Retraction
Haemophilia : the official journal of the World Federation of Hemophilia,
02/2023, Letnik:
29, Številka:
S1
Journal Article
Recenzirano
Retraction: P139 ‘Brave‐Bleeding rates in hemophilia A: Real‐world evidences in Brazil’, M.C. Ozelo, A. Rosa‐Borges, A. N. Prezotti, L. C. Oliveira published as part of Poster Presentations Special ...Issue: 13th Annual Congress of European Association for Haemophilia and Allied Disorders 2020, 5–7 February 2020, The Hague, The Netherlands 26:S2 10.1111/hae.13911 The above poster from the Haemophilia, Special Issue: 13th Annual Congress of European Association for Haemophilia and Allied Disorders 2020, 5–7 February 2020, The Hague, The Netherlands, published online on 28 January 2020 in Wiley Online Library (wileyonlinelibrary.com), and in Volume 26, S2 has been retracted by agreement between the authors, the journal Editor, Cedric Hermans, Chief Operating Officer, Angelos Athanasopoulos, from the European Association for Haemophilia and Allied Disorders, and John Wiley and Sons Ltd. The retraction has been agreed upon following the admission of the authors that this article contained data that was incorrect and affected the findings of the poster. Only this poster is retracted and the rest of the supplement is not affected.
Background: Patients with severe hemophilia may show very varied bleeding tendencies, and the reasons for this heterogeneous clinical expression are unclear. The factor VIII/FIX genotype is the main ...determinant of the residual factor activity; however, different bleeding phenotypes have also been reported in patients sharing the same mutation. Such global coagulation tests as thrombin generation assays are tools with which to investigate different coagulation profiles among severe hemophiliacs. Objectives, patients and methods: This case–control study was aimed at comprehensively evaluating the role of genotype and endogenous thrombin potential (ETP) as predictors of the clinical phenotype in severe hemophiliacs with an extremely mild bleeding tendency (cases, n = 22), in comparison with those showing a typical bleeding tendency (controls, n = 50). Results: Cases were more frequently affected by hemophilia B than by hemophilia A, and showed a lower incidence of severe FVIII/FIX gene defects (referred to as null mutations), higher FVIII and FIX antigen levels and higher ETP values in platelet‐rich plasma than controls (P < 0.05). By multivariate logistic regression, only non‐null mutations were confirmed as an independent predictor of a mild clinical phenotype. Conclusions: These results indicate that non‐null mutations represent the main determinant of the bleeding tendency, and that ETP measurement in platelet‐rich plasma is able to identify severe hemophiliacs with a mild clinical phenotype.
Severe and moderate haemophilia A and B in US females Di Michele, D. M.; Gibb, C.; Lefkowitz, J. M. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
March 2014, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Summary
Haemophilia A and B are rare X‐lined hemorrhagic disorders that typically affect men. Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor ...VIII (FVIII) or factor IX (FIX) <0.01 U mL−1) or moderately severe (FVIII/FIX 0.01–0.05 U mL−1) phenotypes. However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal. A national multi‐centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females. Twenty‐two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health‐related quality of life (HR‐QoL). Clinical data were compared as previously indicated. Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease‐ and treatment‐related complications and access to treatment. Gynaecological and obstetrical bleeding was unexpectedly infrequent. F8 or F9 mutations, accompanied by extremely skewed X‐chromosome inactivation pattern (XIP), were primary determinants of severity. HR‐QoL was diminished by arthropathy and viral infection. Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia. An ongoing international case‐controlled study will further evaluate these observations. Novel mechanistic questions are raised about the relationship between XIP and both age and tissue‐specific FVIII and FIX expression.
F8 IVS9+5G>A mutation causes moderate haemophilia A Li, Delei; Chang, Wei; Tang, Ning ...
Haemophilia : the official journal of the World Federation of Hemophilia,
March 2019, 2019-03-00, 20190301, Letnik:
25, Številka:
2
Journal Article
Summary Haemophilia A and B are hereditary haemorrhagic disorders characterised by deficiency or dysfunction of coagulation protein factors VIII and IX, respectively. Recurrent joint and muscle ...bleeds lead to severe and progressive musculoskeletal damage. Existing treatment relies on replacement therapy with clotting factors, either at the time of bleeding (ie, on demand) or as part of a prophylactic schedule. The major complication of such therapy is the development of neutralising antibodies (ie, inhibitors), which is most frequent in haemophilia A. Treatment might improve considerably with the availability of new modified drugs, which might overcome existing prophylaxis limitations by reducing dosing frequency and thereby rendering therapy less distressing for the patient. Subcutaneous administration of some new therapies would also simplify prophylaxis in children with poor venous access. Gene therapy has the potential for a definitive cure, and important results have been obtained in haemophilia B. Despite improvements in haemophilia care, the availability of clotting factor concentrates for all affected individuals worldwide remains the biggest challenge.
The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an ...increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment‐related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult‐to‐treat patients. Some alternative, non‐ITI approaches for inhibitor management, are also proposed.
Summary
The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study ...aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.
In vivo gene therapy is rapidly emerging as a new therapeutic paradigm for monogenic disorders. For almost three decades, hemophilia A (HA) and hemophilia B (HB) have served as model disorders for ...the development of gene therapy. This effort is soon to bear fruit with completed pivotal adeno-associated viral (AAV) vector gene addition trials reporting encouraging results and regulatory approval widely anticipated in the near future for the current generation of HA and HB AAV vectors. Here we review the clinical development of AAV gene therapy for HA and HB and examine outstanding questions that have recently emerged from AAV clinical trials for hemophilia and other monogenic disorders.
Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the ...development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.
In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.
No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.
Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
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