in different SCD genotypes were studied.

Results: We had 60 admissions among 26 patients and 58 admissions received more than 1 dose of ceftriaxone. The pre- and postceftriaxone hemoglobin levels were 85.5 and 83.7 mg/dl respectively (p = 0.1359). We sub-categorized the children into HbSS and HbSC genotypes and compared the hemoglobin values post ceftriaxone which did not show any difference. Despite receiving 10 doses of ceftriaxone, the hemoglobin levels did not show any fall and none of them showed acute clinical deterioration.

Discussion: Increasing case reports on CIIHA in children especially with SCD causes wariness of using the most preferred antibiotic. The actual incidence of CIIHA remains unknown. We hence tried to retrospectively analyze the effect of ceftriaxone in children with SCD.

Among 60 admissions none of them showed clinical deterioration and the post ceftriaxone hemoglobin levels were similar to the pre ceftriaxone levels. Similarly, the number of doses did not have any effect on the hemoglobin levels.

Also, the HbSC genotypes behaved similar to the HbSS genotypes and there were no appreciable differences in hemolysis between the 2 groups.

Conclusion: Although the complication of CIIHA should be borne in mind, it should not be a limiting factor to offer ceftriaxone and would be premature to defer in the SCD population. Larger multi-centric trials are required to understand the actual incidence of CIIHA in paediatric population.

Topics: 004–Clinical, public health and epidemiological studies

A.O.D. Ofakunrin¹, E.S. Okpe¹, R. Olaosebikan², T.O. Afolaranmi³, K. Bello⁴, A.S. Sagay⁵, S. Oguche¹

Department of Pediatrics, University of Jos/Jos University Teaching Hospital¹, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University², Department of Community Health, University of Jos/Jos University Teaching Hospital³, Department of Pediatrics, Jos University Teaching Hospital⁴, Department of Obstetrics and Gynaecology, University of Jos/Jos University Teaching Hospital⁵

Background: Hydroxyurea is a sickle cell disease-modifying therapy that is capable of reducing the morbidity, mortality and improving the quality of life of patients with sickle cell anemia. However, its uptake has been reported to be low both in the developing and developed countries.

Aims: The aim of this study was to describe the clinical profile of children with sickle cell anemia who were on hydroxyurea and the pattern of uptake of the medication at the Jos University Teaching Hospital (JUTH), Jos, North-Central Nigeria.

Methods: This was a cross-sectional study using a review of registry data of the haematology-oncology unit of the department of Paediatrics, JUTH from January 2016 to January 2023. The registry which started in 2016 was supported by a National Institute of Health grant (D43 TW010130). The registry as of January 2023 has a total number of 1168 children with SCD of which 517 were on hydroxyurea. The registry, which is still active, archives all sickle cell-related events in all the patients both at admissions and during clinic visits including the hydroxyurea history. The routine utilization of hydroxyurea among Paediatric patients in JUTH began in 2017. Prior to this period, only six patients were on hydroxyurea and they all commenced the medication from another facility before they started accessing care at JUTH.

The required data were extracted from the registry by two research assistants and this was validated by the lead researcher by comparing the extracted information with the data in the registry. The information extracted included the demographic characteristics of the subjects, hydroxyurea history which included date of initiation, duration of use of the medication, the current dosage, indication for hydroxyurea and motivation for hydroxyurea initiation. Data analysis was carried out using SPSS version 23.0 for Windows and descriptive statistical test was carried out on the variables.

Results: A total of 517 children with sickle cell anaemia aged 1–17 years who were on hydroxyurea were recruited, of which 278 (53.8%) were males. Of the 517 patients, 309 (59.8%) commenced hydroxyurea on account of frequent vaso-occlusive crises (≥2 episodes per year), 35 (6.8%) due to acute chest syndrome, 26 (5.0%) due to stroke, and 147 (28.4%) were offered hydroxyurea as a routine medication. The median duration on hydroxyurea was 41 months (IQR 29–56 months), while the median current dosage of the medication was 500 mg (IQR 300–700 mg). The decision to use hydroxyurea among 320 (62%) of the subjects was influenced by reports from other patients (or patients’ care givers) who were treated with the medication.

Hydroxyurea uptake increased from 6 patients (1.2%, 6/500) in 2016 to 517 patients (44.3%, 517/1168) in 2023.

Conclusion: Increased hydroxyurea uptake among sickle cell anemia patients is feasible and patients-driven advocacy could help increase the uptake.

Topics: 004–Clinical, public health and epidemiological studies

D. Jain¹, F.J. Kirkham²

Government Medical College¹, UCL GOSH Institute of Child Health²

Introduction: In homozygous sickle cell anemia (SCA), without prophylactic treatment, time-averaged mean of the maximum velocity (TAMMV) >200 cm/sec (Abnormal) on non-imaging transcranial Doppler (TCD) predicted a 40% risk of stroke over the following 3 years¹; regular blood transfusion or hydroxyurea reduces the risk substantially. Imaging TCD is more widely available, with TAMMV) >185 cm/sec considered Abnormal if there has been angle correction, although there are few follow-up data on whether this is the appropriate threshold for stroke risk.

Aim:

Methods: The current study was conducted in consecutively recruited stable children with SCA SCA in India, in a steady state of health. Middle cerebral artery velocity (MCAV) was measured using either an imaging machine (Lasiq s8) or a portable non-imaging TCD (DWL) and a 2 Mhz probe.

Results: 163 children and youth aged 2–18 (median 7) years, 97 (59%) male underwent TCD (82, 52%, non-imaging).

Five (2.5%) had previously had a clinical stroke, all with normal TCD (2 imaging), although one had PSV of 190 cm/sec and internal carotid artery narrowing on MRA.

In the 158 without previous stroke, for Non-Imaging (n = 79) and Imaging (n = 79) respectively, 3 (4%) and one (1%) children had Abnormal and 3 (4%) and none had Conditional velocities. For non-imaging, the range of TAMMV was 40–233 cm/sec and for imaging, TAMMV was 43–270 cm/sec. Nine patients had low or unobtainable intracranial TAMMV (<50 cm/sec).

Of the 107 followed up for 1 to 53 (median 43) months, 3 died, each of causes unrelated to sickle cell disease (one Dengue, one Human Immundeficiency Virus, one Chronic Myeloid Leukaemia). One with Imaging TAMMV of 194 cm/sec had a stroke.

Discussion: Non-imaging and imaging TCD screening is feasible in Indian SCD populations. It is important to establish an appropriate Imaging TCD protocol, including cutoffs for Angle-corrected TAMMV. Outcome data are needed, particularly for imaging TCD. These data provide the rationale for implementing systematic screening for screening with TCD to reduce the risk of stroke in children affected by SCD in India.

Topics: 004–Clinical, public health and epidemiological studies

M. Mamman¹, A.R. Bako¹

Ahmadu Bello University Zaria¹

Background: Although Nigeria has one of the fastest growing sickle cell disease (SCD) populations globally, there is paucity of data on the effects of SCD on students, particularly of tertiary institutions, which are likely to suffer most from the physical and psychological burdens of the disease. The aim of this study is to examine the effects of SCD among students in tertiary institutions of Kaduna State.

Methods: First, a retrospective analysis of all admissions at the tertiary institutions over a 5-year period (2017–2021) was conducted to identify students with SCD. The student's record was obtained from either academic record office or medical record office in the institutions for recording of students with SCD. The study recruited participants from six tertiary institutions with a sample size of 384. To complement the questionnaire, two Focus Group Discussions (FGDs) were held at both the State and federal institutions. Data were analyse with R programming language.

Results: The findings of this study revealed that out of the 385 participants, 258 (67%) were male, while 127 (33%) were female. Majority (88%) of the respondents are between the ages of 21–30 years and majority (88%) of the SCD patients frequently experience crisis every 3 months. About 65% of the SCD patients reported missing academic activities between 7 to 10 days in a month. And about 36% of the SCD patients used massage as a means of coping strategy to manage the crisis. The general trend of SCD patient among the undergraduate in tertiary institution of Kaduna state from 2016–2021 is on the reduction stage. Many of the undergraduate SCD patients depend on parent income in the school. Undergraduates of tertiary institutions with sickle cell disease (SCD) are at risk of underperforming academically as they miss classes and lectures due to rate of crisis occurrence.

Conclusion: Many tertiary institutions in Kaduna state do not have data on SCD. It is therefore urgent to establish a data base on SCD and health related issues. It was also found that the academic performance of undergraduate students with SCD was negatively affected, and that they reported missing more days due to the frequency of crisis experienced. Special attention and SCD facilities should be made available in all the health care institutions to tackle the needs of SCD patients among the undergraduate students.

Topics: 004–Clinical, public health and epidemiological studies

P. Kountouris¹, C. Stephanou¹, M.M. Nwegbu², O.E. Nnodu², M. Oni³, N.M. Archer³, L. Tshilolo⁴, N. Mohamad⁵, B.A. Zilfalil⁵, A. Glenthøj⁶, A. Waziri⁷, R.Z.A. R. Sabudin⁸, A.B. Waqar⁹, M.D. Diamantidis¹⁰, K. Michailidou¹, A. Didio¹¹, V. Giannuzzi¹¹, F. Bonifazi¹¹, C.W. Lederer¹, on behalf of the International Hemoglobinopathy Research Network (INHERENT)¹²

The Cyprus Institute of Neurology & Genetics¹, Centre of Excellence for Sickle Cell Disease Research and Training, University of Abuja², Dana-Farber/Boston Children's Cancer and Blood Disorders Center³, CEFA-Monkole Institut de Recherche Biomédicale⁴, Universiti Sains Malaysia, Health Campus⁵, Danish Red Blood Cell Center, Department of Hematology, Co penhagen University Hospital-Rigshospitalet⁶, Ahmadu Bello University Teaching Hospital⁷, Universiti Kebangsaan Malaysia Medical Centre⁸, University of Lahore⁹, General Hospital of Larissa¹⁰, Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus¹¹, International Hemoglobinopathy Research Network (INHERENT)¹²

Background: Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenesis is well established, the diverse clinical manifestations and the varying degree of severity of hemoglobinopathies are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterization of several genetic modifiers by previous studies, these are, as yet, insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalized treatment. The International Hemoglobinopathy Research Network (INHERENT) has recently been established to investigate the role of genetic modifiers in hemoglobinopathies, through a large, multiethnic genome-wide association study (GWAS).

Aims: This pilot study aims to test the operational feasibility of the INHERENT study in different geographic and healthcare settings and, thus, identify potential challenges in performing the envisioned GWAS within the INHERENT network.

Methods: INHERENT members participating in the pilot study have been selected based on their geographic location, disease group distribution (SCD/thalassemia) and hemoglobinopathy-specific healthcare policy. Currently, a total of ten healthcare providers from Cyprus, Denmark, DR Congo, Greece, Malaysia (2), Nigeria (2), Pakistan, and USA participate in the pilot study, which aims for a global recruitment of over 800 patients with an inherited hemoglobinopathy. The following steps of the study implementation are tested: (a) local bioethics approval on the basis of the applicable local legal framework, (b) patient enrollment, (c) sample/data collection, (d) genotyping of globin genes, (e) centralized GWAS experiments, and (f) statistical analysis of GWAS data.

Results: A survey was designed to understand the rules in different countries and sites and, therefore, allow a better preparation of the study material and data exchange across the network. The INHERENT study protocol has been developed to enable a common approach among all participating centers. Specifically, a common case report form (CRF) has been developed on REDCap to facilitate standardized collection of phenotypic data, which include data parameters related to demographics, laboratory measurements, clinical complications, and treatment regimens. In addition, common experimental protocols have been developed for the GWAS experiments, including collection, storage, and transfer of samples, and for determining the α and β genotypes.

Summary/Conclusion: The INHERNET pilot study will test common standards developed within the INHERENT network and will enable early identification and resolution of key challenges associated with the execution of a large, multi-ethnic study for hemoglobinopathies. The pilot, as a prerequisite for the scale-up of INHERENT GWAS to the full network membership, will thus enable study of a hemoglobinopathy population with unprecedented sample size and diversity, to allow novel discoveries and expand knowledge on underlying genetics and to pave the way for advanced personalized treatment and diagnosis.

Funding: The INHERENT pilot study was supported through a grant from Agios Pharmaceuticals Inc.

Topics: 004–Clinical, public health and epidemiological studies

B.P.A. Prado Jr¹, F.A. Silva¹, A.C. Silva-Pinto¹, L. Moraes², D.T. Covas¹

Hemocentro de Ribeirão Preto¹, Terumo BCT, Medical Affairs²

Introduction: Blood transfusion is a mainstay of long-term Sicke Cell Disease (SCD) first-line treatment for primary and secondary prevention of stroke. Manual transfusion (MT) or automated red blood cell exchange (aRBCX) can reduce the complications of chronic transfusions and maintain target haemoglobin thresholds. The benefits of manual versus automated red blood cells exchange have rarely been documented in Brazil. We aim to describe our Centre experience of overseeing SCD patients either treated with regular MT or aRBCX for the prevention of stroke and compares the safety and efficacy of both procedures.

Methods: This retrospective observational case study was conducted with 04 adult patients with SCD treated in a period from 2002–2023 at Hemocentro of University of Sao Paulo, Ribeirao Preto, Brazil. Clinical and haematological data were recorded and analyzed.

Results: Both procedures were well tolerated. A total of 950 transfusion procedures for 04 adult SCD patients who were enrolled in regular transfusion program were performed with a total of 589 MT (2–9 years) and 361 aRBCX procedures over a period of 16 years.

The median level of HbS% post-aRBCX was significantly lower than MT (16.88% vs. 44.4%, p ≤ 0.001). Patients on aRBCX had longer intervals between two procedures when compared with MT, with the absence of recurrent acute clinical events. The median period between sessions was (51 days in aRBCX vs. 21 days in MT, p ≤ 0.01). Although the average packed Red Blood Cells units per pacient needed for aRBCX procedure was more than the double that was needed for MT procedure, the median ferritin level was lower post-aRBCX compared with MT procedures (278 µg/L vs. 974 µg/L). Due a consistent and accurate red cell antigen matching donor program in our centre prior to transfusion, the alloimmunisation rates was consistent reduced from 0,41 to 0,061 per 100 units of red cells transfused.

Conclusions: aRBCX is more effective in controling HbS levels and sickle cell-related complications with longer intervals between clinic visits. Our data demonstrate that although more pRBCs were transfunded, the ferretin levels was reduced post- aRBCX without increasing alloimmunization risk. This is a sucessful single centre experience in the management of SCD patients, where we demonstrated that patient access to aRBCX treatment can reduce geographical inequalities in the management of sickle cell disease.

Topics: 004–Clinical, public health and epidemiological studies

M.S. Fuseini¹, Z.E. Gbedemah¹, L. Mowatt², A. Adenekan³, A. Ahmed⁴, N. Osuji⁵, R. Bourkiza⁶, E. Mensah⁶, W.M.K. Amoaku⁷, S. Sivaprasad⁸, K.N. Amissah-Arthur⁹

Korle Bu Teaching Hospital¹, University of the West Indies and the University Hospital of the West Indies², Lagos University Teaching Hospital and College of Medicine University of Lagos³, Komfo Anokye Teaching Hospital⁴, North Middles ex University Hospital NHS Trust⁵, London North West University Healthcare NHS Trust⁶, University of Nottingham and Nottingham University Hospitals Trust⁷, Moorfields Eye Hospital NHS Foundation Trust and Moorfields NIHR Clinical Research Facility⁸, Korle Bu Teaching Hospital and University of Ghana School of Medicine and Dentistry⁹

Background: Sickle cell retinopathy (SCR) is a well-recognised complication of Sickle cell disease (SCD) and causes significant ocular morbidity. The need for a personalised approach to sickle cell retinopathy has been evident for several years. This is partly due to a paucity of evidence available for translation into widely agreed clinical management plans and protocols.

Aim: This study aims to investigate the trends in the global research landscape with regard to SCR.

Methods: Bibliometric analysis was conducted to explore the patterns in worldwide research endeavours related to SCR between 1954 and 2023. Utilising a dataset comprising 799 SCR publications indexed in Scopus, Python scripts were developed to automatically extract, refine, and scrutinise multiple aspects. These aspects encompassed the number of publications and the authors’ affiliations in terms of their national and institutional associations, quantification and identification of funding sources, as well as the cumulative number of citations garnered by each publication. Additionally, the extent of international collaboration was investigated by assessing the authors’ country of origin, providing a comprehensive overview of joint efforts across nations.

Results: The research effort on SCR to date has been mainly led by the United States of America (USA), which accounted for over 40% (398) of all publications with either full or partial contributions. European Union member countries also made significant contributions of 28% (227), and the United Kingdom (UK) contributed 8% (71) of the publications. African countries had the least involvement in research efforts on SCR, contributing 25 publications from Nigeria and 6 from Ghana. Among the Caribbean islands, Jamaica had the most involvement with partial or full contributions in 43 publications. Other contributors were Cuba with 3 publications, as well as Trinidad and Tobago, and Martinique with 1 publication each. About 80% of published manuscripts had authors from a single country whilst 20% had authors from at least 2 countries. The country that had the highest collaborative points was the USA. Out of 824 declared funding sources for research on SCR, 497 were for research undertaken in the USA, 38 in the UK and Jamaica, and only 2 for those involving Nigeria and Ghana.

Summary/Conclusion: The output of research on SCR has been mainly from the high-income countries in the North.

Regrettably, outputs from African and Caribbean countries that bear substantial disease burdens, have been limited.

Additionally, international collaboration between high-income countries and West Africa and the Caribbean is lacking. Establishing collaborative networks between nations in the Global North and the Global South is imperative to enhance the worldwide understanding of SCR.

Topics: 004–Clinical, public health and epidemiological studies

L.E. Gani¹, L.G. Daniel¹, H. Usman², Y.C. Tanimu³, L.Z. Elisha¹, J.O. Gani⁴, B.P. Inusa⁵, H.T. Mohammed²

Kaduna State University Library¹, ARISE-Kaduna State University², ARISE- College of Education Gidan Waya³, AR ISE-GREAT PANAF SCHOOLS⁴, Guy's and St Thomas’ Hospital⁵

Background: Sickle cell disease (SCD), a hereditary condition that affects over 50 million people worldwide, is becoming more common (Acharya et al., 2023 & John et al., 2020). It is predicted that 15 million children will be born with Sickle cell disease (Beri et al., 2021) over the next 20 years, with sub-Saharan Africa carrying the majority of the disease's burden (Inusa et al., 2018). Sickle cell disease is the most prevalent hereditary blood condition in Africa, with 75% of all cases occurring (Wastnedge et al., 2020). This figure is predicted to rise as a result of globalization and population growth.

Despite this, SCD is frequently regarded as an unnoticeable disability (Srikanthan, 2023) and is not well understood by the general public in some contexts. The poor understanding of SCD has led to disparities in care, poor health outcomes, social marginalization, discrimination, stress, and stigmatization. Other challenges are lack of government support and inadequate interventions for people living with the disease. This study in Kaduna, Nigeria aims to investigate these issues using the ecological model of healthcare.

Aim: To determine the awareness of SCD by university undergraduates in the light of the ecological model framework.

Methods: A qualitative case study was carried out between May 2023 and June 2023 with 60 students of the faculty of Arts at Kaduna State University, Kaduna Nigeria. Students from six departments which are English and Drama, Nigerian Language and Linguistics, French, Arabic, Christian Religion Studies, Islamic Studies, and History. The semi-structured interviews were recorded, and the data were analyzed and interpreted by thematic analysis.

Result: The discussion of findings was arranged in line with the four theoretical constructs.

The construct of Intrapersonal/individual factors (CIIF)

Findings from this study revealed that the respondents who are undergraduate students at KASU are aware of the existence of SCD, they know that the disease is hereditary but they are not aware of any support that students living with the disease receive from the university.

The construct of Interpersonal factors (CIF)

The major aspect identified as the interpersonal factor is that KASU SCD warriors in KASU are bold, shy, arrogant, and need attention always. However, a few of them socialize and interact very well with the students while others keep to themselves.

Construct of Community Factors (CCF)

The construct of community factor uncovered that people try to avoid SCD warriors in the community (stigmatization). Secondly, they are called sicklers meaning that they will die at any moment and thirdly are denied certain rights and privileges such as job opportunities.

The construct of Society Policy Factors (CSPF)

This study identified the availability of rules/laws/policies to serve as guidelines on SCD in society. The findings revealed that the undergraduate students are not aware of the existence of any policy in KASU or anywhere. The finding exposed that the availability of the policies/guidelines/laws will create awareness, give statistics, and help in the prevention and management of SCD.

Conclusion: The Urie Bronfenbrenner's model developed in the 1970s applied in this study has aimed to create awareness and knowledge about SCD. It is expected to lead to positive change in SCD health care outcomes, increase the quality of life, reduce the burden of the disease, and attract intervention in Low-and Middle-income Country Settings.

Topics: 004–Clinical, public health and epidemiological studies

R.A.M. Ahmed¹, H.M.M. Mirghani²

Assistant Professor, Alneelain University, Pediatric Department¹, Consultant Pediatrician and Haematologist, Gaafar Ibnauf pediatric tertiary Hospital²

Background: Abnormalities in vascular function due to sickle cell anemia has been demonstrated which affect their blood pressure reading. Higher systolic blood pressures are associated with earlier mortality, strokes and renal insufficiency.

Aims: The goal of study to assess the systemic blood pressure reading among Sudanese children with sickle cell anemia.

Methods: This Cross sectional analytic study included 200 patients with sickle cell anemia (5–≤18 years old), who were seen during routine follow up visits in Fathelrahman El-bashir health center. Children with stroke and vaso-oclusive crises were excluded. The data collected after taking an informed concent which included history of sickle cell complications and admissions. Anthropometric measurements, blood pressure, Complete blood count and serum creatinine were measured for all participants.

Results: Majority of patients have low reading of blood pressure (57.5%). Pre-hypertension was reported in (1.5%) and hypertension in (1%) of patient. Majority of participants (90.5%) in this study have e-GFR (≥90 ml/min/1.73 m²) with mean estimated GFR was (152.90 ± 76.08), which indicate hyperfiltraion. The analysis revealed that blood pressure reading show significant association with nutritional status, total number of admission and with frequency of Vaso-occlusive crises (p value < 0.05). It also identified that the blood pressure was influence by hemoglobin level and estimated glomerular filtration rate.

Conclusion: This study revealed that despite lower reading of the blood pressure in children and adolescent with sickle cells anemia they at risk of hypertension, early detection of hypertension is essential to establish effective treatment to prevent end organ damage.

Topics: 004–Clinical, public health and epidemiological studies

A.B. Abaan Butt¹, I.T. Indu Thakur², H.M. Helen Murphy³

Cardiff Medical School¹, Cardiff and Vale UHB - Child Health², Cardiff and Vale UHB - Paediatric Oncology³

Background: Sickle cell disease (SCD) encompasses a group of inherited blood disorders with significant morbidity and mortality.

Hydroxycarbamide, an oral medication, is currently the only proven licensed medication in the UK to prevent recurrent sickle cell crises. The medication raises levels of Haemoglobin F and thereby proportionally reduces the levels of pathological Hameoglobin S. In 2018 the British Society for Haematology (BSH) published guidelines for the use of hydroxycarbamide in children with SCD.

Aim: Evaluate the clinical practice in Noah's Ark Children's Hospital, Wales in comparison to the national guidelines provided by the BSH on the use of hydroxycarbamide in children with SCD.

Methods: Data was collected from 37 eligible patients who have a diagnosis of SCD (HbSS or HbSß0) through the Welsh Clinical Portal and paper notes and used to populate a hydroxycarbamide audit tool. Data and statistical analysis were performed to obtain results pertaining to patient demographics, hydroxycarbamide treatment details, blood test results, and admission rates before and after the initiation of hydroxycarbamide.

Results: All eligible patients (100%) were receiving treatment except one who had to cease treatment due to adverse effects. There was variability in the age of initiation due to a variety of factors such as being diagnosed before the recent guidelines and patient/parent reluctance. Most patients (84%) were commenced on the recommended dose (mean = 17 mg/kg) but in some instances, the dose fell outside the guidelines. Blood test results did not align with expectations possibly due to varied treatment durations and missing preinitiation test data. Admission rates were significantly reduced following treatment (p = 0.0001).

Conclusions: The findings suggest Noah's Ark Children's Hospital is meeting BSH guidelines in terms of offering hydroxycarbamide to all eligible patients. Recommendations include improving documentation and optimizing follow-up. The audit highlights the importance of following the guidelines and individualized care for children receiving hydroxycarbamide.

Topics 007–Health services and outcomes research including psychology

F.B. Fedele Bonifazi¹, A.D. Antonella Didio¹, L.R. Lucia Ruggieri¹, A.D.S. Ashel Dache Sunday², B.I. Baba Inusa³

Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus¹, Barau Dikko Teaching Hospital, Kaduna State University², King's College London/Guy's and St Thomas' NHS Foundation Tru st³

Background: Despite progresses have been made in the management of sickle cell disease (SCD) (1), huge disparities exist between high-income and middle-low-income countries¹ where policies and funding are still inadequate, healthcare workers are insufficiently trained and diagnostic tools and treatments are scarce.^2-4 The use of transcranial Doppler (TCD) to identify SCD children at high risk of stroke, has led to significant reduction in the incidence of SCD-associated stroke.⁵ Chronic transfusion therapy is the standard of care for stroke prevention and management of recurrent episodes of acute chest syndrome or severe pain.⁶ However, in low-income countries specific challenges occur, such as inadequate blood supply, risk of infections, alloimmunization, organ damage from iron overload and poor acceptance due to sociocultural factors. Financial constraints also arise from the cost of iron overload monitoring including liver magnetic resonance imaging (MRI) and the cost of iron chelation itself.⁶

Aims: This study aims to map and analyze the organization of healthcare centers for SCD patients in African countries and Lebanon in relation with accessibility and readiness of specific health technologies used for SCD complications management. A pilot experience investigated 10 centers in 4 Nigerian States (Kaduna, Katsina, Federal Capital Territory-Abuja and Kwara) in 2020. All centers perform basic laboratory tests on SCD patients and almost all adopt the National Guidelines for the control and management of SCD. All facilities perform Alkaline Gel Electrophoresis for SCD screening, while more than one half blood film. Screening services are mainly paid out of pocket by the patients. No online SCD patient registry is established at the centers.

Methods: This is a questionnaire-based prospective study. A descriptive analysis will be performed by adopting software for statistical analysis (e.g., R studio; Statistical Package for the Social Science [SPSS]).

Results: Based on their relevance in the applicable national and international guidelines on SCD management, 3 health technologies were identified: blood transfusion service, MRI and TCD devices. One ad hoc questionnaire for each of them, designed according to the WHO Service Availability and Readiness Assessment (SARA) approach⁷ (Table 1), was prepared to collect information about the technology, its usage, availability of accessories and supplies, maintenance procedures, staff and training. LimeSurvey will be used to manage delivery to reference persons and data collection.

Applications for ethics approval in the concerned countries is under submission according to the applicable national and international laws.

Conclusion: Full results are expected by the end of 2024. This will allow to describe healthcare centers organization in terms of services accessibility and readiness. The aim is both to contribute to the assessment of the needs of patients, families and healthcare professionals in terms of information, training and support in monitoring and reporting of SCD symptoms, acute complications, and treatments and to facilitate the adoption of more appropriate health policies by providing decision makers with the description of possible gaps to be addressed at local and country level. This would pave the way towards a more effective management of SCD patients in those countries where the burden of the disease is higher.

Table 1. Survey parameters/indicators.

This study will be conducted within the African Research and Innovative initiative for Sickle cell Education (ARISE)—that has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (grant agreement No 824021)—in collaboration with the Consortium for Advancement of MRI Education and Research (CAMERA).

Topics 007–Health services and outcomes research including psychology

A.A. Abubakar Abdulkareem¹, F.B. Fedele Bonifazi², A.D. Antonella Didio², A.L. Annalisa Landi², L.R. Lucia Ruggieri², L.D. Livingstone Dogara³, B.I. Baba Inusa⁴

Barau Dikko Teaching Hospital, Kaduna State University¹, Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus², Department of Haematology and Blood Transfusion, Faculty of Basic Clinical Sciences, Kaduna State University College of Medicine³, King's College London/Guy's and St Thomas' NHS Foundation Trust⁴

Background: Sickle cell disease (SCD) patients are at greatest risk for death in the first 5 years of life.¹ Problems associated with SCD and its complications have been addressed from different perspectives such as genetic counselling, knowledge, and awareness, pharmacological treatments, patient and physician relationship, caregiver's perspectives on treatment as well as socio-economic perspectives.^2–6 However, while these perspectives have helped to better understand the problems, few studies are reported in literature to assess the needs of patients and healthcare workers.

In addition, in our knowledge, none of them has been conducted in the centers concerned by this study.

Aims: This study is proposed as the extension of a pilot experience (NCT04505969), conducted in 2020 in 4 selected Nigerian centers in Kaduna and Katsina States, to assess the needs of patients and healthcare workers.The pilot showed adequate satisfactory rate among patients and healthcare professionals about their experience with SCD management in the center. However, a lower satisfaction score was highlighted with reference to the access to treatment. 90.5% of the interviewed healthcare professionals are overall satisfied with their work with SCD patients. Poor training and equipment are the main needs. Participants also expressed the need for more space in both clinic and laboratory and for standardized procedures. The need to have an electronic patient's registry, for patients’ followup, and to create awareness of SCD is crucial as well.

Methods: This is a prospective questionnaire-based study. The analysis will be performed by adopting software for statistical analysis (e.g., R studio; Statistical Package for the Social Sciences [SPSS]).The questionnaires will be administered to SCD patients or parents/legally designated representatives of children with SCD or relatives involved in the daily management of patient's disease and healthcare professionals working with SCD patients (i.e., doctors, nurses and laboratory scientists and technicians).

Results: Thirty-seven centers across Nigeria were identified (Figure 1). Two questionnaires were developed, one addressed to patients/parents/legally designated representatives and another one for healthcare workers.The electronic questionnaires will be set up and delivered by using Google Form. For healthcare workers the link to the questionnaire will be sent out via email to identified reference persons of the centers. The questionnaire for patients will be sent to the healthcare workers identified as reference persons who will then forward the link to patients or parents/legally designated representatives of the children with SCD. The patients will be randomly identified by the healthcare workers themselves among those attending their center and according to the inclusion and exclusion criteria. Before completing the online questionnaire, all participants will be asked to give their informed consent for study participation. The application for the ethics approval is under submission at the National Health Research Ethics Committee and local committees, if required.

Conclusion: Full results are expected by March 2024. They will allow us to have a clearer picture of the needs of patients and healthcare workers, to better identify any gap and improve the SCD management in Nigeria. Moreover, similar studies are being planned in Angola, Kenya and Zambia.

Figure 1. Geographical distribution of the centers.

This study will be conducted within the African Research and Innovative initiative for Sickle cell Education (ARISE) that has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie SkłodowskaCurie grant agreement No 824021.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

R. Colombatti¹, J. Kanter², M.R. Abboud³, E. Wu⁴, E.L. Jerome Clay⁴, A. Campbell⁵, A. Inati⁶

University of Padova¹, University of Alabama at Birmingham², American University of Beirut Medical Center³, Novo Nordisk, Inc.⁴, Children's National Hospital⁵, Lebanese American University School of Medicine⁶

Background: In sickle cell disease (SCD), a single β-globin gene mutation causes sickle hemoglobin (HbS) to polymerize and red blood cells (RBCs) to aggregate, leading to hemolytic anemia and vasoocclusive events. These events often present as a vasoocclusive crisis (VOC), an acute pain episode. From infancy onwards, patients experience recurrent VOCs, chronic hemolytic anemia, long-term organ damage, and systemic comorbidity occurrences resulting in a shortened lifespan. Therefore, novel, safe therapies are urgently needed for children with SCD to prevent organ damage and cumulative comorbidity from early life on.

Etavopivat is a once-daily, selective erythrocyte pyruvate kinase (PKR) activator in clinical development to treat patients with SCD and other hemoglobinopathies. The hypothesis is PKR activation will reduce HbS polymerization and improve RBC membrane function by decreasing 2,3-diphosphoglycerate and increasing adenosine triphosphate. This prompts a decrease in RBC sickling and hemolysis, thus reducing microvascular obstruction and anemia.^1,2

Aims: To describe the design of HIBISCUS-KIDS (PACTR202209604592389), a single-arm, open-label, Phase 1/2 trial evaluating the pharmacokinetic (PK) response, safety, and tolerability of etavopivat in pediatric patients with SCD.

Methods: Patients will receive 400 mg etavopivat dose daily for a 24-week primary treatment period followed by a 72-week extension period (Figure). Up to 50 patients aged 12 to <18 years will be enrolled at 15 sites located in Canada, Kenya, Lebanon, Nigeria, Turkey, and UK. After Week 12, data on safety, PK, and clinical activity including annual VOC rate, fatigue, central nervous system events, and patient-reported outcomes will be evaluated by the sponsor and shared with the safety review committee to inform decisions on a potential inclusion of patients <12 years old.

Inclusion criteria are a confirmed SCD diagnosis with any documented genotype, a hemoglobin value of ≥5.0 to <10.5 g/dL and ≥2 VOCs in the past 12 months. Key exclusion criteria are hospitalization, hospital or clinic visit for ≥10 VOCs within 12 months before treatment start, or hospitalization for any SCD-related complication within 14 days of the screening period.

The primary objective is to assess etavopivat PK based on the primary endpoints: maximum concentration, area under the concentration–time curve, and steady-state etavopivat plasma exposure in children with SCD. Safety and tolerability of etavopivat during the 24-week primary treatment period are a co-primary endpoint and will be analyzed based on the number of reported adverse events (AEs), severe AEs, and AEs related to etavopivat, premature discontinuations, dose interruptions, and dose reductions of etavopivat.

Key secondary and exploratory study objectives are to assess the effects of etavopivat on hemoglobin response, VOC occurrences, changes in fatigue and cerebral blood flow, silent cerebral infarct incidences, and functional capacity.

Results: This study is in progress and results are not yet available. Enrollment has commenced in Lebanon, with four patients screened and randomized. Enrollment across the remaining sites is planned.

Summary: Etavopivat is a novel, investigational, selective PKR activator with the potential to improve RBC health and lifespan. This Phase 1/2 study will assess the safety and tolerability of etavopivat in children with SCD and add pediatric data to the Phase 2/3 HIBISCUS trial (NCT04624659).

Topics 004–Clinical, public health and epidemiological studies

M.A.S. Salvino¹, B.A. Antman², F.C.A. Asirwa³, S.C. Chonat⁴, L.D.F. de Franceschi⁵, P.E. Eleftheriou⁶, A.I. Inati⁷, J.M. Mahlangu⁸, E.N. Nur⁹, S.P.P. Payán-Pernía¹⁰, A.C. Charania¹¹, D.G. Gradinaru¹¹, A.H. Hsia¹², Y.L. Luder¹¹, T.P. Perretti¹¹, S.S. Sreckovic¹², P.B. Bartolucci¹³

Hospital São Rafael–IDOR/PPGMS-UFBa¹, Department of Pediatric Hematology, Adana Acibadem Hospital², International Cancer Institute (ICI)³, Department of Pediatrics, Emory Univers ity School of Medicine and Aflac Cancer and Blood Disorders Center, Children's Healthcare⁴, Medicina Interna, Azienda Ospedaliera di Verona-Policlinico G.B. Rossi⁵, University College London Hospital⁶, Lebanese American University School of Medicine, Byblos, and NINI Hospital⁷, Haemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Hospital and University of the Witwatersrand and NHLS⁸, Amsterdam UMC⁹, Servicio de Hematologia, Hospital Universitario Virgen del RocÍo, Instituto de Biomedicina de Sevilla (IBiS)¹⁰, F. Hoffmann-La Roche Ltd¹¹, Genentech, Inc.¹², Service de Médecine Interne, CHU Henri Mondor¹³

Background: In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related.^1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies.

Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vasoocclusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.³ Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose.⁴ Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824).

Aims: CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs.

Methods: Pts 12–55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β⁰ thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Figures 1 and 2). Concurrent SCD-directed therapies are allowed.

CROSSWALK-a

Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months).

Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated.

CROSSWALK-c

Pts with 2–10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2–4) and monthly maintenance SC doses Weeks 5–49 for 48 weeks of treatment.

Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated.

Primary results will be published upon trial readout.

Funding Statement

These studies are funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Disclosures: M.A.S. is a consultant for F. Hoffmann-La Roche Ltd, Novartis, AstraZeneca, Takeda, Orphan Drugs, Abbvie, Amgen, Pfizer, and MSD; received research funding from F. Hoffmann-La Roche Ltd, Novartis, Takeda, Amgen, and Pfizer; received honoraria from F. Hoffmann-La Roche Ltd, Novartis, Takeda, Amgen, Pfizer, Gilead, Abbvie, AstraZeneca, and MSD; participated in speakers bureau for F. Hoffmann-La Roche Ltd, Novartis, Takeda, Amgen, Pfizer, Gilead, Abbvie, AstraZeneca, and MSD; and is a member on the Board of Directors or advisory committee of ABHH and SBTMO. F.C.A. is a consultant for MSD; received research funding from F. Hoffmann-La Roche Ltd, GBT, Pfizer, Genentech, Inc., Bausch, and Celgene; received honoraria from Millennium, MSD, Genentech, Inc., F. Hoffmann-La Roche Ltd, AstraZeneca, Merck, and Novartis; and is a member on the Board of Directors or advisory committee of the American Society of Clinical Oncology (ASCO), ESMO/ASCO Curriculum Working Group committee and College of Oncologists of East, Central and Southern Africa (ECSACO), President. L.D.F. is an employee of the University of Verona; received research funding from Agios and Bristol; and is a member on the Board of Directors or advisory committee of F. Hoffmann-La Roche Ltd and Vifor. P.E. received honoraria from Pfizer, GBT, Alexion, Forma Therapeutics, and Agios. E.N. is a consultant and participated in speakers bureau for Novartis. C., Y.L., and T.P. are employees of F. Hoffmann-La Roche Ltd. D.G. is an employee of and holds equity in F. Hoffmann-La Roche Ltd. A.H. is an employee of Genentech, Inc. S.S. is an employee of Genentech, Inc.; ended employment in the past 24 months with F. Hoffmann-La Roche Ltd; holds equity in F. Hoffmann-La Roche Ltd and Genentech, Inc. P.B. is a consultant for AddMedica, Novartis, F. Hoffmann-La Roche Ltd, Global Blood Therapeutics, Bluebird, Emmaus, Hemanext, and Agios Pharmaceuticals; received research funding from AddMedica, Fabre Foundation, Novartis, and Bluebird; is a member on the Board of Directors or advisory committee of Novartis (Steering Committee); received lecture fees from Novartis, AddMedica, and Jazz Pharma; and is the co-founder of INNOVHEM. A., S.C., A.I., J.M., and S.P.P. declare no disclosures.

All authors received support for third-party writing assistance, furnished by Akshaya Srinivasan, PhD, of MediTech Media Ltd and funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

F.A.K. Alkhaja¹, M.V.A. Anthony¹, N.S.O. Oommen¹

Dubai Thalassemia Center¹

Background and Aim: UAE, accounts as one of the most common regions with thalassemia, with prevalence of β-globin gene defects of 8.5%.¹ The past few decades have witnessed extensive advancement in the field of hematopoietic stem cell transplantation (HSCT) since it was established by Pesaro Group as the only definitive cure.² As crucial it is to provide optimum care, it is equally important to evaluate patients' overall understanding of the given options. Numerous publications attempted to assess patients' post (HSCT) quality of life and complications. However, there weren't sufficient publications evaluating patients' level of knowledge and follow up care.

Method: This was a cross-sectional study to survey the guardians/patients who underwent (HSCT) following Dubai Thalassemia Centre. Ethical approval was obtained from the Dubai Scientific and Research Committee and informed consents were obtained from all participants. A validated questionnaire was given to patients/guardians at the outpatient clinic from July to October 2019. The questionnaire evaluated knowledge post (HSCT) and follow up care. Post survey we have educated all participant on their knowledge gaps. Data obtained were analyzed using SPSS version 23.0.

Results and Discussion: 195 subjects participated in the study, of them 103 participants answered all the questions. 63% were guardians and 37% patients. 27% and 22% of patients underwent transplantation in London and USA respectfully.

Conclusion: Although the patients had appropriate background information regarding HSCT, the results of our study demonstrate that the care receivers were inadequately informed especially in the fields concerning fertility and disease status. This knowledge is critical for many reasons, one of it being vital in reducing the future prevalence of the disease as well as improving their quality of life. Doubtlessly, this study will play a crucial rule in enhancing patients’ knowledge in areas that require improvement.

Topics 002–Novel therapies, gene therapies and bone marrow transplant

S.F.L. Fritch Lilla¹, N.A.H. Hart¹, R.T. Tran¹

Children's Minnesota¹

Introduction: Four-gene deletion α-thalassemia major (ATM) is a severe and rare form of thalassemia resulting in significantly decreased hemoglobin production and subsequent sequelae. It can be fatal in-utero or soon after birth without intervention. Currently, the only curative therapy available for individuals with ATM is bone marrow transplant1.

Case Description: We present the case of a 16-year-old Hmong female with a history of ATM, now status post two matched sibling donor bone marrow transplants (MSD-BMT.) She required a second transplant due to graft failure with the first transplant. Her second transplant with the same donor resulted in mixed chimerism with persistent anemia and Hb H production.

She was diagnosed in-utero due to worsening cardiomegaly and severe fetal anemia by MCA velocity measurements. Neither amniocentesis for diagnostic testing nor in-utero transfusions were pursued per parents’ request. She was born premature at 30 6/7 weeks gestation due to worsening maternal preeclampsia and was critically ill at birth with hydrops fetalis and a hemoglobin of 2.5 g/dL requiring a single volume exchange. After a 2 month hospitalization she was discharged and subsequently managed on a chronic transfusion program with resultant iron overload.

Curative therapy with 8/8 MSD-BMT was attempted with her 1st transplant at 3 years of age. Post-transplant she was noted to have mixed chimerism in the T-cell and monocyte fractions and had declining engraftment despite rituximab and 3 donor lymphocyte infusions with continued transfusion dependence. At 5 years old she had a second MSD-BMT from the same donor. She again struggled with partial engraftment and mixed chimerism. Her last chimerism 4 years post MSD-BMT showed 12% donor in CD33 and 56% donor in CD3. Despite mixed chimerism, she was transfusion independent with hemoglobin 9–10 g/dL. She developed hypersplenism with worsening cytopenias and ultimately underwent splenectomy at 8 years old. Subsequent post-transplant complications included severe pneumococcal sepsis with secondary amputation below-the-knee 4 years after splenectomy at 12 years old and metastatic papillary thyroid cancer at 13 years old. When she returned to hematology at 13 years of age she was noted to have ongoing anemia (9.4–9.9 g/dL) and elevated hemoglobin H (47.6%–50.4%) concerning for persistent alpha thalassemia presumed secondary to mixed chimerism. Additional lab findings included elevated absolute retic count 0.202–0.273 M/μL total bilirubin 2.3–2.8 mg/dL, nucleated red blood cells 7–14/100 WBCs, and soluble transferrin receptor 10.3 mg/L. Her hemoglobin H levels remain similar to baseline ATM levels raising concern for high levels of nonfunctional hemoglobin and increased risk of tissue-level hypoxia.^2,3 Despite her low functional hemoglobin level of <5 g/dL she continues to do well clinically without signs and symptoms of anemia. Discussions are ongoing with the family about benefits and risks of resuming chronic transfusion therapy.

Topics 007–Health services and outcomes research including psychology

J.J. Maro¹

Sickle Cell Programme¹

Background: Sickle cell anemia (SCA) poses a significant economic burden on patients, especially those lacking health insurance coverage. In Tanzania, SCA remains a critical health issue, impacting approximately 11,000 births each year. This paper presents a comprehensive case report illustrating the economic impact of SCA on uninsured patient receiving care at Muhimbili National Hospital.

Method: A cost of illness analysis was performed to estimate the economic burden borne by a single patient within a one-month timeframe. The analysis encompassed direct costs (hospitalization expenses, medication fees, and clinical tests) and indirect costs (productivity loss during hospitalization).

Results: The total cost of care for the patient amounted to 1,570,465 Tanzanian Shillings (TZS), equivalent to $671. Hospitalization emerged as the most substantial cost component, accounting for 69% of the total expenses, followed by medications (19%), clinical tests (5%), and indirect costs (7%).

Conclusion: Our cost of illness analysis indicates that the one-month cost of caring for a patient with sickle cell anemia at Muhimbili National Hospital reached 1,600,000 TZS. These findings underscore the urgency of implementing targeted policy interventions aimed at enhancing healthcare accessibility and alleviating the economic burden of sickle cell anemia in Tanzania. Keywords: sickle cell anemia, economic burden, health insurance, cost of illness analysis, Muhimbili National Hospital, Tanzania.

Topics 007–Health services and outcomes research including psychology

P.h.D. Tilicia Mayo-Gamble¹, P.h.D. Velma McBride Murry², E.d.M. Rachel Hanebutt², M.S. Alexis Gorden³, P.h.D. Dominique Bulgin⁴, B.S. Reginald French³

Georgia Southern University¹, Vanderbilt University², Sickle Cell Foundation of Tennessee³, The University of Tennessee, Knoxville⁴

Background: Chronic disease research discoveries, such as sickle cell disease (SCD), are seldom translated into practical application for patient consumption. Few patients have the skills and capacities to locate and if found, to translate and use information emerging from research that hold promise to prevent, improve, and enhance health outcomes. This engagement study—designed in collaboration with stakeholders (e.g., patients, community partners) from the Tennessee SCD Network (TN-SCDN) and the Sickle Cell Foundation of Tennessee—aimed to fill this void in patient-centered outcomes research by building a patient-centered research translation and dissemination model.

Aims: We sought to: (1) increase knowledge and awareness of patient-centered outcomes research on chronic disease management; (2) increase stakeholder recognition of their role in the translation of research findings; (3) train stakeholders for active engagement in research dissemination; and 4) engage stakeholders in the development of a patient-centered, scalable dissemination model.

Methods: To discern existing dissemination capacity readiness and practices, the research team conducted a series of stakeholder-led sessions with African American adults (N = 22) living with SCD or caregivers of an individual living with SCD. These qualitative sessions—a semi-structured focus group (general insight), a community leader-facilitated education forum (research translationfocused knowledge), and a community engagement studio (research dissemination-focused preferences)—to understand patient perspectives more deeply on the challenges of receiving research findings and barriers to using these findings. Each session provided insight for the translation of new discoveries for the development of a tailored research dissemination model.

Results/Stakeholder Engagement: Activities for patient capacity building included training in comparative effectiveness research principles and research article critique. Stakeholders then reviewed the project database, self-selected relevant articles, translated findings, and identified platforms for widespread dissemination. Stakeholders were selected to form the Community Advocacy Community Advocacy Training Empowerment and Research (C.A.T.E.R) Taskforce. The C.A.T.E.R Taskforce members attended dyadic virtual meetings of SCD patient collaborators and authors were held to offer insights on the relevance of patients’ engagement in research to expand dissemination efforts beyond scientific journals.

Conclusion: Content analysis revealed key themes across a variety of dissemination and translation topics; exemplar quotes showcase the lived experiences of SCD patients and their caregivers, regarding patient-provider communication, comfort understanding of research articles, and methods of implementation for research findings into care practices, including pain management. Based on feedback a systematic review of the Patient-Centered Outcomes Research Institute research database of relevant chronic disease management empirical articles was also conducted to create a projectspecific database. Our findings hold promise for practical solutions to address chronic disease by advancing translation and dissemination through patient engagement. An outcome of this study includes dissemination materials for distribution among community-based organizations.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

N. Naami¹, S. Lobitz²

Community Hospital Herdecke¹, Community Hospital Mittelrhein²

Background: Sickle cell disease (SCD) is a hereditary blood disorder affecting children worldwide. Parents play a crucial role in managing the disease and providing optimal care for their children with SCD. Especially in the beginning, education about this complex disease is difficult, especially if clinical signs have not yet appeared due to the early discovery of the disease. This can lead to suboptimal treatment of the disease and possible complications. Modern social media platforms, such as Instagram, TikTok, and YouTube, offer an innovative opportunity to disseminate medical information in a captivating and understandable format. This study introduces a novel pediatric education project that utilizes social media educational videos to enhance parental understanding of SCD.

Aims: The study seeks to address potential suboptimal treatment and complications arising from delayed awareness of the risks of SCD. By curating evidence-based content, the aim is to create engaging and concise videos tailored to parental preferences and needs, subsequently improving parental understanding of SCD and enabling informed healthcare decisions.

Methods: The content of the educational videos was curated based on evidence-based guidelines, expert recommendations, and input from patients. We took a user-centered approach and focused on creating both entertaining and concise videos that meet the needs and preferences of parents seeking information about SCD. The videos were shot in a vertical format suitable for social media, have an easy digestible maximum length of 90 s and where uploaded to Instagram and TikTok for free access.

Results: A series of educational videos were produced, covering key aspects of SCD, including disease pathophysiology, common signs and symptoms, disease management, potential complications, and psychosocial support for affected families. These videos were designed to be captivating, informative, and easy to understand to ensure maximal reach and impact.

Conclusion: The implementation of social media educational videos to educate parents of children with SCD represents a promising approach to enhance parental understanding of the disease. By delivering vital information in a modern, accessible, and captivating format, parents can be empowered to make informed decisions regarding their child's healthcare management. This project bridges the knowledge gap, fosters proactive involvement in disease management, and encourages early interventions, ultimately leading to improved health outcomes and quality of life for children with sickle cell disease. Furthermore, this innovative approach to pediatric education may serve as a model for engaging and empowering parents in managing other chronic pediatric conditions effectively.

Topics 007–Health services and outcomes research including psychology

L.J. McCarthy¹

Oxford University Hopsitals¹

Background: Transition is the term used in health care services that describe the process of moving from child to adult services, and usually happens over a few years. There is numerous evidence to demonstrate that where there is little or no coordinated planning and preparation for young people, the result can be poor health outcomes, reduced engagement and dissatisfaction with health care.^1,2 This can in turn lead to longer term financial pressures on health services to meet increasing morbidities. It is important to get this process right in order to improve outcomes for all.

In our service, young people are introduced to the concept of transition around the age of 13 years in an annual review appointment. They are then invited to attend regular nurse led transition appointments over the next few years and are also invited to a well being group and to have a tour of the adult unit they will eventually move to. We had noticed that attendance was sometimes poor (Did not attend-DNA), required additional admin support in managing appointments and also lack of engagement with other aspects of the pathway. I wanted to increase attendance, engagement and ultimately improve outcomes.

Aims: To improve transition resources for Young people (YP) with a chronic condition (haemoglobinopathy disorder) Reduction in number of DNAs. There will be increased engagement from Young people and family with the transition processes Ultimately: Young people will be more knowledgeable, confident and empowered when they transfer to the adult team Young people will continue to engage with adult services and have potential for better health outcomes.

Methods: Audit attendance figures and DNA for transition clinics. To develop a short (2–3 min) animation video which will introduce the YP to the transition journey (It will be generic and potentially a national resource).

Research what is already available nationally to use (be efficient).

Video resource will be more engaging and encourage young people to participate Animation content/script/visuals will be driven by the young people Secure funding.

Short survey of YP to determine the value and interest in the video.

Focus group of young people to create storyboard/dialogue.

Approach animation companies and appoint provider Commission animation company.

Edit/refine video content with young people's focus group.

Share finished resource.

Results and Next Steps: Use the video, alongside usual resources, with young people when introducing start of transition https://www.youtube.com/watch?v=sGwznaKxqMM.

Audit attendance at Transition appointments and well being attendance after 6/9 months of using the resource Survey young people after 6/9 months to establish value.

Continue to review transition process and effectiveness with other team members and YP.

Collaborate with Trust wide/National transition initiatives to increase efficiency and to maximise impact.

Run twice yearly information event on transition for both parents and young people.

Topics 004–Clinical, public health and epidemiological studies

N.P.F. Mkangara, Rugajjo, Urio¹, N.P.F. Mkangara ¹

Muhimbili University of Health and Allied Sciences¹

Background: Sickle cell disease (SCD) is widespread over much of Sub-Saharan Africa, affecting up to 3% of all births in some areas, but it is still a low-priority disease in most African countries. Kidney disease is common in SCD and accounts for 16%–18% of mortality among patients with SCD. Nonetheless, in Tanzania, little is known about the coexistence of SCD and renal disease, and little is known about the factors that influence kidney disease progression in SCD patients.

Aim: To determine the prevalence and determinants of progressive kidney disease among patients with SCD attending Muhimbili National Hospital, Dares Salaam, Tanzania.

Methods: This was cross-sectional study among 369 SCD patients registered in SPARCO-Tanzania and attending the hematology clinic at the Muhimbili National Hospital within a period of 5 months. Participants were consecutively enrolled into the study using a convenient sampling method. After receiving ethical clearance from the MUHAS Research Ethics Committee and written informed consent from study participants, data were collected. Participant data and clinical parameters such as blood pressure and random blood glucose were collected using a standardized tool. Blood and urine samples were also collected for the measurement of serum creatinine, urine creatinine, and urine albumin. The Chi-square test and multivariable logistic regression was used to determine the association and predictive power of socio-demographic and clinical parameters (including age, sex, blood pressure, and microalbuminuria-to-creatinine ratio >30 mg/g). Statistical significance is defined as a p < 0.05. Data were processed using the IBM Statistical Package for the Social Sciences (SPSS) v24.0. Budget: A total of USD 15,000 will be required for the study and this will be funded by the Sickle Pan African Research Consortium (SPARCO)-Tanzania, which is funded by the NHLBI of the US National Institutes of Health (NIH) under grant number U01HL156853.

Results: Patients who were enrolled were 363 of which female were 52.1%. Majority of patients between the age of 5–18 years old and of these enrolled patients 59.8% were on both folic acid and hydroxyurea treatment. Only 1.1% found to be hypertensive while 0.5% were diabetic. The overall prevalence of kidney disease among these patients was found to be 49% and it was found to be more prevalent again in patients at the age between 5 and 18 years. It was also found that hypertensive patients had an increased chance of developing kidney disease by 4.2-fold while those with diabetes and microalbuminuria in urine had an increase by 9.1 and 2.6 respectively. We found that there was a difference in prevalence of kidney disease while using UriScan (ACR) and while using the normal serum creatinine which is normally being used at clinic of which it was again found that the difference was 14.4 which means that there is a chance of missing 14 patients when using urine creatinine while comparing with serum creatinine

Conclusion: The prevalence of kidney disease among sickle cell disease in patients attending MNH was 49% and as we will see in the results microalbuminuria still carries a significant role in the development of kidney disease together with other clinical markers which were hypertension and diabetes. The study has also shown that there is a chance of missing 14 patients when performing urine creatinine as compared with the serum creatinine it was discussed further in the discussion part below

Recommendation: Microalbuminuria, hypertension together with diabetes should be screened routinely at clinic as the can help in preventing the development and even predicting the occurrence of kidney disease among sickle cell disease patients at clinics and another study should be conducted between patients with sickle cell and those who do not have sickle cell to predict as to whether these predictors carry equal chance or risk in developing or progressing to kidney disease.

Topics 004–Clinical, public health and epidemiological studies

H.M.H. Haji¹, F.U. Urio², E.B. Balandya², S.N. Nkya², B.K. Kidenya³, A.J. Jonathan²

Muhimbili University of Health and Allied Sciences (MUHAS)¹, MUHAS/SPARCO Tanzania², CUHAS/SPARCO Tanzania³

Background: Fetal hemoglobin (Hb F) is predominantly present in F cells, which are red blood cells containing measurable amounts of fetal hemoglobin. In sickle cell disease (SCD), the level of Hb F has a significant impact on the disease's clinical course. Individuals with higher Hb F levels generally experience a less severe course of the disease. However, some patients with high Hb F levels can still have severe symptoms. This diversity can be attributed to the concentration of Hb F distributed per F cell (Hb F/F cell). Therefore, it is hypothesized that the amount of Hb F/F cell is crucial in determining the clinical outcome of SCD rather than the overall level of Hb F and the number of F cells.

Broad Objective: To determine the association between fetal hemoglobin parameters and disease severity in SCD patients in Tanzania.

Methodology: A retrospective cohort study involved secondary data analysis of 92 SCD individuals aged 6 years and above who were at their steady state and not on hydroxyurea, conducted at the Muhimbili University of Health and Allied Sciences between September 2022 and February 2023. This study was nested within the ongoing parental study, titled “Comparative study of Sickle Cell Disease (SCD) modifiers in Ghana, Nigeria and Tanzania; investigation of fetal hemoglobin parameters and clinical manifestation.”

Hematological and social demographic data were obtained from Sickle PanAfrican Research Consortium (SPARCO) Tanzania registry and Hb F/F cell was calculated by the formula; Hb F/F cell = (Hb F% × MCH pg)/F cell%.

STATA version 15 was used for analysis, categorical variables were presented as proportion and continuous variables were presented as median and IQR. Mann–Whitney test was used to compare Hb F parameters among age and sex, and the association of Hb F parameters and termination events and recurrent events was examined using univariable binary logistic regression and univariable ordinal logistic regression respectively. A p < 0.05 was considered statistically significant.

Results: Among the 92 SCD patients, 53 (57.4%) were below 18 years, the median age was 16 years (IQR: 10, 21) and male to female ratio was 1:1. The levels of Hb F parameters were generally low, below the cut of points of high levels used in this study with median levels of 4.45% (IQR: 2.33, 7.15), 21.60% (IQR: 13.20, 32.45), and 5.63 pg (IQR: 4.00, 7.98) respectively. Males had significantly higher levels of Hb F/F cell compared to females, with a median of 6.44 pg (IQR: 4.3, 9.5) and 5.34 pg (IQR: 3.5, 6.5) respectively (p = 0.004). Also, we observed that as the percentage of Hb F and F cells increased, there was a significant reduction in the risk of receiving multiple blood transfusions (p = 0.016, 95% CI: 0.802–0.969) and (p = 0.02, 95% CI: 0.947–0.995) respectively. However, Hb F/F cell level had no significant association with disease severity (termination events).

Conclusion: Hb F and F cells level remain a significant predictor of sickle cell events (blood transfusion) while Hb F/F cell showed no statistically significant association with disease severity in SCD patients in this cohort.

Recommendation: Larger sample size study to increase statistical power and enhance the ability to detect significant associations. Utilize a prospective study design to collect data over a specific period, allowing for the examination of continuous trends and assessment of connections between variables.

Topics 007–Health services and outcomes research including psychology

D.O. Omodele¹

BHRUT-Queens Hospital¹

Background: Our team was chosen to be part of the NHSI transition collaborative (Cohort 2). This opportunity allowed us to completely transform our transition programme. We adopted the “Ready Steady Go” programme as a model and named our own programme “Get Ready, Are You Set? Off We Go!” This initiative aimed to make the transition smoother for teenagers and their families while involving the adult team in the process.

Aims: Our main goal was to create a collaborative transition process that involved teenagers, their parents, and our staff. We also wanted to improve the experience for teenagers who were transitioning. In the past, many teenagers were simply moved to adult services without proper preparation. We wanted to change that and ensure a more gradual and comprehensive approach as we understand that transition is not a one-size-fits-all all rather, it requires an individualised approach.

Methods: We emphasised communication as a foundation for our strategy as engaging the teenagers in this programme is the key to its success.

We developed an informative leaflet for patients, explaining the three transition stages and expectations throughout this programme.

We organised virtual workshops that provided teenagers with the tools and knowledge needed for their transition to adult services, e.g., what their responsibilities are to themselves and practicing the art of self-advocacy. We divided the 148 teenagers in transition into three stages: 12–13-year-olds for Stage 1 “Get Ready,” 14–15-year olds for Stage 2 “Are You Set,” and 16-year-olds for Stage 3 “Off We Go.” Every teenager was informed about the programme and received invitations to the workshops.

Results: Our efforts led to a successful transition of over 100 patients from 2020 to 2022. While workshop attendance increased gradually, we are still working on improving engagement. We now conduct two workshops per stage, attracting 8–15 teenagers per session, indicating growing interest and participation.

Summary: Our collaboration with NHSI Cohort 2 has transformed the way we handle teen healthcare transition at BHRUT. “Get Ready, Are You Set? Off We Go!” has ushered in a new era of prepared and collaborative transitions. With over 100 successful transitions, ongoing workshops, and increasing engagement, we are reshaping healthcare transition practices within our trust and also exploring other avenues that ensures the teenagers are empowered towards confidently managing their condition and doing so independently.

Conclusion and Recommendations: In conclusion, our experience underscores the importance of collaboration, information sharing, and workshops in enhancing teen healthcare transitions. Moving forward, we would continue to explore outreach efforts (e.g., peer mentoring programme), refining workshop content based on teenagers input, and exploring innovative digital platforms to sustain engagement. The inclusion of an interactive quiz has been a hit with all the teenagers and remains a consistent feature during these workshops. Our journey highlights that engaging teenagers in healthcare transition is both a process and a valuable experience that most definitely makes a big difference to their healthcare transition outcomes.

Topics 007–Health services and outcomes research including psychology

L.A. Allawi¹, R.A. Awadzi¹, K.A. Anie¹

London North West University Healthcare NHS Trust¹

Background: Within the context of the Darzi Fellowship Programme, this project explores a leadership-driven change initiative aimed at addressing challenges related to sickle cell disease (SCD), framed by the healthcare inequalities and negative attitudes spotlighted in the NoOne's Listening Report (APPG and Sickle Cell Society, 2021). Underscoring the importance of understanding contextual factors for effective problem-solving and community trust.

Aims: The aim was to enhance the quality of SCD care and patient experiences by engaging stakeholders through co-production, guided by the application of strengths-based methodologies. The focus revolved around on redefining and reshaping care quality and experience.

Methods: This involved the establishment of a Sickle Cell Patient Group through active listening and trust-building. Collaboratively, the group designed a patient experience questionnaire and drove quality improvements, including the development of the Sickle Cell Simulation Programme.

Results: The co-created patient experience survey will serve as an ongoing metric in regular service meetings, providing comprehensive insights into patient experiences, care quality, and overall project impact. Meanwhile, to allow swift assessment of initiatives, smaller feedback loops were created to measure impact, such as presimulation and postsimulation surveys to gather participant insights. However, the most notable outcome was the establishment of recognized and supported platform for patient voices within the healthcare organisation to guide future endeavours.

Conclusion: In conclusion, this change initiative underscores the pivotal role of context, co-production, and continuous evaluation in advancing SCD care and patient experiences. Success hinged on collaborative stakeholder efforts, innovative methodologies and a clearly defined shared purpose.

Topics 004–Clinical, public health and epidemiological studies

D.B.K. Betukumesu Kabasele¹, A.N.M. Aloni Ntenani Michel², J.L.G. Gini Ehungu¹, M.M.T. Mikobi Minga Tite¹, O.K. Kazadi Wa Kazadi¹, F.K. Kajingulu Francois¹, L.M.B. Longo Mbenza Benjamin¹

University Clinic of Kinshasa¹, University Clinic of Kinshasq²

Background and Objective: Platelet-to-lymphocyte ratio (PLR) was introduced as cheap and readily assessed biologic markers of subclinical inflammation in sickle cell disease.

Microalbuminuria and hyperfiltration, early markers of sickle cell nephropathy (SCN) have been reported to be associated with platelet-to-lymphocyte ratio (PLR). This association has not yet been assessed in Congolese sickle cell disease (SCD) children. Therefore, the aim of the present study was to assess the association between PLR and early markers of kidney disease in SCD children living in the Democratic Republic of Congo (DRC).

Patients and Methods: In this cross-sectional study, we have investigated 175 SCD children from four centers (Kinshasa university clinics, CMMASS, CMD Diamand, and Biamba Marie Mutumbo Dikembe) that give a comprehensive care to SCD patients. The PLR were calculated from full blood count. Elevated albuminuria and hyperfiltration, as the main outcomes of the study, were defined by urinary albumin/creatinine ratio (ACR) ≥30 mg/g and estimated glomerular filtration ratio (eGFR) >130 mL/min per 1.73 m² for females and >140 mL/min per 1.73 m² for males, respectively. Logistic regression analysis was used to assess the relationship between RPL and early sickle cell nephropathy.

Results: Of the 175 SCD children enrolled, 41 (23.4%) and 67 (38.3%) of them presented with abnormal albuminuria and hyperfiltration, respectively. RPL >130 was observed in 90 (51.4%) patients. RPL was strongly, significantly and independently associated with both abnormal albuminuria (aOR 3381; IC 95% 2, 22–1, 63; p = 0.000) and hyperfiltration (aOR 2, 19; 95% IC 2, 98–22, 25; p = 0.010).

Conclusion: The present study has shown that nearly fifty two out of one hundred SCD children bear a high platelet to lymphocyte ratio that is strongly and significantly associated with early markers of kidney disease.

Topics 007–Health services and outcomes research including psychology

D.O. Omodele¹, A.S. Momoh-Ojewuyi¹

Queens Hospital Romford¹

Background: Our team was chosen to be part of the NHSI transition collaborative (Cohort 2). This opportunity allowed us to completely transform our transition programme. We adopted the “Ready Steady Go” program as a model and named our own programme at BHRUT “Get Ready, Are You Set? Off We Go!” This initiative aimed to make the transitioning seamless for teenagers and their families while involving the adult team in the process.

Aims: Our main goal was to create a collaborative transition process that involved teenagers, their parents, and healthcare professionals. We also wanted to improve the experience for teenagers who were transitioning. In the past, many teenagers were simply moved to adult services without adequate transition preparedness. We wanted to change that and ensure a more gradual and comprehensive approach as we understand that transition is not a 'one size fits all' rather, it requires a patient-centered approach.

Methods: We emphasised communication as a foundation for our strategy as engaging the teenagers in this programme is the key to its success. We developed an informative leaflet for teenagers, explaining the three transition stages and expectations throughout this programme. We organised virtual workshops that provided teenagers with the tools and knowledge needed for their transition to adult services, e.g., topics included what their responsibilities are to themselves and practicing the art of self-advocacy. We divided the 148 teenagers in transition into three stages: 12–13-year-olds for Stage 1 “Get Ready,” 14–15-year-olds for Stage 2 “Are You Set,” and 16-year-olds for Stage 3 “Off We Go.” Every teenager was informed about the programme and received invitations to the workshops.

Results: Our efforts led to a successful transition of over 100 patients from 2020 to 2022. While workshop attendance increased gradually, we are still working on improving engagement as not all teenagers attended scheduled workshops within each stage. We now conduct two workshops per stage, initially attracting 2–3 teenagers which gradually increased to 8–15 teenagers per session, indicating growing interest and participation. We've discovered that maintaining consistency is crucial, and we persist in introducing innovative methods to encourage teenagers' participation in these workshops.

Summary: Our collaboration with NHSI has transformed the way we handle healthcare transition at BHRUT. “Get Ready, Are You Set? Off We Go!” has ushered in a new era of prepared and collaborative transition. With over 100 teenagers transitioned into adult care, ongoing workshops, and increasing engagement, we are reshaping healthcare transition practices within our trust and also exploring other avenues that ensure the teenagers are empowered towards confidently managing their condition and doing so independently.

Patient feedback: 17-year-old teenager said “I now realise the value of attending all the workshops I was invited to. They would have better prepared me to truly comprehend my condition and equip me with the skills to manage it independently.”

Conclusion: In conclusion, our experience has emphasied the significance of working together, sharing information, and interactive workshops in enhancing healthcare transition for teenagers. Looking ahead, we plan to connect more with our teenagers, fine-tune workshop content based on their feedback, and explore creative digital methods to maintain their engagement. The interactive quiz, which teenagers have responded positively to, will continue to evolve. Our journey has highlighted the importance of including teenagers in their healthcare transition process, which is a gradual yet impactful undertaking.

We aim to establish a strong partnership with the Sickle Cell Society's peer mentoring program to further enrich the transition process. Additionally, we have identified the need for improved post-transition care, and our commitment to collaborative improvement remains unwavering.

Topics 005–Clinical, infection and nutritional deficiencies

A. Momoh-Ojewuyi¹, K. Ramakotaiah¹, D. Omodele¹, R. Mensah¹

Queens Hospital Romford¹

Introduction: When a child known to have sickle cell disease presents to the Emergency Department with a history of sudden onset bilateral loss of vision, it is very easy to conclude that this is likely as a result of sickle cell disease, but this was not the case in our 5-year-old patient.

Clinical Case: We present a case of a 5-year-old girl who presented with the history of sudden onset bilateral painless total loss of vision while on holidays from the United Kingdom to Nigeria. She was known to have sickle cell disease and she has been on a disease modifying treatment with Hydroxycarbamide and she has been relatively well on this. She was said to have been well prior to her symptoms with bilateral loss of vision and there was no history of fever. She complained of leg pains later.

The Parent had taken her to the hospital immediately during the holidays and she had medical assessment including an ophthalmology review and they were informed of mild papilloedema and were advised to do an MRI brain scan. While awaiting an MRI brain scan to be organised, the parent ended their holidays and brought the child back to the UK urgently within 24 h of the symptoms for continuation of care by the doctors she is known to in the UK.

She was investigated thoroughly which did not show any specific finding to explain the acute loss of vision. She had a Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiogram (MRA) brain scans which did not show any acute infarction or significant focal lesion. No acute occlusion or stenosis. The Circle of Willis was intact. Our patient had an urgent ophthalmology review which confirmed there was loss of vision.

Further ophthalmology reviews at the Moorfields showed flash VEPs from the right and left were markedly abnormal suggesting severe post-retinal dysfunction. The rod and cone flash ERGs were within normal limits. Our patient was transferred for specialist review at the Royal London Hospital for further investigations and treatments. She had a lumbar puncture, and blood tests positive for MOG IgG antibodies.

She was diagnosed with Myelin Oligodendrocyte Glycoprotein (MOG) antibodies positive optic neuritis.

She received 5 cycles of plasmapheresis without complications. She also received IV Methylprednisolone for 5 days and then oral prednisolone 30 mg daily which was weaned by 5 mg weekly. She has completely recovered after treatments.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the central nervous system characterized by attacks of immune-mediated demyelination predominantly targeting the optic nerves, brain, and spinal cord. The disease has a predilection for children.

MOGAD may have a monophasic or relapsing course. Attacks usually develop over days and may plateau with variable recovery over weeks to months. Attacks may be preceded by an infectious illness or vaccination.

A positive myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibody test, fulfilled when the MOG-IgG is clearly positive and other investigations include MRI brain and spine, lumbar puncture and ophthalmology review as we did in the case of our patient.

MOG antibodies demyelination is treated with Intravenous (IV) high dose steroid treatment for 3 - 5 days and then oral steroids which was then weaned off gradually. Other treatments are IV immunoglobulins or plasma exchange as in the case of our patient.

Prognosis:

After an initial attack there can be recurrent episodes and if there are frequent relapses, then a maintenance treatment may be required to prevent further episodes with, e.g., Azathioprine, Mycophenolate Mofetil (MMF) or Rituximab.

Conclusion: When a patient known to have a chronic medical condition presents to the hospital with other symptoms, we should not think of the chronic medical condition alone but to think about other differential diagnosis. As in the case of our patient that had a different problem from sickle cell.

Topics 001–Basic and translational

A.D. Waziri¹, S. Awwalu¹, D. Monteiro², Y. Daniel², A. Hassan¹, P.I. Baba³

Ahmadu Bello University Teaching Hospital Zaria, Nigeria¹, Guys and St Thomas Hospital, London², Evelina, Guys and St Thomas Health Trust³

Introduction: Hemoglobin C-O Arab is an infrequent condition with limited literature documentation. The underlying mutations in HbC and HbO-Arab affect positions 6Glu → Lys and 121Glu → Lys of the Beta globin gene respectively. Interestingly, when both HbC and HbO-Arab are inherited, the individual has the same mutations (Glu → Lys) at different positions (6 and 121) of the same globin chain. The consequences of these interactions make this a unique and enigmatic condition.

Aim: To report HbCO-Arab mimicking HbSS in a patient.

Method: A case report of the patient's clinical note.

Results: A 26-year-old lady presented to the Haematology Day Care (HDC) of Ahmadu Bello University Teaching Hospital Zaria, Kaduna Nigeria due to varying Hb electrophoresis results. She gave a history of recurrent headaches, occasional bone pains, and easy fatiguability. However, no history of jaundice or blood transfusions. Hb electrophoresis done at 6 years was suggestive of HbSS. No history suggestive of sickle cell complications except for a history of parapneumonic effusions at the age of 21 years. Two of her siblings are said to be patients with sickle cell disease.

There was no jaundice, pallor, cyanosis, or sickle cell habitus. Four previous Hb electrophoreses using alkaline media revealed a single band in the S position except for one which showed two bands in the S and C regions. A repeat upon presenting to us showed a single band at the S region on alkaline electrophoresis. Hematocrit over three years ranged from 32.7% to 40.8% (see attached Figure 1).

Given the atypical presentation (history and physical examination) and discrepancies in electrophoreses results, HPLC was done (see attached Figure 2). The presence of an unknown band further added to the diagnostic dilemma. The sample was then sent to the Synnovis Special Haematology Laboratory at Guys and St Thomas Hospital London for further testing. Sanger sequencing was performed on the beta-globin genes. This demonstrated compound heterozygous mutations for Hb C due to the HBB;c.19G>A and Hb O-Arab due to the HBB;c.364G>A mutations.

Conclusion: There is a need to have a high index of suspicion and domesticate diagnostic algorithms, especially in resourceconstrained settings.

Topics 004–Clinical, public health and epidemiological studies

Aisha Arshad¹, Nadia Farhan Essa¹, Farhan Essa Abdullah¹

Dr. Essa Laboratory and Diagnostic Centre¹

Background: Iron deficiency anaemia (IDA) and β-thalassaemia minor (BTM) are considered to be important cause of microcytic hypochromic anaemia. Studies have evaluated various cell parameters which are easily available on electronic cell counters in IDA and BTM in different ethnic populations. In the literature, there is also some information about platelet indices and their link with IDA and different hemoglobinopathies.The current study was planned to evaluate the role of platelet parameters in IDA and different forms of hemoglobinopathies.

Materials and Methods: An observational and cross sectional study conducted during the period of September 2020 to February 2022 at Dr. Essa Laboratory and Diagnostic center. A total of 1365 participants were included. Clinical details were recorded through Hb electrophoresis history form. CBC was performed using XP-100 and Hb Electrophoresis was done using Bio-Rad D10 analyzer. All parameters were calculated as in mean, standard deviation and percentages using SPSS version 23.

Results: A total of 1365 participants were enrolled in the study. The iron deficiency anemia (IDA) was more common in patients 971 (71%) followed by thalassemia minor 276 (20%), thalassemia major 90 (7%), HbD disease 20 (1.46%) and HbE disease 08 (0.5%) The most common presenting complain was weakness observed in 933 (68.3%) patients followed by vertigo in 230 (16.8%) and body pain in 102 (7.47%) patients. The mean age of patients was 22.41 ± 9.89. Females were higher in number as 312(%) and males were 150(%).

The hematological characteristics were explained significant low levels of Hb 5.9 ± 2.95 and MCV 17.3 ± 4.9 were observed in Thalassemia major patients with p = <0.001.The significant highest platelet counts of 366 ± 162 with highest MPV of 11 ± 2 fl were observed in IDA patients.The PDW was raised in Thalassemia major with mean of 13.3 ± 3.6 and P-LCR was raised in IDA 28.5 ± 2.67.

Conclusion: Although thalassemia is a genetic disease but higher frequency was found in our population with IDA and thalassemia minor. The elevated levels of platelet parameters were found in IDA which can be used in early detection of IDA as compared to BTM at early level of diagnosis. Studies with large number of sample size are needed to validate it more precisely.

Topics 004–Clinical, public health and epidemiological studies

D.R.S. Sinha¹

Pt JNM Medical College Raipur¹

Background: Sickle cell disease (SCD) is a disorder marked by a single-point mutation in the beta-globin gene. There are many genetic variations seen between the patient's genotype and phenotype. Clinical symptoms are brought by RBC breakdown and blood vessel occlusion. Along with other manifestations, the patient needs to handle pain crises and systemic manifestations. Enormous variation is observed in morbidity patterns and clinical characteristics too. Hydroxyurea is a globally accepted disease-modifying agent which sounds to be effective in managing clinical squally and probably preventing complications of SCD. The current study is aimed to document the morbidity pattern and impact of Hydroxyurea therapy in the Sickle Cell Institute's Raipur's Outpatient Department.

Materials and Methods: This cross-sectional study was conducted among randomly selected 65 patients (adults and children above 6 years). After the acquisition of informed consent, relevant data were collected in a predesigned pretested questionnaire. The appropriate statistical exercise was applied for the interpretation of results and inferences.

Results: Out of all 65 included in the study, acute febrile illness 54 (83%) and 53 (81.5%) reported pain crises observed to have the most common morbidity among them. Followed by 55.4% (36), and 33(50.8%) jaundice and difficulty breathing respectively. Joint pain was most commonly observed complain preferably at the knee joint (76.9%). Other complaints are Hand Foot Syndrome (24.6%), Epistaxis (27.7%), and Acute Chest Syndrome (14, 21.5%). Vaso-occlusive crisis (72.4%), difficulty in walking (60.0%) and eyesight (35.4%), Leg ulcers (9.2%), and Dactylitis (3.1%) were also documented as clinical manifestations among study participants. Less than half (29, 44.46%) had an awareness of SCD. Hydroxyurea therapy was highly significant in improving the patient's clinical picture (p < 0.01), especially following the frequency of hospitalization & requirement for blood transfusion.

Conclusion: Pain crisis is the most common morbidity among study participants with a low level of knowledge about SCD with febrile illness. Hydroxyurea therapy was found to be quite effective as diseasemodifying therapy, especially for reducing the frequency of blood transfusion and lowering hospitalization rates among SCD patients.

Topics 004–Clinical, public health and epidemiological studies

A.D.S. Sunday¹, D.A.A. Ameh²

Kaduna state university pediatrics department faculty of clinical sciences/Barau Dikko teaching hospital¹, Biochemistry Department, Ahmadu Bello University, Zaria, Nigeria²

Background: Pregnancy Induced Hypertension (PIH) includes a group of hypertensive disorders which develop during pregnancy and is one of the most common obstetric complications (Cunningham et al., 2010). Several works on cardiovascular diseases (CVD) in sickle cell disease (SCD) which deal with dyslipidemia, smoking, poor diet, hypertension, sedentary lifestyle and obesity (Takasaki, 2005). SCD patients are known to be more predisposed to venous thrombo-embolism (VTE) than the general population (Ataga, 2003). Among the reported processes involved in the development of VTE in SCD dyslipidemia is the most important (Kanthe, 2012; Setty, 2001). Many efforts have been made in seeking emergent or new cardiovascular risk factors to improve CVD prediction. And, in an attempt to optimize the predictive capacity of the lipid profile, several lipoprotein ratios or “atherogenic indices” have been defined. These indices could prove to be a better alternative to the routine investigations. One of them is cardiac risk ratio (CRR) which is frequently used for risk assessment of CVD and is given by the total cholesterol to high-density lipoprotein cholesterol (HDLC) ratio. Atherogenic index of plasma (AIP), calculated as, log (triglyceride/HDL-C). It has recently been proposed as a marker of plasma atherogenicity because it is increased in people at higher risk for coronary heart disease and is inversely correlated with LDL particle size NCBI (2011).

Aim: The study aims to evaluate the lipid profile of pregnant women across the trimesters and to investigate the risk of developing CVDs during pregnancy, by atherogenic indices and also to state the importance of calculating AIP in SCD patients.

Methods: Presumed healthy pregnant women attending Barau Dikko Teaching Hospital (BDTH) antenatal clinic, Kaduna, Nigeria.

Ethical approval was obtained from Kaduna State Ministry of Health. Ref No. MOH/ADM/744/VOL.1/423. Informed consent was sought from all pregnant women using the standard protocol. The sample size was calculated using the formula described by Naing et al. (2006). About 5 ml of venous blood sample was collected by a trained laboratory personnel from the selected pregnant women after thorough sterilization of the site with 70% of alcohol using sterile disposable plastic syringe. The blood sample was transferred into the sample bottle containing no anticoagulant and the serum separated by centrifugation at 3000 rpm. Lipid Profile: serum total cholesterol (TC), TG, and HDL was analyzed by using AGAPE test kit.

Results: One hundred and eighty (180) apparently healthy pregnant women participated in the research. Considering the AIP, result shows that the pregnant women in the first and second trimester were associated with medium cardiovascular risk (0.1–0.24) while 26% in the third trimester have high risk (>0.24) of developing CVD (Table 2). Values of CRR was in the normal ranges across the trimesters (Table 2) and AC values shows cardiovascular risk at the 3rd trimester, having a value >3.

Summary: there was high risk of developing CVD by the pregnant women, particularly in SCD patients. Therefore, Atherogenic Indices during pregnancy should be calculated during pregnancy.

Conclusions: the calculated AIP of the pregnant women in the first and second trimester were associated with medium cardiovascular risk while 26% in the third trimester have high risk (>0.24). AIP value is higher in SCD patients than non SCD patients.

Topics 003–Artificial intelligence, deep learning and other technological advancements in hemoglobinopathies

M. Reschke¹, J.P. Gross², J. Hegner², G. Sürücü³, J. Seiler⁴, O. Penack⁵, D. Weschke⁶, D. Higgins⁶, L. Oevermann²

Charité–Universitätsmedizin Berlin, Department of Pediatric Oncology & Hematology¹, Charité-Universitätsmedizin Berlin, Department of Pediatric Oncology & Hematology², Institute of Transfusion Medicine, H&I Laboratory, Charité–Universitätsmedizin Berlin³, Berlin Institute of Health at Charité–Universitätsmedizin Berlin⁴, Charité–Universitätsmedizin Berlin, Department of Hematology, Oncology and Tumorimmunology⁵, Berlin Institute of Health at Charité–Universitätsmedizin Berlin⁶

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative therapy option for patients with hemoglobinopathies.

Serious, possibly life-threating complications, such as Graft-versus-Host Disease (GvHD), occur in 30%-50% of patients undergoing HSCT and should be avoided at all costs, especially in hemoglobinopathies.^1–3 There is no reliable way to predict the individual risk of suffering from complications like GvHD during the course of HSCT, because the huge amount of multidimensional parameters influencing clinical outcome is impossible for a human to compute accurately.

Reliable prediction of complications supports patients and physicians to make informed decisions, simplifies the choice of the optimal donor to avoid complications and enables superior, individualized planning of conditioning and prophylaxis. Up to date, prediction of complications is based on physician's knowledge and experience, which varies between them, rather than evidence for individual situations.

MatchGraft.AI is an artificial intelligence-based machine-learning tool that predicts the individual risk of acute Graft versus Host Disease, relapse of malignant disease and overall risk of death, using only pretransplant data. The model was trained and tested on retrospective data of an international, multicenter cohort.

Aim: The aim of this study is to explore the standard of care of choosing an HSCT donor and compare the choice with real world data and MatchGraft.AI.

Methods: We developed an electronic questionnaire with 200 short patient histories including all parameters Matchgraft.AI is using. Pediatric and adult, benign and malignant cases with different donor types (matched unrelated, matched sibling, haploidentical family donor) are represented. This real-world data is derived from a retrospective cohort of pediatric and adult patients of Charité Universitätsmedizin. 50 international experts in HSCT will choose a donor and predict the individual risk of acute GvHD, risk of relapse and overall death for 50 individual patients.

Cases are allotted randomly according to the physician's specialty (adult/pediatric physician, both). Questionnaires are anonymized. Answers are not traceable to the expert. Personal results compared with real world outcome and MatchGraft.AI can be provided to participants, if they wish.

Results: We compare sensitivity and specificity of MatchGraft.AI to the standard of care, which is expert opinion and real-world outcome.

We examine first, whether the choosing of a donor is dependent on the individual physician or consistent throughout different HSCT experts. Second, we analyze how precise HSCT experts can predict the occurrence of severe complications for patients planned to undergo HSCT. Third and last, we will see how well MatchGraft.AI can predict the occurrence of severe complications for patients planned to undergo HSCT in comparison.

Conclusion: This study will provide important data about the standard of care in HSCT donor choosing and for the planned prospective study evaluating MatchGraft.AI.

Topics 004–Clinical, public health and epidemiological studies

A. Abdulkareem¹, L. Ruggieri², F. Bonifazi², L.A. Dogara¹, B. Inusa³

Barau Dikko Teaching Hospital, Kaduna State University¹, Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus², King's College London, UK³

This study aim at investigating the need of healthcare professional involved in sickle cell disease management in Nigeria, using grounded theory as a framework. The aim is using this framework is to build a theory that can be tested and confirm.

The study used qualitative methodology and case study as a research design. Purposive samling was used to select respondent in the study interview and FGD was used to collect data from the study. Themantic analysis was use to analyse the collected data findings from the healthcare professionals revealed the need for more space for the laboratory services as well as the transfusion service. Training of personnel, including either physicians, technicians, or nurses, is one of the main needs experienced in all the selected centres.

Conclusion: Results of this study show an adequate needs of healthcare professionals about their perceptions with SCD management in the centre. Evaluating healthcare workers needs is crucial to tailor implementation measures to improve clinical and diagnostic services paving the way for a successful management of SCD in Nigeria, where the burden of the disease is significant. However, results can be considered quite realistic.

Topics 001–Basic and translational

N.I. Igbineweka¹, J. Van Loon²

Imperial College London¹, European Space Agency²

A fundamental question in human biology and for hematological disease is how do complex gene-environment interactions lead to individual disease outcome? This is no less the case for sickle cell disease (SCD), a monogenic disorder of Mendelian inheritance, both clinical course, severity, and treatment response, is variable among affected individuals. New insight and discovery often lie between the intersection of seemingly disparate disciplines. Recently, opportunities for space medicine have flourished and have offered a new paradigm for study. Two recent Nature papers have shown hemolysis and oxidative stress to play key mechanistic roles in erythrocyte pathogenesis during spaceflight. This oral presentation reviews existing genetic and environmental modifiers of the sickle cell disease phenotype. It presents evidence for erythrocyte pathology in microgravity environments and demonstrates why this may be relevant for the unique gene-environment interaction of the SCD phenotype. It also introduces the hematology and scientific community to methodological tools for evaluation in space and microgravity research. The increasing understanding of space biology may yield insight into gene-environment influences and novel treatment paradigms in SCD and other hematological disease phenotypes.

Topics 004–Clinical, public health and epidemiological studies

A.M.N. Nasiri¹

King Faisal Specialist Hospital and Research Centre¹

Introduction: Sickle cell disease (SCD) is defined as an autosomal recessive disorder characterized by the production of abnormal hemoglobin S and is correlated with high morbidity and mortality. The clinical consequences of SCD include pain crisis, acute chest syndrome, and strokes. Spontaneous epidural hematoma is a rare manifestation in sicklers with few cases reported in the literature.⁶ The pathophysiology is not completely understood. However, a few explanations have been reported over the years that include vasoocclusion of the bone resulting in bone infarction, microfracture due to rapid expansion of hematopoiesis of the inner cortex, and sludging of the sickle cells in the diploic veins-all result in leaking of blood in the epidural or in the subgalea space.

Patient concerns: A 14-year-old boy known to have SCD (Hb SS) presented to the Security Forces Hospital with a history of diffuse headache associated with nausea that started 12 h prior to presentation.

Diagnosis: Computed tomography (CT) showed bilateral frontal epidural hematoma and subgaleal space.

Intervention: A multidisciplinary team was created (hematology, neurology, neurosurgery, and interventional radiology) and a plan was formulated as follows: Continuous monitoring of the patient's neuro vital signs and transfuse the patient with blood and platelets in addition with Levetiracetam.

Outcomes: The patient was discharged after 9 days of hospital admission. He has remained symptom-free post-transfusion. Postdischarge CT scan showed a reduction in the hematoma size.

Conclusion: A high index of suspicion is needed for a prompt diagnosis and treatment of this rare complication of SCD. The management strategy of EDH depends on the level of consciousness of the patient upon presentation. Surgical approach with craniotomy and evacuation or conservative management have been used with full recovery of the patients.