International databases open the door to improved care for rare bleeding disorders

Abstract The development of registries through international collaboration has facilitated better understanding of the rare bleeding disorders. Such work has shown that rare bleeding disorders are heterogeneous and need to be studied singularly, and that heterozygous patients may bleed. There is a need to understand the minimum plasma coagulant activity level to prevent spontaneous bleeding. Moreover, due to the low prevalence of rare bleeding disorders, the management of this patient population remains a challenge. Data collection on clinical history, efficacy and side effects of treatment needs to be harmonised

Hypercoagulability and the risk of recurrence in young women with myocardial infarction or ischaemic stroke: a cohort study

Background: We aimed to investigate the role of hypercoagulability on the risk of lifetime cardiovascular recurrences after myocardial infarction or ischaemic stroke. Methods: Young women (< 50 years) with either myocardial infarction (n = 197) or ischaemic stroke (n = 107) were followed between 1995 and 2012 in the RATIO follow-up study. To determine whether hypercoagulability affects the risk or recurrence, a coagulation score based on acquired and inherited markers was compiled and used in a quartile analysis. Hazard ratios (HRs) obtained from Cox proportional models and adjusted for several cardiovascular risk factors were used to compare quartiles of the coagulation score for the risk of recurrence. Results: During a median follow-up of 19 years, 59 cardiovascular recurrences occurred. In patients with myocardial infarction no association was found between a high prothrombotic score and recurrences (highest quartile vs lowest quartile HR 0.7, 95% CI, 0.3–1.8). Conversely, ischaemic stroke patients with a high prothrombotic score showed a doubling in risk of long-term cardiovascular recurrences (HR 1.9, 95% CI 0.6–6.3) compared with ischaemic stroke patients and low levels of the score, with a dose response relationship. Conclusions: An increased coagulation tendency might be associated with long-term cardiovascular risk in women with ischaemic stroke, but not in women with myocardial infarction

A Systematic Review

Background and Purpose Hypercoagulability increases the risk of arterial thrombosis; however, this effect may differ between various manifestations of arterial disease. Methods In this study, we compared the effect of coagulation factors as measures of hypercoagulability on the risk of ischaemic stroke (IS) and myocardial infarction (MI) by performing a systematic review of the literature. The effect of a risk factor on IS (relative risk for IS, RRIS) was compared with the effect on MI (RRMI) by calculating their ratio (RRR = RRIS/RRMI). A relevant differential effect was considered when RRR was >1+ its own standard error (SE) or <1−SE. Results We identified 70 publications, describing results from 31 study populations, accounting for 351 markers of hypercoagulability. The majority (203/351, 58%) had an RRR greater than 1. A larger effect on IS risk than MI risk (RRE>1+1SE) was found in 49/343 (14%) markers. Of these, 18/49 (37%) had an RRR greater than 1+2SE. On the opposite side, a larger effect on MI risk (RRR<1-1SE) was found in only 17/343 (5%) markers. Conclusions These results suggest that hypercoagulability has a more pronounced effect on the risk of IS than that of MI

Molecular characterization of the first missense mutation in the fibrinogen Aalpha-chain gene identified in a compound heterozygous afibrinogenemic patient

AbstractCongenital afibrinogenemia is a rare coagulopathy characterized by extremely low levels of functional and immunoreactive fibrinogen in plasma, associated with a hemorrhagic phenotype of variable severity. It is transmitted as an autosomal recessive trait and is invariantly associated with mutations affecting 1 of the 3 fibrinogen genes (FGA, FGB, and FGG, coding for Aα, Bβ, and γ chain, respectively). Most genetic defects causing afibrinogenemia are truncating mutations, whereas only few missense mutations (6) have been identified so far, all located in FGB.In this study, the mutational screening of an afibrinogenemic Italian male identified the first missense mutation (Met51Arg) in FGA leading to afibrinogenemia. The patient was a compound heterozygote for a previously described frameshift mutation (1215delT) in the same gene. Met51Arg involves a residue located at the very beginning of the coiled-coil domain, in a region demonstrated to play a pivotal role in hexamer formation. In-vitro expression experiments showed that Met51Arg strongly reduces secretion of hexameric fibrinogen, whereas traces of not completely assembled trimeric intermediate were found in conditioned media. Western blot analysis on the proband's plasma confirmed the presence in vivo of the trimeric fibrinogen, supporting the hypothesis that Met51Arg prevents the final step of fibrinogen assembly

Risk of diagnostic delay in congenital thrombotic thrombocytopenic purpura

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Laboratory testing in hemophilia: Impact of factor and non‐factor replacement therapy on coagulation assays

The advent of extended half‐life (EHL) recombinant clotting factors and innovative non‐factor replacement therapeutics, such as emicizumab, offers several advantages over existing products for the prophylactic treatment of people living with hemophilia (PwH). These include low annual bleeding rates with less frequent dosing, higher trough plasma concentrations, and a more convenient route of administration. However, increasing use of these therapies poses challenges to clinicians and coagulation laboratories due to the lack of standardized assays for monitoring of hemostatic parameters, and the potential for misinterpretation of test results, which may jeopardize patient safety. Definitive diagnosis of hemophilia and treatment monitoring is reliant on demonstrating factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B) deficiency using a functional coagulation assay. The most frequently used assays are based on activated partial thromboplastin time, using a one‐stage or two‐stage process. While one‐stage and chromogenic assays have performed well with human‐derived FVIII and FIX and full‐length recombinant products, EHL recombinant factors are heterogeneous in structure and mode of action and therefore show wide variation in activity levels between different one‐stage assays, and between one‐stage and chromogenic assays. In the context of the recommended stepwise approach for laboratory diagnosis of hemophilia, we examine the diagnostic challenges associated with the use of EHL factors and novel non‐factor therapeutics and consider the optimal diagnostic approach in PwH who are receiving these treatments. Ultimately, accurate diagnostic solutions are a prerequisite for personalized therapy to minimize treatment burden and improve quality of life in PwH

Arg77His and Trp187Arg are the Most Common Mutations Causing FXIII Deficiency in Iran

The aim of this study was to review the literature for the genetic mutations causing inherited factoe XIII (FXIII) deficiency in patients from Iran, where the consanguineous marriage is common. Data were collected from 30 patients (18 males and 12 females) with FXIII deficiency, from 26 unrelated families. Data of mutation analysis were obtained from 2 previously published studies. A total of 7 mutations consisting of 5 new mutations and 2 previously reported mutations were identified. Of the 5 novel missense mutations, 2, Arg77His and Trp187Arg, were the most common in Iranian FXIII-deficient patients. In regions like Iran with high rate of consanguineous marriages, the identification of common mutations in disease like severe FXIII deficiency increases the capacity to make a precise screening and diagnosis assays to screen and diagnose families with high risk of FXIII deficiency for prevention of clinical complications in them

Ultrasound Detection of Subquadricipital Recess Distension

Joint bleeding is a common condition for people with hemophilia and, if untreated, can result in hemophilic arthropathy. Ultrasound imaging has recently emerged as an effective tool to diagnose joint recess distension caused by joint bleeding. However, no computer-aided diagnosis tool exists to support the practitioner in the diagnosis process. This paper addresses the problem of automatically detecting the recess and assessing whether it is distended in knee ultrasound images collected in patients with hemophilia. After framing the problem, we propose two different approaches: the first one adopts a one-stage object detection algorithm, while the second one is a multi-task approach with a classification and a detection branch. The experimental evaluation, conducted with $483$ annotated images, shows that the solution based on object detection alone has a balanced accuracy score of $0.74$ with a mean IoU value of $0.66$, while the multi-task approach has a higher balanced accuracy value ($0.78$) at the cost of a slightly lower mean IoU value

Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies

Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: a) engineering vectors to increase transgene expression; b) aligning interests of the health system with costs and challenges for pharmaceutical industry; c) refining patient eligibility criteria, and endpoints definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are poorly available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy; be functional in a restricted cellular subset; avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should be also explored. Aligning interests and obligations of pharmaceutical industry with those of the health system is critical for AAV-based GT success. Costs and challenges for pharmaceutical industry include a) removing impurities from AAV; b) validating tests to measure treatment efficacy, c) promoting training programs to standardize vector genomes delivery, d) collecting long-term follow-up data, and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clearcut outcomes are mandatory as endpoints of unequivocal efficacy data

Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: The A-SURE study

Introduction: Haemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8-12 hours typically administered every 2-3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use. Methods and analysis: A-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect. Ethics and dissemination: Study approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.This work was fully funded by Swedish Orphan Biovitrum AB (publ