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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.We aimed to evaluate nonacog alfa pharmacokinetics in real world clinical practice based on FIX levels in patients receiving prophylaxis.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.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.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.

Introduction Von Willebrand Disease is a common inherited haemorrhagic disorder due to a deficiency of Von Willebrand Factor (VWF). In case of surgical procedures in patients who are not responsive or have contraindications to desmopressin, replacement therapy with VWF concentrates is indicated. Until recently, only plasma-derived VWF concentrates were available. A new recombinant VWF (rVWF) concentrate that contains no Factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France since 2018. Aim Describe real-world experience of using rVWF in surgical procedures. Methods Sixty-three surgeries for 55 patients were retrospectively analysed in 7 French haemostasis centres. Results During minor surgeries, the median (range) number of infusions was 1 (1-8) with a preoperative loading dose of 35 (19-56) rVWF IU/kg and a total median dose of 37.5 IU (12-288). During major surgeries, the median (range) number of infusions was only 3 (1-14) with a median preoperative loading dose of 36 IU (12-51) rVWF IU/kg, and a total median dose of 108 IU (22-340) rVWF IU/kg. The overall clinical efficacy was qualified as excellent/good in 61 of the procedures (97%), moderate in 1 (1.5%) and poor in 1 (1.5%). There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events, anti-VWF antibodies or adverse events were reported. Conclusion This French 'real-world' experience shows that a few infusions and low doses of rVWF provided effective prevention of bleeding in major and minor surgeries in inherited VWD, with no clinically significant safety concerns.

Introduction To date, there is no specific recommendation or evaluation of the morbidity of prostate surgery in patients with haemophilia (PWH) although this surgery is common and at high risk of bleeding. Aim To assess the post-operative morbidity of benign prostate hyperplasia (BPH) surgeries and of oncological prostate interventions in patients with mild haemophilia A or B. Methods We performed a monocentre, epidemiological, in real life study. Data were collected between 1 January, 1997 and 1 September, 2020 and focused on prostate biopsy, radical prostatectomy, prostate radiotherapy, simple prostatectomy, transurethral resection of prostate (TURP) and laser-vaporisation in patients with mild haemophilia A or B. Results Between 1 January, 1997 and 1 September, 2020, 51 interventions were performed on 30 patients with mild haemophilia. Haemophilia A represented 93.33% of the population and haemophilia B 6.67%. For prostate biopsies (n = 24), median length of hospitalisation was 4 days and only one patient needed a blood transfusion. No patient needed re-admission. For prostatectomy (n = 10), one patient presented with intra-operative and post-operative bleeding. Two patients required re-admission. The other patients did not present any significant haemorrhagic symptoms. For radiotherapy (n = 4), two patients presented a grade II complication (radiocystitis and radiorectitis). For BPH surgeries, during hospitalisation, laser-vaporisation (n = 5) was less haemorrhagic than TURP (n = 5) but after hospital discharge, 60% of patients presented a haemorrhagic complication with two readmissions and one surgical re-explorations. Conclusion Performed in a specialised centre, prostate surgeries and interventions in patients with mild haemophilia is feasible with acceptable morbidity.

Introduction The development of an anti-FVIII inhibitor is the most serious complication of haemophilia A occurring in up to 30% of severe haemophilic patients. The current management of haemophilia A with inhibitor uses bypassing agents (BPA) and represents a significant therapeutic burden together with a limited adherence to prophylactic treatment. Emicizumab is the first monoclonal antibody developed in haemophilia A approved for the prevention of bleeding episodes in patients with anti-FVIII inhibitor. Aim The purpose of this study is to evaluate the incremental cost-effectiveness ratio (ICER) of emicizumab versus BPAs. Methods A Markov model was developed over a five-year time horizon to estimate the comparative costs and benefits of the different therapeutic approaches in this rare disease. Model inputs were clinical, including annual bleeding rate and quality of life, and economical including mainly costs of prophylaxis, bleeds and adverse events. Results Emicizumab treatment is dominant, ie lest costly and more effective, in the base-case analysis saving 234 191 € for a gain of 0.88 QALY. This is confirmed by both the deterministic and probabilistic sensitivity analyses. The main limit of the study remains the absence of long-term clinical data allowing to relate treatment consumption to clinical benefit, especially in the progression of haemophilic arthropathy. Conclusion Our results show that emicizumab is a cost-effective treatment allowing to consider an easy to implement prophylactic treatment for haemophilia A patients with anti-FVIII inhibitors.

International audience; Haemophilia is characterized by a congenital deficiency of clotting factor VIII or IX. One of the consequences of haemophilia is joint bleedings. Repetitive haemathroses induce cartilage damage and chronic synovitis leading to joint deterioration, and to definitive haemophilic arthropathy which is source of walking disability. Three-dimension gait analysis (3DGA) appears particularly relevant in the case of haemophilia because it allows an evaluation of several joints in weight-bearing situations. The purpose of this study was to review the interest and the contribution of 3DGA in the management of patients with haemophilia. The greatest interest of gait analysis would be to detect early walking changes with a non-invasive and well-tolerated examination, especially in paediatric population. In adulthood, this technic may be also useful to help detect walking worsening in patients known to have already arthropathy. However, it takes time to realize and needs expensive equipment, which limits its possibility of routine use. Although generalizations of these results remain difficult,especially to compare patients with haemophilia to normal population. Indeed, in the studies, patient groups are small and usually heterogeneous in terms of age and target joints. It certainly results of the rarity of the disease. So, it could be interesting to perform a study with a larger cohort in order to allow subgroup analysis, helping to define clearly the place of 3DGA in the strategy of haemophilia evaluation.

Introduction: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. Aim: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. Methods: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1, without inhibitors, were included. Data were summarized descriptively. Results: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. Conclusion: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care. (Less)

Summary 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.

Type 2N von Willebrand's disease (VWD) is characterized by a factor VIII (FVIII) deficiency and a low FVIII/VWF ratio related to a markedly decreased affinity of von Willebrand factor (VWF) to FVIII. Type 2N VWD is diagnosed using assays allowing the measurement of plasma VWF capacity to bind FVIII (VWF:FVIIIB). These assays, crucial in order to distinguish type 2N VWD patients from mild haemophiliacs A and haemophilia A carriers, remain exclusively homemade and limited to laboratories possessing a high level of expertise in VWD. We evaluated the first commercial ELISA (Asserachrom® VWF:FVIIIB; Stago) comparated to a reference method in a multicentric study involving 205 subjects: 60 healthy volunteers, 37 haemophiliacs A, 17 haemophilia A carriers, 37 patients with type 2N VWD, 9 heterozygous carriers for a 2N mutation and 45 patients with miscellaneous other types of VWD (all previously characterized). A diluted plasma sample adjusted to 10 IU dL(-1) of VWF:Ag was incubated with a rabbit antihuman VWF polyclonal antibody. After removing the endogenous FVIII, recombinant FVIII (rFVIII) was added and bound rFVIII was quantified using a peroxydase-conjugated mouse antihuman FVIII monoclonal antibody. The intra-assay and inter-assay reproducibility was satisfactory. In all subgroups, both methods were well correlated. All type 2N VWD patients exhibited a markedly decreased VWF:FVIIIB (lower than 15%) and all heterozygous 2N carriers had a moderately decreased VWF:FVIIIB (between 30% and 65%). All controls (healthy subjects, haemophiliacs A and haemophilia A carriers) had a normal VWF:FVIIIB (higher than 80%) except one healthy volunteer and three haemophiliacs who exhibited a moderately decreased VWF:FVIIIB suggesting a heterozygous status for a 2N mutation. In conclusion, the Asserachrom® VWF:FVIIIB is easy to perform, standardized and accurate for type 2N VWD diagnosis with a 100% sensitivity and specificity.

*Laboratoire d’hemostase Etablissement Franc ais du Sang, Besanc on; †Departement d’hematologie biologique CHU deMontpellier, Hopital Saint Eloi, Montpellier;^ ‡CEA, iBEB Service de Biochimie et Toxicologie Nucleaire, Bagnols sur Ceze;§Laboratoire d’Hematologie Centre de Biologie et Pathologie EA-2693, Centre Hospitalier Regional et Universitaire, Lille;¶Centre Regional de Traitement de l’Hemophilie, Laboratoire hematologie, CHU Hotel-Dieu, Nantes; and^ kCentre Regionalde Traitement de l’Hemophilie, Service d’hematologie CHU Besanc on, Besanc on, France

Summary. In the early nineties, the occurrence of hepatitis A outbreaks in some patients with haemophilia in some countries led French health authorities to recommend hepatitis A virus (HAV) vaccination in HAV-seronegative haemophiliacs. The French ‘Suivi therapeutique National des Hemophiles’ cohort permitted to assess the implementation of this recommendation by the analysis of the vaccinal process, i.e. HAV seropositivity assessment and vaccination of HAV-seronegative patients, in a survival approach. In a subgroup of 812 patients diagnosed earlier than 1990 (prevalent cohort), the implementation of vaccinal process increased quickly from 0% in 1993 to 41.8% in 1994 and to 71.2% in 1996, suggesting a ‘notification effect’. The vaccinal process was associated to three cofactors in a Cox model analysis (age, severity of haemophilia, centre of treatment). No infection was observed during the survey in this group. In another subgroup of 201 boys born since 1993 (incident cohort), 27.5% and 15.4% patients remained exposed to the risk at 3 and 5 years from diagnosis respectively, again with a ‘centre effect’, which might be linked to various factors such as regain in confidence for products or economic reasons. Only five infectious seroconversions were assessed over the 7-year survey, which represents 14.5 cases per 1000 person-year incidence without any relationship with products. Our data combined with the contemporary hepatitis A epidemiology and the current safety of anti-haemophilic concentrates, should lead to a new assessment of the risk of hepatitis A in haemophiliacs. We suggest that among patients with bleeding disorder, as well as in other populations, HAV prevention policy might be stressed on those who already suffer from chronic liver disease and/or travel in endemic countries.