Haemophilia最新文献

Introduction: Iron deficiency (ID) impairs cognitive and physical function. Females with bleeding disorders (FBD) are at risk of ID as a result of bleeding symptoms.

Aim: This study aimed to report the overall incidence and prevalence of ID in FBD, identify factors associated with ID and describe the screening practices for and management of ID within haemophilia treatment centres (HTC).

Methods: Electronic surveys were distributed to medical providers caring for FBD within HTCs participating in the American Thrombosis Haemostasis (ATHN) affiliate network to gather data on practices for screening of ID and the use of iron supplementation. We next used the ATHNdataset to identify females 13-40 years of age receiving care at an ATHN-affiliated HTC between 2015 and 2019. Prevalence and incidence of ID were estimated based on the presence of one of the following lab results: transferrin >360 mg/dL, total iron binding capacity (TIBC) >460mcg/dL, % saturation <20% or ferritin <50 ng/mL, and clinical and demographic characteristics associated with ID were identified using logistic regression.

Results: Although all providers reported screening for ID, only 70% did so as part of their routine practice and significant variation existed in the form of iron supplementation used. Only 3.6% of participants in the ATHNdataset were tested for ID, and 71.9% of tested participants were ID. Black or African American race, platelet disorder and heavy menstrual bleeding were associated with increased risk of ID.

Conclusion: ID is highly prevalent among FBD and is underrecognised and undertreated. Practitioners should standardise practices to identify and manage ID.

Introduction: Comorbidities and public health conditions in haemophilia are receiving increasing attention.

Aim: To analyse the prevalence of comorbidities and mortality in people with haemophilia (PwH) compared to matched controls in subgroups (factor consumption and sex).

Methods: This study used longitudinal individual-level data (11 years) from national registers in three Nordic countries (Denmark, Finland and Sweden) from the MIND study (NCT03276130) for PwH and matched controls (1:5 on birth year and sex). It compared the prevalence of arthropathy, human immunodeficiency virus (HIV), hepatitis, depression, anxiety, hypertension, ischaemic heart disease, atrial fibrillation, stroke, diabetes, cancer, kidney disease and epilepsy, and mortality. Three severity subgroups for PwH were identified by use of factor concentrates and sex, including female carriers.

Results: Data for 2716 PwH (24,921 person-years) were analysed. PwH had increased prevalence of single and multiple comorbidities (p < 0.001), and increased mortality (p < 0.001). Arthropathy was more prevalent in all male PwH subgroups in Nordic countries, and among women including carriers in Sweden (odds ratios: ∼2→12). Arthropathy was a concomitant comorbidity alongside depression, hypertension, cardiovascular conditions, diabetes, hepatitis and HIV. Hypertension was more prevalent for PwH than controls in most subgroups. Hepatitis and HIV had the highest odds ratios among PwH in Denmark and Sweden.

Conclusion: Arthropathy occurs in combination with a complex of comorbidities. The potential common pathophysiologic denominator should be further explored. Higher prevalence of comorbidities and mortality rates in men and women with haemophilia call for a holistic approach with more ambitious treatment goals for PwH across severities and sexes.

Trial registration: The MIND Study was registered at ClinicalTrials.gov: NCT03276130.

Introduction: Type 1 plasminogen deficiency (PLGD-1), or hypoplasminogenaemia, is an ultra-rare autosomal-recessive disorder characterised by fibrin-rich lesions on mucous membranes, often leading to serious complications if left untreated. Prior treatments have shown limited and inconsistent success, but IV PLG concentrate (Ryplazim) offers a targeted therapy.

Aim: This study investigated the long-term safety and efficacy of IV PLG concentrate treatment for PLGD-1 patients.

Methods: A long-term study (NCT03642691) followed 12 participants who had previously been included in pivotal or expanded access trials of IV PLG concentrate. Participants received 6.6 mg/kg IV PLG concentrate infusions, with dosing frequency adjusted based on clinical response and plasminogen levels. Safety assessments and plasminogen level measurements were conducted.

Results: The median treatment duration during this long-term follow-up study was 41 months (range: 25-42 months). The median total exposure for participants in this study throughout the clinical development was 68 months (range: 28-71 months). No new or recurring ligneous lesions occurred when participants adhered to the prescribed regimen. Temporary disruptions in the drug supply led to some lesion recurrences, which resolved upon resuming the prescribed dosing frequency. A total of 2165 infusions were administered in this study, and most adverse events were mild. No anti-plasminogen antibodies or treatment-related fatalities occurred.

Conclusion: Long-term treatment with IV PLG concentrate is safe and effective for PLGD-1, demonstrating the potential for tailored dosing regimens. This study highlights the importance of individualised treatment and provides valuable insights into managing this ultra-rare disorder.

Introduction: Data regarding long-term clinical outcomes in Asian patients with acquired haemophilia A (AHA) was limited.

Aim: This study aimed to evaluate the effectiveness of current treatments and their outcomes in a real-world setting among Thai patients with AHA.

Methods: This was a retrospective cohort study conducted at a university-based hospital. Patients' characteristics, treatment patterns and disease outcomes were collected. Univariate and multivariate Gray's competing risk analyses were used to examine the factors related to the time to disease response.

Results: From 2009 to 2022, 69 AHA patients with a median age of 68 years (range 36-97) were enrolled. The majority of cases were characterised by the absence of an underlying aetiology (82.6%) and presented as major bleeding (71.0%). As first-line treatment, 79.7% were treated with steroid monotherapy, and 13.0% received a combination of steroid and rituximab. Thirty-one patients (44.9%) received at least one dose of haemostatic agents. After a median time to follow-up of 24.9 months (interquartile range 1.6-78.5), 41 patients (59.4%) attained first disease remission. Factor VIII below 1 IU/dL and the combination of steroid and rituximab were associated with time to disease remission, with subdistribution hazard ratio of 0.3 (95% confidence interval [CI], 0.1-0.7) and 5.2 (95% CI, 2.0-13.4), respectively. The most common complication in this cohort was infection (40.6%).

Conclusion: The combination of steroid and rituximab demonstrated efficacy in the management of AHA. In addition, infectious complications were a significant concern when treating AHA patients.

Introduction: The Phase 3 studies, XTEND-1 (NCT04161495) and XTEND-Kids (NCT04759131), showed once-weekly efanesoctocog alfa provided high-sustained factor VIII (FVIII) activity levels that translated into highly effective bleed prevention in patients with severe haemophilia A.

Aim: This analysis evaluated the efficacy and safety of efanesoctocog alfa for perioperative management during XTEND-1 and XTEND-Kids.

Methods: Patients undergoing major or minor surgery were to receive a single preoperative 50 IU/kg dose, with additional 30 or 50 IU/kg doses every 2-3 days as needed following major surgery. Outcomes assessed included FVIII activity levels, number and dose of efanesoctocog alfa injections, surgeon's/investigator's assessment of haemostatic response, total factor consumption, estimated blood loss, number and type of blood transfusions, and safety.

Results: In XTEND-1, 11 adults/adolescents underwent 12 evaluable major surgeries (6 orthopaedic). Eleven surgeries had one preoperative dose (median [range]: 49.9 [13-52] IU/kg); one had no preoperative dose. Median (range) total consumption from Day -1 to 14 was 163.3 (45-361) IU/kg. In XTEND-Kids, two children underwent major surgery with a single preoperative loading dose (60.4 and 61.9 IU/kg). Across trials, 15 adults/adolescents underwent 18 minor surgeries and 8 children underwent 9 minor surgeries, with a single preoperative dose or no preoperative dose (5 surgeries in adults/adolescents). Haemostatic response was rated excellent for all surgeries. No surgeries required blood transfusion. No safety concerns or inhibitor development was reported.

Conclusion: Efanesoctocog alfa provided highly effective perioperative protection in patients with severe haemophilia A.

Trial registration: XTEND-1: NCT04161495 https://clinicaltrials.gov/study/NCT04161495; XTEND-Kids: NCT04759131 https://clinicaltrials.gov/study/NCT04759131.

Introduction: Congenital afibrinogenemia is a rare bleeding disorder characterized by the complete absence of plasma fibrinogen, primarily caused by homozygous or compound heterozygous mutations in the FGA, FGB and FGG genes.

Aim: To deepen our understanding of the pathogenic mechanisms of afibrinogenemia through the study of natural variants.

Methods: We conducted a literature review of all publications up to 2024 that report cases of afibrinogenemia with confirmed genetic diagnoses, focusing on the impact of mutations on fibrinogen synthesis, assembly and secretion.

Results: We classified the pathogenic mechanisms of afibrinogenemia into the following seven categories: (1) Chromosomal structural variations, such as large deletions, disrupt the integrity of the fibrinogen gene cluster. (2) Splice site mutations interfere with the proper splicing of precursor mRNA, resulting in abnormal transcripts that cannot encode functional fibrinogen chains. (3) Start codon mutations prevent the initiation of translation, halting the synthesis of fibrinogen polypeptides. (4) Nonsense and frameshift mutations introduce termination codons, resulting in truncated fibrinogen chains. (5) Signal peptide mutations disrupt the targeting of polypeptides to the endoplasmic reticulum, preventing further post-translational modifications. (6) Mutations affecting disulphide bonds in the coiled-coil region hinder the assembly of fibrinogen chains, preventing the formation of complete hexamers. (7) Mutations affecting the correct conformation of β and γ nodules cause intra-cellular retention of fibrinogen and prevent its secretion.

Conclusions: This review provides a comprehensive summary of mutations associated with afibrinogenemia, offering insights that contribute to the phenotypic prediction of novel mutations and providing a framework for understanding the molecular mechanisms of afibrinogenemia.

Introduction: Haemophilia A and B is a disease consistently associated with reduced bone mineral density, both in adults and children. However, whether haemophilia also increases fracture risk has not yet been proven.

Aim: This systematic review and meta-analysis aimed to synthesize and analyse studies evaluating the association between haemophilia and fracture risk.

Methods: Comprehensive research was conducted in three electronic databases (PubMed, CENTRAL, and Scopus) up to 30 June 2024. Data were expressed as relative risk (RR) with 95% confidence intervals (CI). The I² index was employed to evaluate heterogeneity.

Results: Fourteen studies were included in the qualitative and four in the quantitative analysis (participants: 13,221, publication years: 2007-2022). Regarding design, five studies were retrospective cohorts, two were case-control, and seven were cross-sectional. Fracture prevalence in people with haemophilia (PWH) was 5.7%, ranging from 1.4% to 27.7% (data from 14 studies), compared with 0.9% in the control group, ranging from 0% to 5.1% (data from 3 studies). In comparison with healthy men, PWH demonstrated increased fracture risk (RR 4.56, 95% CI 1.28-16.25, p = 0.019, I² 90.74%). However, there was insufficient data to categorize fractures according to their location and to compare fracture incidence between patients receiving prophylaxis and those on-demand treatment, as well as according to the type or severity of haemophilia.

Conclusion: This is the first meta-analysis showing a more than 4-fold increased fracture risk in PWH compared with the general population.

Introduction: Patients with musculoskeletal complaints as a result of their bleeding disorder can benefit from primary care physiotherapy. The current study aims to describe physiotherapy services provided in primary care to patients with bleeding disorders and to what extent treatment was already in concordance with treatment recommendations as published in a clinical practice guideline in April 2024.

Methods: Researchers collected data from medical notes of primary care physiotherapists in the Netherlands treating a patient with a bleeding disorder. Collected data included; patient characteristics, condition for which treatment was initiated, total number of sessions, treatment modalities provided and outcome of treatment. Data from medical files was compared with 19 treatment recommendations stated in the newly developed clinical practice guideline.

Results: Data from 86 treatment episodes of 62 patients by 52 different physiotherapists was collected. Treatment episodes were initiated for haemophilic arthropathy (n = 47), joint bleed (n = 24), muscle bleed (n = 9) and synovitis (n = 6). The most frequently provided treatment modalities included manual techniques (in haemophilic arthropathy) and exercise therapy (in all other conditions). The percentage in which treatment was in concordance with the recommendation ranged between 17% and 100%.

Conclusion: The study indicated that exercise therapy was a commonly used treatment modality for all conditions. In contrast with other conditions, manual techniques were a frequently provided treatment modality in haemophilic arthropathy. Treatment was in many instances not in concordance with newly developed treatment recommendations. Dissemination and implementation of the recently developed treatment recommendations have the potential to improve primary care physiotherapy treatment for persons with bleeding disorders.

Background: Despite reports of elevated rates of osteoporosis and fractures in persons with haemophilia (PwH) and von Willebrand disease (PwVWD), routine bone health screening using dual-energy X-ray absorptiometry (DEXA) scans is not consistently implemented for this population across all Haemophilia Treatment Centres (HTCs) in the United States.

Objectives: The primary aim of this study was to examine rates of screening for bone health in PwH and PwVWD with vitamin D levels and DEXA scans.

Methods: We conducted a survey of all federally funded HTCs nationwide from June 2023 to August 2023. Nine multiple-choice questions were developed to explore the roles of HTC providers and their current practices for bone health assessment.

Results: The survey achieved a response rate of 44.8% (66 out of 147 HTCs). Among the responding centres, 21 HTCs (31.8%) reported routinely screening for vitamin D deficiency during annual comprehensive visits, while 13.6% (n = 9) performed regular bone health screenings using DEXA scans. Of these nine centres, three were adult HTCs and six were lifespan HTCs. DEXA scans were ordered either by physicians at the HTC (n = 5, 55.5%) or patients were referred to primary care providers, endocrinologists, or other specialists (n = 4, 44.4%). The top three indications for DEXA scans among the responding HTCs included HIV (n = 7, 77.7%), low physical activity or immobility (n = 6, 66.7%), fractures after a minor fall or injury in patients under 50 years of age (n = 5, 55.5%) and vitamin D deficiency (n = 5, 55.5%). These findings underscore the need for specific standardized screening guidelines to optimize bone health screening in PwH and PwVWD.