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Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required., Objectives and Design: The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq ® ), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered., Methods and Analysis: The primary endpoint is overall perioperative hemostatic efficacy ("success" or "failure") of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries., Ethics: Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki., Discussion: Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients., Trial Registration: CT EU 2022-502061-17-00; NCT05936580., Competing Interests: N.M. has received research funding from Pfizer, consultancy fees from Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sobi, honoraria from Baxalta, Bayer, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi and travels fees from Novo Nordisk, Octapharma, Sobi, and Takeda. F.L. has received personal fees for lectures or consultancy from Bayer, BioMarin, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Takeda. K.H. reports grants for research or clinical studies (to institution) from Bayer, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, and honoraria for lectures or consultancy (to person) from Bayer, Biomarin, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda. M.T.Á.-R. has served on advisory boards and speakers bureau for Amgen, Bayer, BioMarin, Bioverativ, CSL Behring, Grifols, LFB, Novartis, Novo Nordisk, Octapharma, Pfizer, Roche, and Takeda. R.N.V. has received personal honoraria for consulting services from Alexion, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Takeda. P.M. declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. N.D. has received honoraria for participation in advisory boards for Octapharma, Roche-Chugai and SOBI, and has received hospitality by Bayer HealthCare and Novo Nordisk. L.A. has received honoraria for participation in advisory board for Sobi, and has received hospitality by Bayer, CSL Behring, Octapharma, Sobi, and Takeda, and education by LFB. A.-E.L. has acted as a paid consultant, speaker and/or advisor for Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Roche, Sobi, and Takeda. R.C.S. has received honoraria for participation in advisory boards and speakers bureaus from Bayer, Biomarin, CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda. M.N. has acted as a consultant for Bayer, CSL Behring, Novo Nordisk, and Sobi, and has received honoraria for participating in advisory boards for Amgen, Bayer, CSL Behring, Kedrion, Novartis, Novo Nordisk, Sanofi Genzyme, Sobi, and Takeda. S.S. declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. G.G. has received research funding from Bayer and LFB, consultancy fees from Hemab and Novo Nordisk, and honoraria from Bayer and Novo Nordisk. J.O. has received research funding from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, Swedish Orphan Biovitrum, and Takeda; consultancy, speakers bureau, honoraria, scientific advisory board and travel expenses from Bayer, Biogen Idec, BioMarin, Biotest, Chugai, CSL Behring, Freeline, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Spark Therapeutics, Swedish Orphan Biovitrum, and Takeda. M.J. and S.K. are employees of Octapharma., (© The Author(s), 2024.)

Introduction: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level., Aim: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency., Methods: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT)., Results: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR., Conclusion: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life?, Method: MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number., Results: A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis., Conclusion: The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA., (© 2022 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Nonacog alfa, a standard half-life recombinant factor IX (FIX), is used as a prophylactic treatment in severe haemophilia B (SHB) patients. Its half-life determined in clinical studies involving a limited sampling (72 h) was shown to be rather short. In our clinical practice, we suspected that its half-life could have been underestimated., Objectives: We aimed to evaluate nonacog alfa pharmacokinetics in real world clinical practice based on FIX levels in patients receiving prophylaxis., Methods: We retrospectively collected data on patients with SHB receiving prophylaxis from eight centres across France. The terminal half-life (THL), time to reach 5-2 IU/dl and FIX activity at 48, 72 and 96 h were derived by Bayesian estimations using NONMEM analysis., Results and Conclusions: Infusion data (n = 455) were collected from 64 patients with SHB. The median THL measured in 92 pharmacokinetic (PK) studies was 43.4 h. In 26 patients ≤12 years of age, 51 PK studies showed a median time to reach 5 IU/dl of FIX of 70.5 h and a median time to reach 2 IU/dl of 121.5 h. In 38 patients 13-75 years of age, 41 PK studies showed a median time to reach 5 IU/dl of FIX of 92.0 h and a median time to reach 2 IU/dl of 167.5 h. Extending the sampling beyond 72 h makes it possible to observe a plateau, with FIX remaining between 2 and 5 IU/dl for several days and shows that the THL of nonacog alfa might be longer than previously described., Essentials: Nonacog alfa terminal half-life (THL) in patients receiving regular prophylaxis was evaluated in clinical practice. The median THL was estimated to be 36.9 h for patients aged .8-12 years. The median THL was estimated to be 49.9 h for patients aged 13-75 years. For patients aged ≤12 and >12 years, the median times to reach 5 IU/dl were 70.5 and 92 h, respectively; to reach 3 IU/dl, 95.5 and 131.5 h, respectively; to reach 2 IU/dl, 121.5 and 167.5 h, respectively. We suggest that the half-life of nonacog alfa might be longer than previously described in both younger and older patients., (© 2022 John Wiley & Sons Ltd.)

Background: Pregnancy, delivery and the postpartum period expose haemophilia carriers, as well as their potentially affected neonates to a high risk of haemorrhagic complications., Objectives: To describe bleeding complications in haemophilia carriers and their newborns throughout pregnancy and postpartum and to identify potential factors increasing the risk of bleeding in this population., Patients/methods: The ECHANGE multicentre observational cohort study was conducted between January 2014 and February 2019 using the BERHLINGO database comprised of patients from seven French haemophilia centres., Results: During the 5 years study period, a total of 104 haemophilia carriers and 119 neonates were included, representing 124 pregnancies and 117 deliveries. Thirty-five (30%) bleeding events were observed, most of them (83%) occurred during the postpartum period, and 37% were reported during the secondary postpartum. Neuraxial anaesthesia was not complicated by spinal haematoma. Three (2.5%) neonates experienced cerebral bleeding. Caesarean section was associated with an increased risk of maternal bleeding in primary and secondary postpartum periods. Basal factor level <0.4 IU/mL was also found to be associated with an increased risk of bleeding during secondary postpartum., Conclusion: In our cohort, bleeding events occurred in more than a third of haemophilia carriers mainly in the postpartum period, and a significant portion of this bleeding occurred during the secondary postpartum. Haemophilia carriers warrant specific attention during primary and secondary postpartum, in particular in case of caesarean section and low basal factor level. The ECHANGE study is registered at clinicaltrials.gov identifier: NCT03360149., (© 2020 John Wiley & Sons Ltd.)

Competing Interests: Declaration of Competing Interest The authors stated that they had no interests which might be perceived as posing a conflict or bias.

Background: The thrombin generation (TG) assay can assess individual clotting potential. The thrombin generation potential is correlated with the patient's bleeding phenotype and varies from one patient to the other for the same degree of factor VIII or IX deficiency., Objective: To define in vitro for individual haemophilic patients the target factor VIII or IX level required to normalize their TG., Patients/methods: Plasmas from 20 haemophilic patients were spiked with increasing levels of the deficient coagulation factor and TG parameters were measured. The relationships between factor levels and TG parameters were determined by linear regression. The normal range of thrombin generation was defined in 39 healthy male volunteers., Results: Despite inter-individual heterogeneity in basal TG and responses to spiking, a linear relationship was found between factor VIII or IX levels and TG parameters for individual patients. Based on the individual responses of patient plasmas to spiking, it is possible to define in vitro the target factor VIII or IX levels needed to normalize the TG parameters. For both haemophilic A and haemophilic B patients, significant correlations were found between basal peak values and their correction slopes. The correction slope was steeper in haemophilic B patients, so the factor IX level needed to normalize the TG parameters was lower than for haemophilic A patients., Conclusions: The TG assay could be used to determine in vitro the patient-specific factor VIII or IX level to be reached to effectively normalize their TG. These in vitro results should be confirmed by ex-vivo studies., (© 2018 John Wiley & Sons Ltd.)

Introduction: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life., Methods and Analysis: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag., Ethics and Dissemination: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public., Trial Registration Number: NCT02866526; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diffuse venous malformations can be associated with a consumptive coagulopathy characterized by a reduction of fibrinogen level, platelet count and elevated D-dimer level. We report a case of a patient with extensive venous malformations, hemorrhagic symptoms and biological signs of intravascular coagulopathy. She was initially treated effectively with low-molecular weight heparin (LMWH) (enoxaparin 1 mg/kg, bid) and switched to low-dose dabigatran etexilate (110 mg bid) for more than 2 years. Both treatments showed a similar clinical efficacy with the absence of bleeding or thrombotic complications. Compared with LMWH, dabigatran etexilate provided a similar correction of the fibrinogen level and platelet count but was less effective to reduce the D-dimer level. Although dabigatran etexilate can be safely used to control the consumptive coagulopathy secondary to venous malformation and provides a practical alternative to LMWH, its efficacy in vivo at a low dose to reduce the D-dimer level was lower than that of LMWH.

The platelet function analyser (PFA-100) is a biological tool designed to explore primary haemostasis. This system has thus been widely demonstrated as reliable in detecting von Willebrand factor (VWF) deficiency. However, most studies were based on patients benefitting from regular medical care and accurate diagnosis, and it would seem probable that the results were somewhat optimistic, and do not reflect its performances in 'real-world' situations. We have chosen to study the reliability of PFA-100 for screening VWF ristocetin cofactor (VWF:RCo) deficiency. We retrospectively analysed the results (n = 6431) of 4027 patients referred to our centre between October 1997 and June 2013 and in whom PFA-Epi, PFA-ADP, and VWF:RCo activity had been evaluated. We studied the influence of blood group on the results and the performances of each method in a subgroup of 213 patients with genetically confirmed von Willebrand disease. We have shown that the PFA-100 system, in our experience, constitutes an excellent screening test for detecting VWF:RCo deficiency, whatever the clinical situation, in 'real-world' conditions. The negative predictive value (NPV), the positive predictive value, the sensitivity and the specificity were respectively: 0.98, 0.51, 0.98 and 0.40. When values adjusted for blood group are used, NPV and sensitivity are inferior to those using normal values which have not been adjusted for blood group. We have shown the PFA-100 method to be more efficient in screening for VWF deficiency than the VWF:RCo technique., (© 2015 John Wiley & Sons Ltd.)

Factor V (FV) inhibitor arises rarely after using fresh frozen plasma (FFP) to treat inherited FV deficiency and is often a real therapeutic challenge. Here, we report a patient with a severe FV deficiency who developed such an inhibitor and was then treated with recombinant activated FVII (rFVIIa) and platelet concentrates (PC). Monitoring was assessed by thrombin generation assay (TGA). PC were more effective than rFVIIa in treating bleeding, but there was no correlation between the TGA results and clinical efficacy., (© 2014 International Society of Blood Transfusion.)