Roseline D Oiron

Concizumab is an anti–tissue factor pathway inhibitor (TFPI) monoclonal antibody intended for once-daily subcutaneous prophylactic treatment for people with hemophilia A or B with and without inhibitors. Results from the phase 3 explorer7 study confirmed superiority of concizumab prophylaxis over no prophylaxis in reducing the annualized bleeding rate (ABR) in people with hemophilia A or B with inhibitors (HAwI/HBwI). Male patients aged ≥12 years were randomized 1:2 to no prophylaxis (group 1) or concizumab prophylaxis (group 2), or nonrandomly allocated to concizumab prophylaxis (groups 3 and 4). After ≥24 weeks of treatment, patients in group 1 could switch to concizumab prophylaxis. At the 56-week cutoff (defined as when all patients in groups 2-4 had completed the visit at 56 weeks or permanently discontinued treatment), bleed-related efficacy, pharmacokinetics and pharmacodynamics, and safety were assessed. Of the 133 patients enrolled (HAwI, n = 80; HBwI, n = 53), 114 received concizumab prophylaxis (groups 2-4) and 19 were randomized to no prophylaxis (group 1). After ≥24 weeks, 13 patients from group 1 switched to concizumab. Median ABR for treated spontaneous and traumatic bleeding episodes in patients receiving concizumab was 0.8 (interquartile range [IQR], 0.0-3.2) at the 56-week cutoff, consistent with the low bleeding rates (median ABR, 0.0; IQR, 0.0-3.3) at the 32-week cutoff. Concizumab and free-TFPI concentration remained stable over time. No new safety concerns were reported. Longer-term (≥1 year) efficacy and safety results of concizumab prophylaxis for HAwI/HBwI were consistent with the 32-week cutoff results in explorer7. This trial was registered at www.clinicaltrials.gov as #NCT04083781.

Background: Glanzmann thrombasthenia (GT) is an inherited platelet disorder resulting in severely reduced platelet aggregation and increased bleeding tendency. Pregnancy and childbirth in women with GT present significant challenges for both mother and child. Objective: The aim of this study was to present the current clinical practices in pregnancy and childbirth in GT. Methods: A survey on the management of the preconception phase, pregnancy and childbirth in women with GT was conducted by the European Association of Haemophilia and Allied Disorders. Results: Thirty‐seven responses from 18 countries were analysed. Almost all respondents recommended multidisciplinary preconception counselling, though 11% lack access to obstetrics and gynaecology services focused on bleeding disorders. Delay in conceiving was reported by 62%. Ninety‐one percent of respondents indicated that they would screen for platelet alloimmunisation; however, the timing of screening varied. The recommended treatment to prevent postpartum haemorrhage (PPH) most often comprised tranexamic acid (TXA) and recombinant activated factor VII (rFVIIa) (25%) or TXA, rFVIIa and platelet transfusion (22%). The latter combination was also the most frequently recommended treatment to have on standby. Seventy‐five percent would advise a mode of delivery as per obstetric indication and 69% would recommend to avoid neuraxial anaesthesia. Half of the respondents would add pharmacological thromboprophylaxis. Conclusion: There is general consensus on the importance of preconception counselling, the screening for platelet alloimmunisation and the preferred mode of delivery. Opinions regarding the treatment of PPH and the use of thromboprophylaxis vary. The next step is to improve guideline implementation in daily practice while working toward an international consensus‐based guideline.

Introduction: Haemophilia causes spontaneous or prolonged bleeding due to a deficiency in clotting factor VIII (haemophilia A) or IX (haemophilia B). Although substitutive therapies and regular follow‐up can prevent severe haemorrhagic events, adherence to treatment remains a challenge. Transitioning from adolescence to adulthood and from paediatric to adult care is particularly complex for young people with severe haemophilia (PwSH), as it involves gaining autonomy in health management. Objectives: This study aimed to explore factors influencing the success of the transition process in young PwSH, with a focus on adherence to healthcare. Methods: This qualitative study was part of the mixed‐methods TRANSHEMO project. Participants were selected from the quantitative phase of the TRANSHEMO project based on two criteria: adolescents/young adults and adherent/nonadherent to healthcare. Interviews were conducted via video conferencing, transcribed, and thematically analysed to identify key themes affecting the transition process. Results: Twenty‐two interviews were conducted. Four major themes emerged as critical to transition success: (1) Care factors [continuity of care, treatment rituals, and evolving therapies]; (2) Family and social factors [support from family, friends, peers, and overprotection]; (3) Personal factors [understanding haemophilia, risk management, optimism, and coping strategies]; and (4) Autonomy [secondary benefits, independence, proactivity in disease management, and accompaniment by caregivers]. Conclusion: Based on the enlightened determinants, supportive strategies and patient education programs should focus on the development of autonomy, personal factors such as acquisition and application of health literacy in haemophilia care, and family factors such as support from family.

Introduction: Glanzmann's thrombasthenia is a rare inherited platelet disorder characterized by a lack of platelet aggregation. Patients tend to be diagnosed in early childhood with treatment strategies involving a multifaceted approach to prevent and manage bleeding episodes. Unfortunately, there is currently no European consensus regarding the management of GT. Aim: This initiative aimed to gain an understanding of current clinical management of GT across Europe, with the aim of aligning best practice and improving patient outcomes. Methods: The authors, on behalf of the EAHAD Glanzmann Working Group, administered an online survey of 57 questions to European haematologists currently involved in the management of patients with GT. The survey covered topics related to diagnosis, treatment access and selection, immunization, peri‐operative management and use of second‐line therapies. Results: Responses reflected physician consensus around some topics, including peri‐operative treatment, use of recombinant factor VIIa, and concerns around antibody development. However, more varied responses were received on topics such as antibody screening (anti‐ αIIbβ3 antibodies screening conducted by ≤53% of respondents in all countries of interest except France), access to HLA‐matched platelet concentrates (none or limited for 55% of respondents) and duration of platelet transfusions for major surgery (13%–31% for 1, 2, 3 and 4 or more days of transfusions). Conclusion: Establishing comprehensive guidelines to manage GT will enhance patient outcomes by ensuring patients receive high‐quality and effective care as well as standardize care across different healthcare settings.

Desmopressin is often administered to correct factor VIII (FVIII) levels in female hemophilia A carriers (HAC). However, the post-desmopressin FVIII pharmacokinetic profiles have been reported only in small case series in this population. Therefore, this study analyzed the post-desmopressin FVIII and von Willebrand factor response in 361 HAC included at 14 French hemophilia treatment centers. 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 prior/after desmopressin mean basal, peak and recovery FVIII:C levels were 0.34 IU.mL-1 (0.08-0.65), 1.13 IU.mL-1 (0.19-2.69), and 2.85 (1.06-7.13), respectively. Peak FVIII:C was ≥0.5 IU.mL-1 in 95.6% (345/361) and ≥0.8IU.mL-1 in 78.7% (284/361) of patients. The covariate analysis showed a poorer desmopressin FVIII response for null than non-null F8 variants: lower mean peak (1.04 vs 1.23 IU.mL-1, p<5.10-5) and lower percentage of patients with normalized FVIII:C (91.6% vs 98.1%, p=0.0068), higher mean clearance (5898.83 vs 2704.06 IU.h-1, p=1.58.10-15), lower mean AUC0-12h (7.73 vs 9.06 IU.mL-1.h, p<5.10-6), and shorter mean time with FVIII:C ≥0.8 IU.mL-1 (1.9 vs 4.1h, p<6.10-6). HAC with body weight <35 kg had lower peak FVIII:C, higher FVIII clearance, lower AUC0-12h, and shorter time with FVIII:C ≥0.8 IU.mL-1 than HAC with body weight 35-70 kg. The ABO blood type did not influence the response to desmopressin. In HAC, the post-desmopressin FVIII response is strongly influenced by the F8 genotype and body weight.

Introduction: Haemophilia is associated with high disease and treatment burdens. Prospective evaluation of data from patients with haemophilia helps understand and define unmet needs, optimise treatment and improve healthcare outcomes. Aim: To present end‐of‐study data from explorer6 (NCT03741881), a prospective, non‐interventional study across multiple countries in patients with haemophilia (haemophilia A or B without [HA or HB] or with inhibitors [HAwI or HBwI]). Methods: Patients ≥12 years old with severe HA, severe/moderate HB or HAwI/HBwI of any severity were treated according to the local standard of care (SoC). The number of bleeding episodes from enrolment up to a maximum of 115 weeks, physical activity based on data collected by a wrist‐worn physical activity tracker, target joints and Haemophilia Joint Health Score (HJHS) measurements were assessed. Results: A total of 231 patients across 33 countries were enrolled. The mean annualised bleeding rate (ABR) (standard deviation) for treated bleeding episodes was investigated for patients receiving prophylaxis (HA: 4.7 [5.9]; HB: 2.2 [3.0]; HAwI: 10.3 [8.5]; HBwI: 12.4 [14.1]) and those receiving on‐demand (OnD) treatment (HA: 21.5 [17.7]; HB: 10.5 [8.6]; HAwI: 15.2 [14.8]; HBwI: 9.3 [13.3]). Physical activity levels were lowest among patients with HBwI. Target joints were similar among haemophilia types and treatments. Overall, mean and median HJHS total scores were lower for patients receiving prophylaxis compared with OnD treatment. Conclusion: The explorer6 study assessed a large haemophilia patient population in a real‐world setting across 33 countries. The results indicate that an unmet need remains among patients receiving OnD treatment and those with inhibitors. Trial Registration : ClinicalTrials.gov identifier: NCT03741881

Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF‐McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE. Where applicable, the WFH Guidelines for the Management of Haemophilia were analysed.Results: Important differentiating features in applying GRADE were identified. Where a strong evidence base is lacking, data other than those from randomized controlled trials, which may not always be justified, need to be considered, including incorporation of outcomes important to people living with the disease. Justification and stakeholder input to prioritize questions requiring a new guideline, panel composition with necessary patient participation and content expertise were also found to be significant differentiating features.Conclusion: The puristic approach taken in the ISTH Guideline development process, without consideration of accepted adaptations to GRADE implementation, created a missed opportunity for progressing haemophilia care, leading to guideline recommendations that have been widely deemed invalid and obsolete by expert healthcare professionals and by those living with the condition, the very people who are expected to implement or bear the impact of the recommendations. Lessons learnt from this comparative analysis should guide future guideline development and encourage collaboration to further advance haemophilia.

Introduction: Evidence‐based clinical practice guidelines drive optimal patient care and facilitate access to high‐quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non‐randomized and well‐designed observational studies and real‐world data, is challenging. The methodology used for assessing available evidence should consider this critical fact. In formulating guidelines, it is essential to include treatment goals and patient preference.Aim: This paper comprehensively critiques, against this background, the recommendations of the ISTH clinical practice guidelines for the treatment of haemophilia.Methods: Each recommendation was critically reviewed against available evidence as well as existing guidelines and commented upon for its scientific validity, impact on clinical practice and access to care globally. The validity of the way in which the GRADE methodology was applied to existing evidence was also assessed.Results: The critique provided shows that these recommendations have major limitations: they did not state treatment goals and contradict existing guidelines; opportunities for providing access to innovation were missed when the therapeutic benefits of the products approved in the last decades were not included. A major reason for this is the inappropriate adoption of the GRADE methodology without adaptations and without considering treatment goals and patient‐relevant outcomes.Conclusion: These recommendations may mislead healthcare professionals, payers and governments and therefore cannot serve the patient community well. They setback the advances made in haemophilia care because they overlook important available evidence and do not guide clinical practice to contemporary standards.

Background: Platelet transfusion is considered the standard treatment for preventing or controlling severe haemorrhage in Glanzmann thrombasthenia (GT). However, platelet transfusion can have detrimental effects, including the production of anti‐GPIIb/IIIa isoantibodies or anti‐HLA antibodies (Ab) and platelet transfusion refractoriness. Recombinant activated factor VII (rFVIIa) has been proposed as an alternative treatment to platelet transfusion.Methods: We analyzed data from 77 case reports including 100 subjects to investigate the effectiveness and safety of rFVIIa in combination with platelets or antifibrinolytics for preventing or treating non‐surgical bleeds, as well as surgical and obstetrical procedures in GT.Results: The dosage of rFVIIa was consistent with previous recommendations (90 µg/kg per infusion). In subjects without Ab/refractoriness (n = 56), rFVIIa was effective in managing 93% of non‐surgical bleeds (n = 42), 91% of minor (n = 11) and 92% of major (n = 26) surgical procedures and 89% of obstetrical procedures (n = 9). In subjects with Ab/refractoriness (n = 44), rFVIIa was effective in managing 90% of non‐surgical bleeds (n = 39), and 75% of minor (n = 12) and 100% of major (n = 17) surgical procedures. The use of rFVIIa was safe, with 4 (2.7%) serious adverse events associated with rFVIIa.Conclusion: Although the use of rFVIIa is currently restricted to subjects with Ab/refractoriness or when platelets are not available, our findings suggest expanding the indications for rFVIIa to encompass GT without Ab/refractoriness. Frontline use of rFVIIa may be proposed when clinically possible to mitigate the risks associated with platelet transfusion.