The ECHO (MR-004, No. DEC24-269) study provides a real-world evaluation of efanesoctocog alfa (efa), a first-in-class ultra-long-acting factor VIII (FVIII) concentrate, within the French compassionate access (CAA) framework. It aims to characterize the unmet medical needs leading to CAA requests and evaluate the hemostatic efficacy and biological monitoring of efa prophylaxis. This multicenter study included 50 hemophilia A patients (84% severe; median age 31 years), including nine with inhibitor history. While 54% switched from FVIII prophylaxis, 46% transitioned from emicizumab due to persistent breakthrough bleeding (88%) and complex multifactorial scenarios (76%). Over a median 9-month follow-up, weekly efa prophylaxis resulted in a significant 89% reduction in treated bleeds (p < 0.001) and an 85% reduction in joint bleeds (p < 0.001) for the total population. This clinical benefit remained consistent across exploratory subgroups, including for patients previously on emicizumab. No new-onset inhibitors occurred. Biologically, the median centralized day-7 trough level was 7 IU/dL using a drug-calibrated bovine chromogenic substrate assay (CSA, n=31). However, a significant discrepancy was observed in paired comparisons (n=18): local one-stage assays (OSAs) yielded a median of 14 IU/dL, compared to a centralized CSA median of 7 IU/dL (p < 0.001). Notably, this divergence occurred across various local reagents considered acceptable alternatives to Actin FSL for efa monitoring. In conclusion, efa effectively addresses complex unmet needs, including in emicizumab-treated patients. However, the discrepancy between results of local OSAs and drug-calibrated CSA highlights challenges in laboratory monitoring.

ABSTRACT:Desmopressin (DDAVP) is often administered to correct factor VIII (FVIII) levels in female hemophilia A carriers (HACs). However, the post-DDAVP FVIII pharmacokinetic profiles have been reported only in small series in HACs. Therefore, this study analyzed the post-DDAVP FVIII and von Willebrand factor (VWF) response in 361 HACs. A population pharmacokinetic/pharmacodynamic model was developed to analyze the VWF and FVIII levels by taking into account the F8 gene variants (n = 143 [39.6%] with null; and n = 218 [60.4%] with non-null variants), demographic and laboratory covariates. The before/after DDAVP mean basal, peak and recovery FVIII activity (FVIII:C) levels were 0.34 IU/mL (0.08-0.65), 1.13 IU/mL (0.19-2.69), and 2.85 IU/mL (1.06-7.13), respectively. Peak FVIII:C was ≥0.5 IU/mL in 95.6% (345/361) and ≥0.8 IU/mL in 78.7% (284/361) of patients. The covariate analysis showed a poorer DDAVP FVIII:C response for null than non-null F8 variants: lower mean FVIII:C peak (1.04 vs 1.23 IU/mL; P < 5 × 10-5) and patients percentage with normalized FVIII:C (91.6% vs 98.1%; P = .0068), higher mean FVIII:C clearance (5898.83 vs 2704.06 IU/h; P = 1.58 × 10-15), lower mean FVIII:C area under the curve during the first 12 hours (AUC0-12h =7.73 vs 9.06 IU/mL per hour; P < 5 × 10-6), and shorter mean time with FVIII:C ≥0.8 IU/mL (1.9 vs 4.1 hours; P < 6 × 10-6). HAC with body weight <35 kg had lower peak FVIII:C, higher FVIII:C clearance, lower AUC0-12h, and shorter time with FVIII:C ≥0.8 IU/mL than HAC with body weight 35 to 70 kg. In HACs, the post-DDAVP FVIII response is strongly influenced by the F8 genotype and body weight.

Background The Hemophilia Functional Ability Scoring Tool (Hemo-FAST), consisting of a patient-reported outcome (PRO) part and a clinician-reported outcome (ClinRO) part, was developed as a rapid and effective tool to assess functional mobility in clinical practice. This study (NCT04731701) aimed to validate the psychometric properties of Hemo-FAST for assessment of joint health in people with haemophilia (PwH). Methods PwH A or B aged ≥18 years completed questionnaires including the PRO part of Hemo-FAST and the short-form 36 health survey (SF-36) during one study visit. Clinicians completed the Haemophilia Joint Health Score (HJHS) and the ClinRO part of Hemo-FAST at the same visit. Validation was performed using reliability, construct validity, and structure validity assessments. Results The study enrolled 180 PwH A or B from 14 centres across France. Estimated time to complete the PRO part was mean (standard deviation) 4.6 (5.4) minutes. PRO items showed good test–retest reliability (intraclass correlation coefficient value ≥0.70). Inter-rater values were >0.70 for 7/9 ClinRO items, indicating good reliability. All items (15 PRO; 9 ClinRO) had high internal consistency (Cronbach's coefficient alpha: 0.97). Hemo-FAST demonstrated convergent construct validity with HJHS and the SF-36 physical component and discriminant construct validity with the SF-36 mental health component. Hemo-FAST scores distinguished between subgroups of people with expected differences in joint health status, including by haemophilia severity (p < 0.0001). Conclusion This study successfully validated Hemo-FAST as a rapid and reliable tool for the functional assessment of joint health in adults with haemophilia, both in clinical practice and clinical research settings.

BACKGROUND:Haemophilia management aims to prevent bleeding and preserve joint function. Changes in patients' joint health may influence physicians' decisions to adjust treatment. The Haemophilia Joint Health Score (HJHS) and Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score assess joint health but are not routinely used. AIM:To evaluate whether systematic joint examination with HJHS and/or HEAD-US had an impact on treatment management decisions in France, using final data from the A-MOVE study. METHODS:A-MOVE (NCT04133883) was a 12-month prospective, multicentre study, which enrolled persons with haemophilia A (all severities, aged 6-40 years) treated prophylactically or on demand with standard/extended half-life FVIII replacement. At baseline, 6 and 12 months, HJHS/HEAD-US and changes in patients' management were assessed. RESULTS:Eighty-six patients from 20 sites were included in the final analysis; 68 had HJHS/HEAD-US assessments at 12 months. Over 12 months, 24.4% (n = 21/86) of patients experienced an impact on their haemophilia management due to HJHS/HEAD-US scores; these decisions were impacted by HJHS in about half of the patients (52.4%, n = 11/21) and HEAD-US in almost all patients (95.2%, n = 20/21). Both assessments contributed to a change in management decisions in about half of the patients (47.6%, n = 10/21). Twenty-nine patients (33.7%) had haemophilia management decisions impacted by factors other than HJHS/HEAD-US, including physical examination findings (n = 9) and the occurrence of bleeding episodes (n = 8). CONCLUSIONS:Final data from the A-MOVE study show that systematic joint assessments, through functional/physical examination (HJHS) and ultrasound (HEAD-US), may impact treatment management decisions in persons with haemophilia A.

OBJECTIVES:To assess the real-world efficacy and safety of recombinant factor IX albumin fusion protein (rIX-FP) in patients with hemophilia B (HB) in France. METHODS:Data on dosing frequency, weekly consumption, and bleeds before-and-after switching to rIX-FP, were collected from December 2021 to February 2024. Annualized (spontaneous) bleeding rates [A(s)BRs] were calculated only in patients on prophylaxis with a follow-up ≥ 6 months. RESULTS:This interim analysis focused on 77 patients ≥ 12 years; 62 (81%) had severe HB. After switching to rIX-FP, the infusion interval was 14 (7-14) days. Weekly consumption was 43 (35.5-53) IU/kg. ABRs and AsBRs were 0.5 (0-1.9) and 0 (0-0.7) (n = 63) at 18.2 (12.3-21.9) months of follow-up. Prophylactic efficacy of rIX-FP was considered 'Excellent'/'Good' in 65/68 (95%) patients. Among the 43 patients previously treated with rFIXFc, 21 increased the infusion interval from 7 (7-11) days with rFIXFc to 14 (7-14) days with rIX-FP; 33/43 (77%) reduced weekly factor IX (FIX) consumption from 59.95 (46.35-77.93) to 42.5 (35.88-50.25) IU/kg. Patients maintained good protection against bleeds. CONCLUSION:This analysis confirmed that switching to rIX-FP allows for reducing injection frequency and FIX consumption while maintaining good bleed protection.

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.

During several decades, patients with haemophilia have been treated using FVIII and FIX concentrates by haematologists working in specialized comprehensive haemophilia care centres. In the last fifteen years haemophilia treatments have been tremendously improved and novel treatment options have been developed. Gene therapy is one of these innovative approaches and will soon be available on the market. The European Association for Haemophilia and Allied Disorders and the European Haemophilia Consortium recently described a new healthcare setting for the management of patients who will receive gene therapy. This hub-and-spoke model aims to ensure the safe administration and monitoring of gene therapy by expert comprehensive haemophilia care centres, in close collaboration with the proximity haemophilia treatment centres where the patient is followed up. Any adverse events should be managed by both the expert "hubs" in collaboration with the spoke centre to provide the time-liest state-of-the-art treatment and management options to patients receiving gene therapy. All adverse events and efficacy data should be reported lifelong to a centralised registry. French reference centre for haemophilia and the patient's organization AFH worked together to adapt the European Hub and spoke model to the existing infrastructures and organization for rare bleeding disorders in France. This review describes the haemophilia patient's journey for gene therapy in France.

INTRODUCTION:The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described.AIM:Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.

Background Data are limited on prostate cancer (PC) management in patients with haemophilia (PWH). Aim To describe PC screening and diagnosis, treatment modalities and bleeding complications in a group of unselected PWH followed at French Haemophilia Treatment Centres (HTCs) Patients and methods PC screening, management and bleeding complications were retrospectively investigated at 14 French HTCs between 2003 and 2018. Results Among> 1549 > 50-year-old PWHs, 73 (4.7%) underwent PC screening (median age 71.1 years; 67/6 HA/HB, 17/56 severe-moderate/mild). At diagnosis, haematuria was infrequent. Prophylaxis was administered during 76/86 (88%) prostate biopsies (PB) (n = 67 clotting factor concentrates, CFC; n = 9 desmopressin; n = 17 associated with tranexamic acid, TA). Bleeding (11/86, 12.8%) occurred mainly post-prophylaxis (median delay: 7 days): haematuria (9/11, 81.8%), and rectal bleeding (2/11, 18.2%) including one major (1.2%). PC was confirmed in 50/86 PB and in two prostatectomy specimens (total n = 50 patients, n = 6 with only active surveillance). Surgery (n = 28/44 patients) was managed with CFC. Fifteen patients had radiotherapy/brachytherapy, 10 had hormone therapy; CFC-based prophylaxis was only prescribed for brachytherapy (n = 2). Major bleedings occurred in 3/28 (10.7%) and 2/15 (13.3%) patients who underwent surgery and radio/brachytherapy, respectively. No bleeding risk factor was found. Conclusion Our data indicate that PB requires prophylaxis for atleast 7 days, using CFC, desmopressin or TA in function of haemophilia severity. PC surgery should be considered at high bleeding risk. Long-term post-procedural CFC or oral TA could be discussed. Radiotherapy/brachytherapy also should be managed with prophylaxis (CFC or TA).

Background: Patients with symptomatic von Willebrand disease (VWD) should be offered long-term prophylaxis (LTP) to prevent recurrent bleedings. Our objective was to evaluate the effectiveness and safety of Voncento (R), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), administrated in LTP. Methods: We included patients from the OPALE study (May 2016 to April 2021), a French multicenter observational study following patients with inherited VWD, who received a Voncento (R) LTP during the study period. Results: Among the 130 OPALE-study patients, 23 patients (12 women) received a LTP and were therefore included. The median (range) age was 16 (1-85) years; 16 patients were type 3, 1 was type 2A, 6 were type 2B. Before inclusion, 19 (83%) were under LTP and 4 (17%) received on-demand (OD) treatment. The indications for initiating prophylaxis in the overall population were joint bleeding (43%), ear, nose, and throat (ENT) bleeding including epistaxis or oral bleeding (39%), and recurrent muscle hematoma (22%). The medians (ranges) dose of Voncento (R) per infusion, frequency, and weekly dose were 45 (33-109) IU/kg, 2 infusions per week, and 96 (44-222) IU/kg/week, respectively. The median (range) annualized bleeding rate (ABR) was 0.8, 0.7 (0-3.5), and 0 (0-2.3) for type 2A, 2B, 3 patients, respectively. There was no difference regarding to the dose, frequency of infusion, or in terms of ABR in 9/19 patients who replaced previous concentrates with Voncento (R). During the study period, no adverse event was reported. Conclusion: These results suggest that Voncento (R) is effective to prevent recurrent bleedings in patients symptomatic VWD.

Abstract Background The outbreak of coronavirus disease 2019 (COVID-19) exposes vulnerable patients to high risk of mortality. Patients with left ventricular assist device (LVAD) usually have symptoms such as cough, fever, and shortness of breath because of their cardiac condition and comorbidity, therefore these related symptoms challenge the correct diagnosis in time within the COVID-19 pandemic. Case summary We report two case studies of patients with LVAD in whom COVID-19 related symptoms were overlapped by their cardiac status and comorbidities. In the first case, the patient was admitted for suspicion of COVID-19 due to cough and shortness of breath for 1 month. The blood test evocated a high index of suspicion of COVID-19. The nasopharyngeal test for COVID-19 performed on admission and at Day 2 was inconclusive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the test obtained on Day 3 of admission was positive, whereas computed tomography confirmed the diagnosis of COVID-19. This patient developed acute respiratory distress syndrome (ARDS) and nasal epistaxis within 48 h during hospitalization. The ARDS was treated by non-invasive ventilation and probabilistic antibiotics for 3 days and resulted significant improvement. The nasal epistaxis due to international normalized ratio increase was treated by nasal packing and vitamin K antagonist was switched to parenteral heparin infusion. The patient was kept hospitalized for 1 month for further supportive treatment. In the second case, the patient was admitted for recurrent anaemia due to melaena, the patient was tested for COVID-19 because of new-onset symptoms of cough and rhinorrhoea. The first nasopharyngeal test was positive, and sudden increase of anticoagulation status was noted in the setting of gastrointestinal bleeding. The anticoagulation status was controlled by parenteral heparin infusion, and the melaena was disappeared at Day 3. The moderate dyspnoea of the patient was quickly improved with nasal oxygen delivery for 4 days. The patient was discharged at Day 5. Discussion COVID-19 specific symptoms are challenging to distinguish in patients with LVADs, although radiological evidence can be beneficial in the COVID-19 diagnosis. We also observed the need for precise anticoagulation control to avoid bleeding or thrombotic events in these patients.

BACKGROUND:In patients with moderate to severe qualitative and quantitative von Willebrand disease (VWD), even minor surgical procedures can be associated with a risk of life-threatening bleeding. Treatment strategies vary according to the levels of von Willebrand factor (VWF) and Factor VIII (FVIII). The aim of this study was to evaluate the effectiveness and the safety of Voncento® (CSL Behring, Marburg, Germany), a plasma-derived FVIII/VWF concentrate (ratio 1:2.4), during surgeries performed in patients with inherited VWD.MATERIALS AND METHODS:The OPALE study, a French multicentre observational study, was carried out from May 2016 to May 2019. It evaluated and analysed patients with inherited VWD (any type) requiring treatment with Voncento® who underwent surgery.RESULTS:In total, 92 patients were enrolled, and 66 patients underwent 100 surgical procedures: 69 minor and 31 major surgeries conducted in 30 patients with type 1, 50 patients with type 2, and 20 patients with type 3 VWD. During minor surgeries, the median number of infusions was one (range: 1-9), the pre-operative loading dose was 41 IU VWF:RCo kg-1 (range: 18-147), and the total dose was 63 (range: 18-594). During major surgeries, the number of infusions was 4 (range: 1-23), the pre-operative loading dose was 43 (range: 25-66) IU VWF: RCo kg-1, and the total dose was 155 (range: 40-575). The median FVIII:C levels ranged from 78 to 165 IU dL-1 during 5 days after minor surgeries and from 86 and 167 IU dL-1 during 11 days after major surgeries. VW:RCo levels ranged between 35 and 65 IU dL-1 and between 34 and 76 IU dL-1 after minor and major surgeries, respectively. The overall clinical effectiveness was qualified as "excellent" or "good" in 99% of patients. No thrombotic events related to Voncento® were recorded.DISCUSSION:The present study suggests that Voncento® is an effective and well-tolerated therapy for the peri-operative management of patients with all VWD types.

BACKGROUND:Hemophilic arthropathy is a major complication in patients with severe hemophilia. A plastic knee model has been developed for the therapeutic education of patients to promote improved care management and self-treatment skills. The objective of this study was to evaluate the impact of this hemarthrosis-simulating artificial knee (HSAK) on patients' knowledge of their disease and its treatment.METHODS:In this observational study, the impact of HSAK was assessed during individualized education in patients with severe/moderately severe hemophilia A or B at seven hemophilia treatment centers in France. Participants provided written informed consent and completed questionnaires to assess knowledge of their disease (score range: 0-7) and knowledge of their treatment (score range: 0-4). Questionnaires were completed before, immediately after and 6 months after HSAK use. The scores obtained before and after the use of the HSAK were compared.RESULTS:The participants comprised 32 children, 29 teenagers, and 31 adults. The mean (SD) disease knowledge score increased significantly in all age groups of patients from 4.5 (2.0) to 5.9 (1.5; p<0.001) immediately after the training and remained unchanged at 6 months. Mean (SD) treatment knowledge scores were unchanged, but Wilcoxon signed rank testing showed a significant increase after the training course that was maintained at 6 months in children and teenagers.CONCLUSION:These findings suggest that an individualized training course can enhance the understanding of hemophilia in patients of all ages, especially in children and teenagers, and that the HSAK may assist in improving patients' management of their disease.

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project’s progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18–50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs’ cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4–21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7–11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%).

Dense granule disorder is one of the most common platelet abnormalities, resulting from dense granule deficiency or secretion defect. This study was aimed to evaluate the clinical usefulness of the flow cytometric combination of mepacrine uptake/release assay and CD63 expression detection in the management of patients with suspected dense granule disorder. Over a period of 5 years, patients with abnormal platelet aggregation and/or reduced adenosine triphosphate (ATP) secretion suggestive of dense granule disorder were consecutively enrolled. The flow cytometric assays were systematically performed to further investigate dense granule functionality. Among the 26 included patients, 18 cases showed impaired mepacrine uptake/release and reduced CD63 expression on activated platelets, consistent with δ-storage pool deficiency (SPD). Another seven patients showed decrease in mepacrine release and CD63 expression but mepacrine uptake was normal, indicating secretion defect rather than δ-SPD. Unfortunately, ATP secretion could not be measured in 7 out of the 26 patients due to insufficient sample and/or severe thrombocytopenia. This test combination provides a rapid and effective method to detect the heterogeneous abnormalities of platelet dense granule by distinguishing between storage and release defects. This combination is particularly advantageous for severely thrombocytopenic patients and pediatric patients in which only minimal sample is required.