Pub Date : 2026-01-20DOI: 10.1016/j.bcmd.2026.102986
Nita Radhakrishnan , Savitri Singh , Archit Pandharipande , Eby P. Baby , Hari Gaire
Background
Congenital afibrinogenemia is a very rare bleeding disorder which is often life threatening. Data are scarce, and only 29 Indian cases have been officially reported to World Federation of Hemophilia, mostly as isolated descriptions. This study presents a prospectively followed pediatric cohort, evaluating clinical characteristics, outcomes with human fibrinogen concentrate (HFC), and health-system challenges.
Methods
Children diagnosed with afibrinogenemia between 2022 and 2025 at a tertiary centre were prospectively followed. Clinical presentation, diagnostic delay, prior treatments, and outcomes with HFC were analyzed, alongside a structured review of Indian literature and comparison with international data.
Results
Four children (ages 0.25–13 years) constituted 0.36% of the bleeding disorder cohort in our institutional registry (n = 1096). Median diagnostic delay was 8.2 years (range 0.25–12.5). Three were initially misdiagnosed as hemophilia. Major bleeds included recurrent hemarthroses, menorrhagia, and subgaleal/periorbital hematoma. All had Clauss fibrinogen <10 mg/dL. Two children on regular HFC prophylaxis remain bleed-free (median 39.8 months); two on on-demand therapy experience only intermittent bleeds. One developed irreversible blindness before correct diagnosis.
Conclusions
Afibrinogenemia, though rare, can be catastrophic if unrecognized. Early diagnosis and prophylactic HFC markedly reduce morbidity. Strengthening diagnostic capacity, registry reporting, and equitable HFC access are critical in resource-limited settings.
{"title":"Clinical outcomes and health-system challenges in congenital afibrinogenemia: a single-centre prospective case series","authors":"Nita Radhakrishnan , Savitri Singh , Archit Pandharipande , Eby P. Baby , Hari Gaire","doi":"10.1016/j.bcmd.2026.102986","DOIUrl":"10.1016/j.bcmd.2026.102986","url":null,"abstract":"<div><h3>Background</h3><div>Congenital afibrinogenemia is a very rare bleeding disorder which is often life threatening. Data are scarce, and only 29 Indian cases have been officially reported to World Federation of Hemophilia, mostly as isolated descriptions. This study presents a prospectively followed pediatric cohort, evaluating clinical characteristics, outcomes with human fibrinogen concentrate (HFC), and health-system challenges.</div></div><div><h3>Methods</h3><div>Children diagnosed with afibrinogenemia between 2022 and 2025 at a tertiary centre were prospectively followed. Clinical presentation, diagnostic delay, prior treatments, and outcomes with HFC were analyzed, alongside a structured review of Indian literature and comparison with international data.</div></div><div><h3>Results</h3><div>Four children (ages 0.25–13 years) constituted 0.36% of the bleeding disorder cohort in our institutional registry (<em>n</em> = 1096). Median diagnostic delay was 8.2 years (range 0.25–12.5). Three were initially misdiagnosed as hemophilia. Major bleeds included recurrent hemarthroses, menorrhagia, and subgaleal/periorbital hematoma. All had Clauss fibrinogen <10 mg/dL. Two children on regular HFC prophylaxis remain bleed-free (median 39.8 months); two on on-demand therapy experience only intermittent bleeds. One developed irreversible blindness before correct diagnosis.</div></div><div><h3>Conclusions</h3><div>Afibrinogenemia, though rare, can be catastrophic if unrecognized. Early diagnosis and prophylactic HFC markedly reduce morbidity. Strengthening diagnostic capacity, registry reporting, and equitable HFC access are critical in resource-limited settings.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"118 ","pages":"Article 102986"},"PeriodicalIF":1.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.bcmd.2025.102977
Kiranmye Reddy , Jonathan D. Fish , Jennifer Eng , Claire A. Carlson , Jill P. Ginsberg
Purpose
To assess the prevalence and severity of transfusion-associated iron overload (IO) in childhood cancer survivors (CCS).
Patients and methods
Serum iron, total iron binding capacity, percent iron saturation and ferritin were measured in 75 survivors of childhood cancer. In addition, blood bank records were reviewed to determine the total volume of packed red blood cells (pRBCs) administered during cancer therapy. Patients who received ≥120 mL/kg of pRBCs or had a ferritin ≥1000μg/L underwent hepatic R2 and cardiac T2* MRI for iron quantification, echocardiogram, assessment of liver and endocrine function, and genetic analysis for hereditary hemochromatosis.
Results
Forty-nine patients qualified for second level studies. Of these, 35 completed the MRI scans. Fifteen patients had a liver iron concentration (LIC) >3 mg iron/g (moderate hepatic iron overload), including eight patients who had an LIC greater than 7 mg iron/g (severe hepatic iron overload), with a mean LIC of 4.3 mg iron/g (0–15.6 mg iron/g). LIC correlated with total volume of pRBCs and ferritin. No patient had cardiac iron loading by MRI. Eleven patients were heterozygous and one was homozygous for mutations associated with hereditary hemochromatosis. There was no correlation between iron overload and hereditary hemochromatosis gene status.
Conclusion
There is a high prevalence of transfusion-associated iron overload among survivors of childhood cancer. This is concerning given the overlap between organ toxicities associated with cancer treatment and those known to be associated with iron overload. The tight correlation between LIC and ferritin suggests ferritin may be a reliable indicator of iron load in this patient population.
{"title":"Transfusion-related iron overload in survivors of childhood cancer","authors":"Kiranmye Reddy , Jonathan D. Fish , Jennifer Eng , Claire A. Carlson , Jill P. Ginsberg","doi":"10.1016/j.bcmd.2025.102977","DOIUrl":"10.1016/j.bcmd.2025.102977","url":null,"abstract":"<div><h3>Purpose</h3><div>To assess the prevalence and severity of transfusion-associated iron overload (IO) in childhood cancer survivors (CCS).</div></div><div><h3>Patients and methods</h3><div>Serum iron, total iron binding capacity, percent iron saturation and ferritin were measured in 75 survivors of childhood cancer. In addition, blood bank records were reviewed to determine the total volume of packed red blood cells (pRBCs) administered during cancer therapy. Patients who received ≥120 mL/kg of pRBCs or had a ferritin ≥1000μg/L underwent hepatic R2 and cardiac T2* MRI for iron quantification, echocardiogram, assessment of liver and endocrine function, and genetic analysis for hereditary hemochromatosis.</div></div><div><h3>Results</h3><div>Forty-nine patients qualified for second level studies. Of these, 35 completed the MRI scans. Fifteen patients had a liver iron concentration (LIC) >3 mg iron/g (moderate hepatic iron overload), including eight patients who had an LIC greater than 7 mg iron/g (severe hepatic iron overload), with a mean LIC of 4.3 mg iron/g (0–15.6 mg iron/g). LIC correlated with total volume of pRBCs and ferritin. No patient had cardiac iron loading by MRI. Eleven patients were heterozygous and one was homozygous for mutations associated with hereditary hemochromatosis. There was no correlation between iron overload and hereditary hemochromatosis gene status.</div></div><div><h3>Conclusion</h3><div>There is a high prevalence of transfusion-associated iron overload among survivors of childhood cancer. This is concerning given the overlap between organ toxicities associated with cancer treatment and those known to be associated with iron overload. The tight correlation between LIC and ferritin suggests ferritin may be a reliable indicator of iron load in this patient population.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"117 ","pages":"Article 102977"},"PeriodicalIF":1.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1016/j.bcmd.2025.102976
Huayong Song, Lijing Shen, Wen Sun, Ludi Zhang, Lixia Xue, Qingqing Shen, Zikang Chen, Xinqing Lu
Objective
To investigate the relationship of procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) with postoperative delirium (POD) in intensive care unit (ICU) patients, and to identify influencing factors.
Methods
Based on POD occurrence, 120 postoperative ICU patients were split into delirium (n = 72) and non-delirium (n = 48) groups. Clinical data and post-operative 24-h serum PCT, CRP, and IL-6 levels were gathered. Pearson correlation assessed relationships between these inflammatory markers, delirium incidence, and DRS-R-98 scores. Multivariate logistic regression identified predictors, and ROC curves evaluated the predictive value of the inflammatory markers.
Results
Delirium patients were older with higher APACHE II scores, more frequent mechanical ventilation, and longer ICU stays (P < 0.05). Their serum PCT, CRP, and IL-6 levels were higher and positively correlating with POD incidence and severity (DRS-R-98 scores) (r > 0, P < 0.05). These markers were identified as independent POD predictors (OR > 1, P < 0.05), demonstrating good predictive value with AUCs of 0.936 (CRP), 0.894 (PCT), and 0.820 (IL-6).
Conclusion
Postoperative inflammation serves as an independent risk factor for POD in ICU patients. Serum PCT, CRP, and IL-6 levels facilitate early detection and risk assessment, supporting preventive strategies and mitigating POD-related complications.
目的：探讨降钙素原（PCT）、c反应蛋白（CRP）、白细胞介素-6 （IL-6）与重症监护病房（ICU）患者术后谵妄（POD）的关系，并探讨影响因素。方法：将120例术后ICU患者根据POD的发生情况分为谵妄组（72例）和非谵妄组（48例）。收集临床资料及术后24小时血清PCT、CRP、IL-6水平。Pearson相关性评估了这些炎症标志物、谵妄发生率和DRS-R-98评分之间的关系。多因素logistic回归确定预测因子，ROC曲线评估炎症标志物的预测价值。结果：谵妄患者年龄越大，APACHEⅱ评分越高，机械通气次数越多，ICU住院时间越长（P < 0, P < 1, P >）。结论：术后炎症是ICU患者发生POD的独立危险因素。血清PCT、CRP和IL-6水平有助于早期发现和风险评估，支持预防策略和减轻pod相关并发症。
{"title":"Relationship between PCT, CRP, and IL-6 and postoperative delirium in ICU patients and its influencing factors","authors":"Huayong Song, Lijing Shen, Wen Sun, Ludi Zhang, Lixia Xue, Qingqing Shen, Zikang Chen, Xinqing Lu","doi":"10.1016/j.bcmd.2025.102976","DOIUrl":"10.1016/j.bcmd.2025.102976","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the relationship of procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) with postoperative delirium (POD) in intensive care unit (ICU) patients, and to identify influencing factors.</div></div><div><h3>Methods</h3><div>Based on POD occurrence, 120 postoperative ICU patients were split into delirium (<em>n</em> = 72) and non-delirium (<em>n</em> = 48) groups. Clinical data and post-operative 24-h serum PCT, CRP, and IL-6 levels were gathered. Pearson correlation assessed relationships between these inflammatory markers, delirium incidence, and DRS-R-98 scores. Multivariate logistic regression identified predictors, and ROC curves evaluated the predictive value of the inflammatory markers.</div></div><div><h3>Results</h3><div>Delirium patients were older with higher APACHE II scores, more frequent mechanical ventilation, and longer ICU stays (<em>P</em> < 0.05). Their serum PCT, CRP, and IL-6 levels were higher and positively correlating with POD incidence and severity (DRS-R-98 scores) (<em>r</em> > 0, <em>P</em> < 0.05). These markers were identified as independent POD predictors (OR > 1, <em>P</em> < 0.05), demonstrating good predictive value with AUCs of 0.936 (CRP), 0.894 (PCT), and 0.820 (IL-6).</div></div><div><h3>Conclusion</h3><div>Postoperative inflammation serves as an independent risk factor for POD in ICU patients. Serum PCT, CRP, and IL-6 levels facilitate early detection and risk assessment, supporting preventive strategies and mitigating POD-related complications.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"117 ","pages":"Article 102976"},"PeriodicalIF":1.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1016/j.bcmd.2025.102967
C.A. Hernández , M.J.M. Traets , W.W. van Solinge , A.W. Rijneveld , L. Kaestner , T. John , E. Nur , B.J. Biemond , F.A. Kuypers , E.J. van Beers , M.A.E. Rab , R. van Wijk
Red blood cells (RBC) from patients with sickle cell disease (SCD) are continuously exposed to high levels of oxidative stress, which impacts RBC deformability. In this study, we applied a novel technique (oxidantscan) to measure deformability of RBCs under shear stress while exposed to oxidative stress. Using RBCs collected from a cohort of patients with SCD and healthy volunteers, we measured different parameters including T-POD (Time to initiate Oxidant-induced change in Deformability) and EIMin (the minimum deformability reached during the test). T-POD was significantly shorter in patients with HbSS (n = 21, 729 ± 410 s) and HbSC (n = 19, 1031 ± 225 s) when compared to healthy controls (n = 20, 1739 ± 328 s, p < 0.05). Also EIMin was significantly lower in patients with HbSS (0.26 ± 0.10) and HbSC (0.30 ± 0.10) compared to healthy controls (0.54 ± 0.02). These results indicate that RBCs from patients with SCD are more susceptible to oxidative stress, which can be measured in a reproducible and quantifiable way. We also demonstrate that Oxidantscan outcome parameters correlated with sickling behavior and markers of hemolysis, indicating a possible link between these key pathophysiological features and the ability to withstand oxidative stress (all p < 0.05). Finally, we provide preliminary evidence for the potential of this technique to evaluate antioxidant therapy with l-glutamine as SCD RBCs showed a significant improvement in T-POD (11.5 %, p = 0.01) and EIMin (46.9 %, p = 0.03) upon ex vivo treatment with l-glutamine. The Oxidantscan is a promising technique for evaluating the response of SCD RBCs to oxidative stress, providing new insights in disease pathophysiology and potential novel treatment strategies.
镰状细胞病（SCD）患者的红细胞（RBC）持续暴露于高水平的氧化应激，这影响了红细胞的变形能力。在这项研究中，我们应用了一种新的技术（氧化扫描）来测量红细胞在氧化应激下剪切应力下的变形能力。使用从SCD患者和健康志愿者队列中收集的红细胞，我们测量了不同的参数，包括T-POD（开始氧化诱导的变形能力变化的时间）和EIMin（在测试中达到的最小变形能力）。HbSS患者（n = 21、729±410 s）和HbSC患者（n = 19、1031±225 s）的T-POD明显短于健康对照组（n = 20、1739±328 s, p < 0.05）。HbSS患者的EIMin（0.26±0.10）和HbSC患者的EIMin（0.30±0.10）明显低于健康对照组（0.54±0.02）。这些结果表明SCD患者的红细胞更容易受到氧化应激的影响，这可以用一种可重复和可量化的方式来测量。我们还证明了Oxidantscan结果参数与镰状行为和溶血标志物相关，表明这些关键病理生理特征与抗氧化应激能力之间可能存在联系（均p <； 0.05）。最后，我们为该技术评估l-谷氨酰胺抗氧化治疗的潜力提供了初步证据，因为SCD红细胞在体外使用l-谷氨酰胺治疗后，T-POD （11.5%, p = 0.01）和EIMin （46.9%, p = 0.03）显着改善。氧化扫描是一种很有前途的技术，用于评估SCD红细胞对氧化应激的反应，为疾病病理生理学和潜在的新治疗策略提供了新的见解。
{"title":"Oxidantscan: A novel biomarker to assess red blood cell susceptibility to oxidative stress in sickle cell disease","authors":"C.A. Hernández , M.J.M. Traets , W.W. van Solinge , A.W. Rijneveld , L. Kaestner , T. John , E. Nur , B.J. Biemond , F.A. Kuypers , E.J. van Beers , M.A.E. Rab , R. van Wijk","doi":"10.1016/j.bcmd.2025.102967","DOIUrl":"10.1016/j.bcmd.2025.102967","url":null,"abstract":"<div><div>Red blood cells (RBC) from patients with sickle cell disease (SCD) are continuously exposed to high levels of oxidative stress, which impacts RBC deformability. In this study, we applied a novel technique (oxidantscan) to measure deformability of RBCs under shear stress while exposed to oxidative stress. Using RBCs collected from a cohort of patients with SCD and healthy volunteers, we measured different parameters including T-POD (Time to initiate Oxidant-induced change in Deformability) and EI<sub>Min</sub> (the minimum deformability reached during the test). T-POD was significantly shorter in patients with HbSS (<em>n</em> = 21, 729 ± 410 s) and HbSC (<em>n</em> = 19, 1031 ± 225 s) when compared to healthy controls (<em>n</em> = 20, 1739 ± 328 s, <em>p</em> < 0.05). Also EI<sub>Min</sub> was significantly lower in patients with HbSS (0.26 ± 0.10) and HbSC (0.30 ± 0.10) compared to healthy controls (0.54 ± 0.02). These results indicate that RBCs from patients with SCD are more susceptible to oxidative stress, which can be measured in a reproducible and quantifiable way. We also demonstrate that Oxidantscan outcome parameters correlated with sickling behavior and markers of hemolysis, indicating a possible link between these key pathophysiological features and the ability to withstand oxidative stress (all <em>p</em> < 0.05). Finally, we provide preliminary evidence for the potential of this technique to evaluate antioxidant therapy with <span>l</span>-glutamine as SCD RBCs showed a significant improvement in T-POD (11.5 %, <em>p</em> = 0.01) and EI<sub>Min</sub> (46.9 %, <em>p</em> = 0.03) upon ex vivo treatment with <span>l</span>-glutamine. The Oxidantscan is a promising technique for evaluating the response of SCD RBCs to oxidative stress, providing new insights in disease pathophysiology and potential novel treatment strategies.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"117 ","pages":"Article 102967"},"PeriodicalIF":1.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hematopoietic stem and progenitor cells (HSPCs) are valuable for therapies and research due to their self-renewal and differentiation abilities. The ex vivo culture of these cells necessitates conditions that maintain their unique properties and provide a niche-like environment. Human platelet lysate (HPL), a growth factor-rich substance used in stem cell studies, influences various biological pathways. This study investigates HPL's effects on HSPCs' proliferation and erythroid-megakaryocytic differentiation, addressing the need to improve HSPC culture conditions for clinical and research applications. HPL was prepared, and isolated peripheral blood-derived HSPCs were cultured for 7 days in control and 10 % HPL-supplemented groups. Cell counts, viability, and population doubling time (PDT) were measured. Erythroid and megakaryocytic differentiation was assessed using qPCR and flow cytometry. Colony-forming cell (CFC) assays confirmed multilineage differentiation capacity. HPL significantly increased HSPCs proliferation, resulting in a 1.96-fold increase by day 7 and a reduced PDT. CFC assays confirmed that the cells maintained their ability to differentiate into various blood cell types. Flow cytometry showed a decrease in the CD71 marker without affecting the overall red blood cell population. Gene analysis revealed increased β-globin production while other red blood cell-related genes remained stable. Markers and genes associated with megakaryocyte development showed no significant changes. HPL as a culture medium supplement markedly enhances the proliferation of peripheral blood-derived hematopoietic stem cells during cell culture without inducing unwanted bias into the erythroid and megakaryocytic lineages.
{"title":"Ex vivo culture of hematopoietic stem and progenitor cells with platelet lysate: Investigating proliferation and erythroid-megakaryocytic lineage effects","authors":"Farnaz Pirsavabi , Zahra Najafi , Mohammad Ebrahimi Siahboomi , Bewar Othman Hasan , Shaban Alizadeh , Seyyed Hadi Mousavi , Mostafa Saberian , Zahra Kashani Khatib , Saeed Mohammadi , Naser Ahmadbeigi , Azadeh Omidkhoda","doi":"10.1016/j.bcmd.2025.102968","DOIUrl":"10.1016/j.bcmd.2025.102968","url":null,"abstract":"<div><div>Hematopoietic stem and progenitor cells (HSPCs) are valuable for therapies and research due to their self-renewal and differentiation abilities. The ex vivo culture of these cells necessitates conditions that maintain their unique properties and provide a niche-like environment. Human platelet lysate (HPL), a growth factor-rich substance used in stem cell studies, influences various biological pathways. This study investigates HPL's effects on HSPCs' proliferation and erythroid-megakaryocytic differentiation, addressing the need to improve HSPC culture conditions for clinical and research applications. HPL was prepared, and isolated peripheral blood-derived HSPCs were cultured for 7 days in control and 10 % HPL-supplemented groups. Cell counts, viability, and population doubling time (PDT) were measured. Erythroid and megakaryocytic differentiation was assessed using qPCR and flow cytometry. Colony-forming cell (CFC) assays confirmed multilineage differentiation capacity. HPL significantly increased HSPCs proliferation, resulting in a 1.96-fold increase by day 7 and a reduced PDT. CFC assays confirmed that the cells maintained their ability to differentiate into various blood cell types. Flow cytometry showed a decrease in the CD71 marker without affecting the overall red blood cell population. Gene analysis revealed increased β-globin production while other red blood cell-related genes remained stable. Markers and genes associated with megakaryocyte development showed no significant changes. HPL as a culture medium supplement markedly enhances the proliferation of peripheral blood-derived hematopoietic stem cells during cell culture without inducing unwanted bias into the erythroid and megakaryocytic lineages.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"117 ","pages":"Article 102968"},"PeriodicalIF":1.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145617000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.bcmd.2025.102966
Brian D. Chen , Amanda Tapia , Eric Boerwinkle , Clary B. Clish , Robert Gerszten , Misa Graff , Karen L. Mohlke , Alanna C. Morrison , Wimal Pathmasiri , Stephen S. Rich , Jerome I. Rotter , Blake R. Rushing , Susan Sumner , Russell P. Tracy , Kristin L. Young , Bing Yu , Bharat Thyagarajan , Alex P. Reiner , Yun Li , Laura Raffield
Complete blood counts (CBCs) are commonly measured in clinical practice and are associated with different diseases and traits. Statistical adjustment for blood cell abundance or related traits in these metabolomic epidemiology studies is not a common practice. However, it is plausible that common and cheaply measured blood cells would capture some of the variation also captured by metabolomic measures. Here, we assessed the association between metabolites and blood cell traits with a multi-ethnic meta-analysis of named metabolites from untargeted panels in the JHS, MESA, ARIC, and the HCHS/SOL cohorts. Among 2859 metabolite and blood cell trait pairs measured in at least two cohorts, 734 (25.6 %) were significantly associated. We also tested metabolite-blood cell trait pairs in the UK Biobank with a targeted NMR-based metabolomics panel. A large percentage (92 %) of the tested pairs was significant, and adjustment for blood cells altered relationships between metabolites and age and sex. We evaluated metabolite effect size changes for metabolite association with different incident diseases adjusting for CBC traits using the UK Biobank. Most notably, the metabolomic effect sizes on COPD were downweighted after adjustment. Blood cell trait adjustment showed similar but not overlapping effect size changes when compared to adjusting for eGFR, which is a common covariate in metabolomics analyses to account for kidney function. Our results show that statistical adjustment for blood cell traits may reduce confounding and clarify additional predictive power above existing clinical biomarkers in metabolomic studies.
{"title":"Association of metabolomics measurements with blood cell phenotypes","authors":"Brian D. Chen , Amanda Tapia , Eric Boerwinkle , Clary B. Clish , Robert Gerszten , Misa Graff , Karen L. Mohlke , Alanna C. Morrison , Wimal Pathmasiri , Stephen S. Rich , Jerome I. Rotter , Blake R. Rushing , Susan Sumner , Russell P. Tracy , Kristin L. Young , Bing Yu , Bharat Thyagarajan , Alex P. Reiner , Yun Li , Laura Raffield","doi":"10.1016/j.bcmd.2025.102966","DOIUrl":"10.1016/j.bcmd.2025.102966","url":null,"abstract":"<div><div>Complete blood counts (CBCs) are commonly measured in clinical practice and are associated with different diseases and traits. Statistical adjustment for blood cell abundance or related traits in these metabolomic epidemiology studies is not a common practice. However, it is plausible that common and cheaply measured blood cells would capture some of the variation also captured by metabolomic measures. Here, we assessed the association between metabolites and blood cell traits with a multi-ethnic meta-analysis of named metabolites from untargeted panels in the JHS, MESA, ARIC, and the HCHS/SOL cohorts. Among 2859 metabolite and blood cell trait pairs measured in at least two cohorts, 734 (25.6 %) were significantly associated. We also tested metabolite-blood cell trait pairs in the UK Biobank with a targeted NMR-based metabolomics panel. A large percentage (92 %) of the tested pairs was significant, and adjustment for blood cells altered relationships between metabolites and age and sex. We evaluated metabolite effect size changes for metabolite association with different incident diseases adjusting for CBC traits using the UK Biobank. Most notably, the metabolomic effect sizes on COPD were downweighted after adjustment. Blood cell trait adjustment showed similar but not overlapping effect size changes when compared to adjusting for eGFR, which is a common covariate in metabolomics analyses to account for kidney function. Our results show that statistical adjustment for blood cell traits may reduce confounding and clarify additional predictive power above existing clinical biomarkers in metabolomic studies.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"117 ","pages":"Article 102966"},"PeriodicalIF":1.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-07-25DOI: 10.1016/j.bcmd.2025.102951
Camilla V Pires, Jenna Oberstaller, Chengqi Wang, Justin Gibbons, Chiara Micchelli, Min Zhang, Thomas D Otto, Julian C Rayner, Steve Taylor, John H Adams
Background: Malaria causes over 200 million cases and more than half a million deaths annually. In many African regions, hemoglobinopathies, such as sickle cell trait (HbAS), confer partial protection against severe P. falciparum malaria. HbAS significantly reduces the risk of severe, life-threatening malaria by over 90 %. This study aims to describe a new analysis for the piggyBac transposon-based mutagenesis phenotypic screen to identify genes that influence the mechanisms behind this protection and tolerance of P. falciparum to the HbAS intracellular microenvironment, providing insights into potential new targets for malaria intervention and the evolutionary relationship between host and parasite.
Methods: We optimized and successfully employed a phenotypic screen using a piggyBac transposon-mutant library of P. falciparum to identify genetic factors essential for parasite survival in HbAS RBCs. Parasites were cultured in vitro in HbAS and control HbAA RBCs. Parasite growth was assessed via Quantitative Insertion Site Sequencing (QIseq) to determine sensitivity of each mutant in response to the conditions of HbAS RBCs identifying sensitive and tolerant mutants. Finally, a pairwise comparison was performed between HbAS and previously published piggyBac screens to infer potential links between HbAS infection and parasite responses to heat-shock, antimalarial drugs and oxidative stress.
Results: Our findings revealed that P. falciparum mutants sensitive to HbAS growth are associated with genes involved in signaling pathways, exported proteins, and host-interaction genes. These genetic factors overlap with those involved in the parasite's response to oxidative stress and antimalarial drug sensitivity, such as artemisinin derivates and proteasome inhibitor.
Conclusions: Our study identifies genetic factors influencing P. falciparum infection in HbAS RBCs, shedding light on how HbAS may counteract with the parasite, suggesting a connection between sickle-trait infections and other stress responses, such as heat-shock, artemisinin and oxidative stress.
{"title":"Phenotypic screens reveal Plasmodium falciparum genetic factors associated with infection of sickle-trait cells.","authors":"Camilla V Pires, Jenna Oberstaller, Chengqi Wang, Justin Gibbons, Chiara Micchelli, Min Zhang, Thomas D Otto, Julian C Rayner, Steve Taylor, John H Adams","doi":"10.1016/j.bcmd.2025.102951","DOIUrl":"10.1016/j.bcmd.2025.102951","url":null,"abstract":"<p><strong>Background: </strong>Malaria causes over 200 million cases and more than half a million deaths annually. In many African regions, hemoglobinopathies, such as sickle cell trait (HbAS), confer partial protection against severe P. falciparum malaria. HbAS significantly reduces the risk of severe, life-threatening malaria by over 90 %. This study aims to describe a new analysis for the piggyBac transposon-based mutagenesis phenotypic screen to identify genes that influence the mechanisms behind this protection and tolerance of P. falciparum to the HbAS intracellular microenvironment, providing insights into potential new targets for malaria intervention and the evolutionary relationship between host and parasite.</p><p><strong>Methods: </strong>We optimized and successfully employed a phenotypic screen using a piggyBac transposon-mutant library of P. falciparum to identify genetic factors essential for parasite survival in HbAS RBCs. Parasites were cultured in vitro in HbAS and control HbAA RBCs. Parasite growth was assessed via Quantitative Insertion Site Sequencing (QIseq) to determine sensitivity of each mutant in response to the conditions of HbAS RBCs identifying sensitive and tolerant mutants. Finally, a pairwise comparison was performed between HbAS and previously published piggyBac screens to infer potential links between HbAS infection and parasite responses to heat-shock, antimalarial drugs and oxidative stress.</p><p><strong>Results: </strong>Our findings revealed that P. falciparum mutants sensitive to HbAS growth are associated with genes involved in signaling pathways, exported proteins, and host-interaction genes. These genetic factors overlap with those involved in the parasite's response to oxidative stress and antimalarial drug sensitivity, such as artemisinin derivates and proteasome inhibitor.</p><p><strong>Conclusions: </strong>Our study identifies genetic factors influencing P. falciparum infection in HbAS RBCs, shedding light on how HbAS may counteract with the parasite, suggesting a connection between sickle-trait infections and other stress responses, such as heat-shock, artemisinin and oxidative stress.</p>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"115 ","pages":"102951"},"PeriodicalIF":1.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-01Epub Date: 2025-08-05DOI: 10.1016/j.bcmd.2025.102953
Antonella Meloni, Laura Pistoia, Paolo Ricchi, Filomena Longo, Valerio Cecinati, Francesco Sorrentino, Zelia Borsellino, Elisabetta Corigliano, Vincenza Rossi, Michela Zerbini, Priscilla Fina, Luigi Barbuto, Vincenzo Positano, Alberto Clemente
This cross-sectional study compared the prevalence of vascular, hepatic, cardiac, endocrine, and bone complications between adult patients with non-transfusion-dependent thalassemia (NTDT) and neo-transfusion-dependent thalassemia (neo-TDT). We evaluated 97 NTDT patients (44.73 ± 12.98 years, 48.5 % females) and 140 neo-TDT (>4 transfusions/year) patients (44.30 ± 12.13 years, 56.4 % females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. Iron overload (IO) was assessed by magnetic resonance imaging and complications were defined by established clinical criteria. Neo-TDT patients had significantly higher hemoglobin and ferritin levels and a higher prevalence of hepatitis C virus infection. Hepatic IO was more common in NTDT patients, whereas pancreatic and cardiac IO were significantly more frequent in the neo-TDT group. No significant differences were observed in extramedullary hematopoiesis, leg ulcers, hepatic cirrhosis, thrombosis, or pulmonary hypertension. Cardiac arrhythmias and impaired glucose metabolism were significantly more prevalent among neo-TDT patients. Hypogonadism, hypothyroidism, and hypoparathyroidism were more frequent in neo-TDT patients, though not statistically significant. Bone disorders were the most common in both groups, with a significantly higher prevalence in neo-TDT. In conclusion, neo-TDT patients exhibited a greater burden of cardiac arrhythmias, glucose metabolism disturbances, and bone metabolism disorders, highlighting the need for comprehensive and early multi-organ monitoring and timely intervention strategies.
{"title":"Prevalence of multi-organ complications in patients with non-transfusion and neo-transfusion dependent thalassemia: a cross-sectional survey.","authors":"Antonella Meloni, Laura Pistoia, Paolo Ricchi, Filomena Longo, Valerio Cecinati, Francesco Sorrentino, Zelia Borsellino, Elisabetta Corigliano, Vincenza Rossi, Michela Zerbini, Priscilla Fina, Luigi Barbuto, Vincenzo Positano, Alberto Clemente","doi":"10.1016/j.bcmd.2025.102953","DOIUrl":"10.1016/j.bcmd.2025.102953","url":null,"abstract":"<p><p>This cross-sectional study compared the prevalence of vascular, hepatic, cardiac, endocrine, and bone complications between adult patients with non-transfusion-dependent thalassemia (NTDT) and neo-transfusion-dependent thalassemia (neo-TDT). We evaluated 97 NTDT patients (44.73 ± 12.98 years, 48.5 % females) and 140 neo-TDT (>4 transfusions/year) patients (44.30 ± 12.13 years, 56.4 % females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia project. Iron overload (IO) was assessed by magnetic resonance imaging and complications were defined by established clinical criteria. Neo-TDT patients had significantly higher hemoglobin and ferritin levels and a higher prevalence of hepatitis C virus infection. Hepatic IO was more common in NTDT patients, whereas pancreatic and cardiac IO were significantly more frequent in the neo-TDT group. No significant differences were observed in extramedullary hematopoiesis, leg ulcers, hepatic cirrhosis, thrombosis, or pulmonary hypertension. Cardiac arrhythmias and impaired glucose metabolism were significantly more prevalent among neo-TDT patients. Hypogonadism, hypothyroidism, and hypoparathyroidism were more frequent in neo-TDT patients, though not statistically significant. Bone disorders were the most common in both groups, with a significantly higher prevalence in neo-TDT. In conclusion, neo-TDT patients exhibited a greater burden of cardiac arrhythmias, glucose metabolism disturbances, and bone metabolism disorders, highlighting the need for comprehensive and early multi-organ monitoring and timely intervention strategies.</p>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"115 ","pages":"102953"},"PeriodicalIF":1.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-25DOI: 10.1016/j.bcmd.2025.102965
Wenjue Xu , Huiyan Han , Binbin Li , Rui Huang , Qing Lin , Guowei Zhang
Platelet-targeted gene therapy for hemophilia entails modifying a patient's hematopoietic stem cells (HSCs) ex vivo to produce platelets containing coagulation factors, offering a potential cure by localized factor release at injury sites. However, the associated bone marrow transplantation carries significant risks, underscoring the critical need for low-toxicity conditioning regimens to enable clinical translation. This study evaluated G-CSF and 5-FU as conditioning regimens to facilitate the engraftment of HSCs expressing platelet-targeted FIX Padua. Hemophilia B (HB) mice were conditioned with G-CSF, 5-FU alone, or a combination of G-CSF, plerixafor, and 5-FU. Bone marrow mononuclear cells (BM-MNCs) from transgenic donors (2bF9-R338L) expressing platelet-stored FIX Padua were transplanted. G-CSF conditioning enabled long-term engraftment with 1 × 108 BM-MNCs; however, the efficacy declined significantly with lower cell doses. A single-dose of 5-FU (150 mg/kg) administered one day pre-transplant achieved optimal FIX expression and minimal toxicity. Critically, a combined regimen of G-CSF/plerixafor plus timed 5-FU (day -1) yielded stable, long-term platelet FIX expression and phenotypic rescue. The success of 5-FU underscores the importance of creating a transient niche vacancy for donor HSC engraftment. These results demonstrate that this mobilization-based, non-myeloablative conditioning strategy is a promising approach for platelet-targeted gene therapy for hemophilia.
{"title":"Effects of G-CSF and 5-FU as conditioning regimens in platelet-targeted gene therapy for hemophilia B","authors":"Wenjue Xu , Huiyan Han , Binbin Li , Rui Huang , Qing Lin , Guowei Zhang","doi":"10.1016/j.bcmd.2025.102965","DOIUrl":"10.1016/j.bcmd.2025.102965","url":null,"abstract":"<div><div>Platelet-targeted gene therapy for hemophilia entails modifying a patient's hematopoietic stem cells (HSCs) ex vivo to produce platelets containing coagulation factors, offering a potential cure by localized factor release at injury sites. However, the associated bone marrow transplantation carries significant risks, underscoring the critical need for low-toxicity conditioning regimens to enable clinical translation. This study evaluated G-CSF and 5-FU as conditioning regimens to facilitate the engraftment of HSCs expressing platelet-targeted FIX Padua. Hemophilia B (HB) mice were conditioned with G-CSF, 5-FU alone, or a combination of G-CSF, plerixafor, and 5-FU. Bone marrow mononuclear cells (BM-MNCs) from transgenic donors (2bF9-R338L) expressing platelet-stored FIX Padua were transplanted. G-CSF conditioning enabled long-term engraftment with 1 × 10<sup>8</sup> BM-MNCs; however, the efficacy declined significantly with lower cell doses. A single-dose of 5-FU (150 mg/kg) administered one day pre-transplant achieved optimal FIX expression and minimal toxicity. Critically, a combined regimen of G-CSF/plerixafor plus timed 5-FU (day -1) yielded stable, long-term platelet FIX expression and phenotypic rescue. The success of 5-FU underscores the importance of creating a transient niche vacancy for donor HSC engraftment. These results demonstrate that this mobilization-based, non-myeloablative conditioning strategy is a promising approach for platelet-targeted gene therapy for hemophilia.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"116 ","pages":"Article 102965"},"PeriodicalIF":1.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sickle Cell Disease (SCD) is a hereditary condition characterized by a mutation in globin chains of hemoglobin. Polymerization of deoxygenated sickle hemoglobin (HbS) leads to rigid sickle shaped red blood cells (RBC), the primary cause of SCD pathobiology and multiple comorbidities including organ damage and pain. Gene therapy is the only treatment to reduce sickling, but its limitations including high cost, advanced technical resources and age limit pose a major challenge in its application. We examined the potential of a nutraceutical Sailin-HbS, formulated from the extract of 5 different plant sources with anti-oxidant and anti-inflammatory property, to ameliorate RBC sickling. Using sickle RBCs from individuals with SCD (SS-RBCs), Sailin-HbS demonstrated ∼74 % inhibition of sickling under low oxygen conditions; and significantly inhibited hypoxia-induced HbS polymerization by reducing polymerization kinetics at 700 nm. Osmotic fragility tests demonstrated enhanced resistance of SS-RBCs to osmotic stress in the presence of Sailin-HbS. We compared the anti-sickling effect of Sailin-HbS with known anti-sickling agents, Niprisan, SCD 101, AES-103/5-HMF and GBT440/Voxelotor, and found it to be equally and/or more effective. We tested the safety/toxicity of Sailin-HbS in 2 rodent models which showed a high safety threshold, with an oral LD50 exceeding 2000 mg/kg, placing it within the OECD-GHS category class 5. Sub-acute and chronic toxicity assessments in rats reveal no adverse effects on organ function or body weight, biochemical parameters, or complete blood counts, demonstrating its safety profile with established threshold levels. Thus, Sailin-HbS exhibits considerable anti-sickling efficacy without inducing toxicity, suggesting its translational potential in SCD.
{"title":"Anti-sickling efficacy and safety of Sailin-HbS, an indigenous Ayurvedic formulation","authors":"Shruti Bhatt , Anil Bhansali , Apratim Sai Rajesh , Satyabrata Meher , Rabindra Kumar Jena , Bishnu Prasad Dash , Pradip Kumar Panda , Kalpna Gupta , Suman Kundu","doi":"10.1016/j.bcmd.2025.102956","DOIUrl":"10.1016/j.bcmd.2025.102956","url":null,"abstract":"<div><div>Sickle Cell Disease (SCD) is a hereditary condition characterized by a mutation in globin chains of hemoglobin. Polymerization of deoxygenated sickle hemoglobin (HbS) leads to rigid sickle shaped red blood cells (RBC), the primary cause of SCD pathobiology and multiple comorbidities including organ damage and pain. Gene therapy is the only treatment to reduce sickling, but its limitations including high cost, advanced technical resources and age limit pose a major challenge in its application. We examined the potential of a nutraceutical Sailin-HbS, formulated from the extract of 5 different plant sources with anti-oxidant and anti-inflammatory property, to ameliorate RBC sickling. Using sickle RBCs from individuals with SCD (SS-RBCs), Sailin-HbS demonstrated ∼74 % inhibition of sickling under low oxygen conditions; and significantly inhibited hypoxia-induced HbS polymerization by reducing polymerization kinetics at 700 nm. Osmotic fragility tests demonstrated enhanced resistance of SS-RBCs to osmotic stress in the presence of Sailin-HbS. We compared the anti-sickling effect of Sailin-HbS with known anti-sickling agents, Niprisan, SCD 101, AES-103/5-HMF and GBT440/Voxelotor, and found it to be equally and/or more effective. We tested the safety/toxicity of Sailin-HbS in 2 rodent models which showed a high safety threshold, with an oral LD50 exceeding 2000 mg/kg, placing it within the OECD-GHS category class 5. Sub-acute and chronic toxicity assessments in rats reveal no adverse effects on organ function or body weight, biochemical parameters, or complete blood counts, demonstrating its safety profile with established threshold levels. Thus, Sailin-HbS exhibits considerable anti-sickling efficacy without inducing toxicity, suggesting its translational potential in SCD.</div></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":"116 ","pages":"Article 102956"},"PeriodicalIF":1.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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