Search

Introduction: People with haemophilia A (PwHA) experience acute and chronic pain associated with reduced quality of life (QoL)., Aims: This post hoc analysis of pooled data from the HAVEN 1 (NCT02622321), 3 (NCT02847637), 4 (NCT03020160) and STASEY (NCT0319179) studies assessed the impact of emicizumab prophylaxis on pain-related QoL in PwHA., Methods: PwHA received emicizumab during the four studies. In this analysis, pain was assessed using patient-reported responses to pain-specific questions from the Haem-A-QoL/Haemo-QoL-SF and the pain/discomfort dimension of the EQ-5D-5L. Responses were recorded at baseline and at regular intervals for up to 78 weeks following treatment initiation. Additional analyses evaluated the population with target joints at baseline, and the overall population stratified by age, factor (F)VIII inhibitor status and prior treatment., Results: At the data cut-off, 504 PwHA had been treated across the four studies; 464 and 470 completed the Haem-A-QoL/Haemo-QoL-SF and the EQ-5D-5L, respectively. Improvements in pain-related QoL were observed by Week 13 of emicizumab prophylaxis and maintained through Week 78. In the overall population, responses of 'never/rarely' for 'my swellings hurt' and 'pain in joints' increased from 37.0% and 30.0% at baseline to 84.0% and 61.0% by Week 13, suggesting reductions in acute and chronic pain, respectively. Similar improvements were seen in the target joint population, and across all strata. Greater improvements were observed in younger versus older PwHA., Conclusion: Pain-related QoL improved with emicizumab prophylaxis regardless of target joints, age, FVIII inhibitor status or prior treatment. Haemophilia-specific assessments are needed to accurately capture and characterize pain in PwHA., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

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., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

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., (© 2024 John Wiley & Sons Ltd.)

Introduction: Despite the progress in gene editing platforms like CRISPR/Cas9 with the potential to transform the standard of care for haemophilia, the language used to explain and discuss gene editing is not aligned across the haemophilia community. Here, we present the objective and rationale for developing a clear, consistent, and globally aligned gene editing lexicon to address these communication gaps., Methods: Effectively communicating complex gene editing concepts requires a clear and consistent vocabulary. Through collaboration with a diversity of haemophilia stakeholders, our main goal is to develop an accurate, informative lexicon which avoids overpromising or highly technical terminology. Using an innovative process, representatives from several patient and scientific haemophilia organizations and select biotechnology companies will develop and refine language concepts to be tested with approximately seventy participants across the United States of America, United Kingdom, and Germany. Participants will include lived experience experts (LEEs) and haematologists. The process will be overseen by the Lexicon Steering Committee of global experts from leading scientific and patient organizations in the haemophilia and gene editing fields., Results: Initial feedback provided a robust foundation and rationale for building clear, consistent language around gene editing. This lexicon development framework will allow for increased understanding across the haemophilia community, including the development of valid informed consent and shared decision-making materials., Conclusion: Results provide important building blocks for stimuli development and highlight the need for a novel gene editing lexicon. In the next phase, language stimuli will be tested with LEEs and haematologists to better understand audience preferences and help shape the final lexicon., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: As a result of centralisation of haemophilia care to a limited number of intramural settings, many persons with haemophilia have to travel long distances to attend their haemophilia specialised treatment centre. However, regular physiotherapy treatment can be provided by primary care physiotherapists in the person's own region. Due to the rarity of the disease most primary care physiotherapists have limited experience with this population. This study aims to provide a clinical practice guideline for primary care physiotherapists working with persons with bleeding disorders., Method: A list of the most urgent key-questions was derived from a previous study. Literature was summarised using the grading of recommendations assessment, development, and evaluation (GRADE) evidence-to-decision framework. Recommendations were drafted based on four 90 min consensus meetings with expert physiotherapists. Recommendations were finalised after feedback and >80% consensus of all stakeholders (including PWH, physiotherapists, haematologists and the corresponding societies)., Results: A list of 82 recommendations was formulated to support primary care physiotherapists when treating a person with a bleeding disorder. These recommendations could be divided into 13 categories: two including recommendations on organisation of care, six on therapy for adult patients with bleeding disorders and five on therapy adaptations for paediatric care. Therapy recommendations included treatment after a joint- or muscle bleed, haemophilic arthropathy, chronic synovitis, non-haemophilia related conditions and orthopaedic surgery., Conclusion: An evidence-based practice guideline, based on current evidence from literature and clinical expertise, has been developed for primary care physiotherapists treating a person with haemophilia. To improve care, the recommendations should be implemented in daily practice., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Background: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile., Treatment Goals: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment., Conclusion: Capitalizing on the major potential of therapeutic innovations, 'Normalization' of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this-being supported by the data reviewed in this manuscript-the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation., Aim: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec., Methods: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion., Results: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals., Conclusion: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec., (© 2024 BioMarin Pharmaceutical Inc and The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management., (© 2024 John Wiley & Sons Ltd.)

Introduction: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations., Aim: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process., Methods: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia., Results: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care., Conclusion: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely., (© 2024 John Wiley & Sons Ltd.)

Objective: The objective of this study is to assess the reliability and construct validity of ACTIVLIM-Hemo, a newly developed Rasch-built questionnaire designed to evaluate activity limitations in people with haemophilia (PwH), in comparison with the Haemophilia Activities List (HAL), which was developed using Classical Test Theory., Methods: A total of 130 participants with haemophilia A or B were included. They underwent various assessments, including joint health scoring (HJHS), functional tests (TUG and 2MWT) and completed questionnaires such as the BPI, IPAQ, HAL and ACTIVLIM-Hemo. Reliability indices and the minimum detectable change (MDC95) were determined for ACTIVLIM-Hemo and for HAL. Construct validity was evaluated through correlations and multiple linear regression, considering demographic and clinical factors., Results: Both ACTIVLIM-Hemo (Person Separation Index = 0.92) and HAL (Cronbach's α = 0.98) demonstrated high reliability. The MDC95 for ACTIVLIM-Hemo represented 11.6% of its measurement range, while for HAL, it amounted to 18/100 score points. Activity limitations measured by both instruments were significantly correlated with demographic and clinical factors. Joint health (HJHS), pain severity (BPI) and walking performance (2MWT) emerged as the main predictors of activity limitations, explaining 75% of the variance in ACTIVLIM-Hemo and 60% in HAL., Conclusion: ACTIVLIM-Hemo stands as a reliable and valid instrument for assessing activity limitations in PwH. Both instruments exhibited significant correlations with demographic and clinical factors, but ACTIVLIM-Hemo displayed a more homogeneous construct. Given its linear scale and lower MDC95 and better targeting, ACTIVLIM-Hemo shows promise as a patient-centric instrument for assessing responsiveness to treatment during individual follow-up., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Eptacog beta (activated), a recombinant human factor VIIa (rFVIIa), was approved by the US Food and Drug Administration (FDA) in 2020 (SEVENFACT®, LFB & HEMA Biologics) and the European Medicines Agency (EMA) in 2022 (CEVENFACTA®, LFB). In Europe, eptacog beta is indicated for the treatment of bleeds and the prevention of bleeds during surgery or invasive procedures in adults and adolescents (≥12 years old) with congenital haemophilia A or B with high-titre inhibitors (≥5 BU) or with low-titre inhibitors who are expected to have a high anamnestic response to factor VIII or factor IX, or to be refractory to increased dosing of these factors. The efficacy and safety of eptacog beta were evaluated in three Phase III clinical studies, PERSEPT 1, 2 and 3. For the EMA filing dossier, the analysis of data from PERSEPT 1 and 2 differed from the analysis used to support the filing in the US. In this review, we summarise current data regarding the mode of action, clinical efficacy and safety of eptacog beta for the management of haemophilia A and B in patients with inhibitors from a European perspective. In addition to providing a valuable summary of the analyses of the clinical data for eptacog beta conducted for the EMA, our review summarises the potential differentiators for eptacog beta compared with other current bypassing agents., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Elderly people with haemophilia (PwH) develop haemophilic arthropathy, pain, and reduced health-related quality of life (HR-QoL). The condition of elderly mild haemophilia patients have rarely been evaluated. This study aimed to compare joint status, pain, and HR-QoL between elderly with mild, moderate/severe haemophilia and healthy elderlies., Methods: Knee/ankle abnormalities were assessed by ultrasound (HEAD-US) and physical examination (HJHS 2.1). Pain severity and pain interference were investigated using the Brief Pain Inventory. Pressure pain thresholds (PPTs) were obtained at knees/ankles and forehead. Functional limitations were evaluated using the 2-Minute-Walking-Test, Timed-Up-and-Go and HAL. The EQ-5D-5L questionnaire evaluated HR-QoL. Healthy controls (HCs) and elderly individuals with moderate/severe and mild haemophilia were compared using Kruskal-Wallis and Mann-Whitney U tests., Results: From the 46 elderly PwH approached, 40 individuals (≥60 years) with haemophilia A/B (17 moderate/severe; 23 mild) and 20 age-matched HCs were recruited. Moderate/severe PwH displayed worse joint status, lower PPTs, and poorer HR-QoL than mild PwH and HCs (p-value = .010-<.001). HEAD-US abnormalities were observed in 100% of knees and 94% of ankles in moderate/severe PwH, versus 50% of knees and 61% of ankles in mild PwH. Pain was reported by 80% and 57% of moderate/severe and mild PwH, respectively. Low PPTs, functional limitations, and poor HR-QoL scores were likewise observed in some mild PwH, yet without significantly differing from HCs., Conclusion: This study highlights poor joint/functional status, pain, and HR-QoL outcomes in elderly with moderate/severe haemophilia. A few mild haemophilia subjects presented joint abnormalities, pain, functional limitations, and poor HR-QoL, without significantly differing from HCs., Highlights: Elderly individuals with mild haemophilia have not yet been extensively studied, whereas moderate/severe haemophilia individuals have proven to suffer from haemophilic arthropathy, pain, and poor health-related quality of life (HR-QoL). Using a case-control design, joint status, pain, and HR-QoL outcomes were examined in elderly haemophilia individuals and compared with those of healthy controls (HCs). Elderly moderate/severe haemophilia individuals exhibited worse joint status, increased joint pain sensitivity, and reduced HR-QoL compared with both mild haemophilia subjects and HCs. A subset of mild haemophilia subjects exhibited poor joint status, pain, and HR-QoL outcomes, without any differences noted when compared with HCs., (© 2023 John Wiley & Sons Ltd.)

Introduction: With the increasing complexity of haemophilia care and the advent of numerous therapeutic innovations, there is an unmet need for documentation and data collection tools tailored to people with haemophilia (PwH). To date, no fully integrated haemophilia-specific electronic health record (EHR) has been described in the literature., Aim: To evaluate the feasibility of integrating a haemophilia-specific navigator into the Epic EHR., Methods: Based on clinical experience and registry datasets, we identified key variables describing both PwH and carriers of haemophilia. These were then incorporated into a REDCap database, which served as a starting point for the development of a comprehensive haemophilia flowsheet. We built a dedicated haemophilia navigator within Epic that includes a flowsheet featuring up to 212 variables, as well as customised note templates and patient lists integrating data from the haemophilia flowsheet., Results: It was feasible to develop a haemophilia navigator within Epic over the course of 12 months. The navigator's flowsheet enables systematic and comprehensive clinical assessment of PwH and carriers, while customised patient lists provide a quick summary of each patient's profile to the haemophilia treatment centre staff and highlight issues that require an intervention. In our clinical practice, patients actively participated in the new documentation process and responded positively to the navigator., Conclusion: Adapting EHRs to the needs of PwH and carriers promotes holistic care for this population and provides an opportunity for patient empowerment. Such haemophilia-specific EHRs are expected to promote standardisation of care and facilitate the collection of registry data on a national and international level., (© 2023 John Wiley & Sons Ltd.)

Background: Emicizumab is approved to prevent bleeding in patients with congenital haemophilia A with or without inhibitors. However, no randomized trials addressed the efficacy of emicizumab in acquired haemophilia A (AHA)., Aims: To report the clinical and biochemical response of emicizumab in AHA., Methods: This single-centre retrospective study included seven adults with AHA between November 2020 and May 2022. We collected patient characteristics, laboratory coagulation parameters, the use of haemostatic agents, bleeds and thrombotic events. Treatment was monitored using chromogenic FVIII assays. The assay with human reagents assesses both the emicizumab FVIII-like-activity and native patient FVIII-activity. The assay with bovine reagents only measures the patients' native FVIII-activity as emicizumab does not bind to bovine reagents., Results: Patients presented with spontaneous hematoma (n = 7), intramuscular bleeding (n = 2), haematuria (n = 2) and/or gastro-intestinal bleeding (n = 2). Six patients had major bleedings. At diagnosis, APTT was prolonged (91 seconds, IQR 73-103), FVIII activity was 0% (IQR 0-1) and FVIII inhibitor 182 BU/mL (IQR 104-228). Emicizumab was administered weekly (3 mg/kg) for 4 weeks, and thereafter every 2 weeks until regression of the inhibitor. Three patients received activated FVIIa (cumulative dose of 1.7 mg/kg, IQR 1.2-2.2). All bleedings were controlled after treatment initiation, without further bleeds. After starting emicizumab, FVIII-like activity reached ≥5% at 12 days (IQR 7-14), whereas recovery of the intrinsic FVIII-activity ≥5% occurred at 128 days (IQR 88-173), coinciding with the disappearance of the FVIII inhibitor. There were no safety issues., Conclusion: In this AHA case series, no new clinically relevant bleeds were observed after initiation of emicizumab in conjunction with standard immunosuppressive therapy., (© 2023 John Wiley & Sons Ltd.)

Introduction: People with haemophilia (PwH) suffer from knee and ankle joint pain, but the association with structural damage remains underexplored. They report activity limitations but it is unclear which factors contribute to lower limb activity limitations (LL-AL)., Aims: This study aimed (i) to analyse the association between ankle joint pain and structure and (ii) explore the contribution of haemophilia-related, individual and psychological factors to LL-AL in PwH., Methods: This study included 104 moderate/severe PwH. Ankle pain intensity was assessed with a numeric rating scale and pain sensitivity with algometry (pressure pain threshold (PPT A )). Ankle structure was assessed with MRI (IPSG-MRI) and ultrasound (HEAD-US), joint health with the Haemophilia Joint Health Score (HJHS). The HAL-LOWCOM subscore evaluated LL-AL. A Spearman correlation analysed the correlation between ankle pain and structure. The contribution of haemophilia-related factors (joint health, overall pain (Brief Pain Inventory-Pain Severity (BPI-PS)), functional status (2-Minute-Walking-Distance, Timed Up and Go); individual factors (age, BMI) and psychological factors (fear and avoidance beliefs over physical activity (FABQ-PA) and work (FABQ-Work), anxiety and depression) to LL-AL was explored using a regression analysis., Results: Only low correlations were found between ankle pain intensity and structure (IPSG-MRI, HEAD-US). PPT A was unrelated to structure. Altogether, HJHS, overall pain (BPI-PS), FABQ-Work and age explained 69% of HAL-LOWCOM variance, with 65% explained by the combination of HJHS and BPI-PS., Conclusion: No meaningful associations were found between ankle pain and structural damage, suggesting that other factors may contribute to PwH's ankle pain. In contrast, mainly haemophilia-related factors explained LL-AL variance., (© 2023 John Wiley & Sons Ltd.)

Introduction: Pain is a major issue in people with haemophilia (PwH). Few studies comprehensively assessed pain in PwH using a biopsychosocial framework and studies in mild PwH are lacking., Aim: To assess pain prevalence, pain interference and their relationship with health-related quality of life (HR-QoL) in male adults with haemophilia., Methods: A survey was initiated by the Belgian national member organisation. Pain in the last 24 h, pain severity (BPI-PS) and pain interference (BPI-PI) scores were obtained with the Brief Pain Inventory short-form (BPI). HR-QoL was evaluated with the EQ-5D-3L, giving the health utility index (EQ-HUI). Associations between EQ-HUI, BPI-PS and BPI-PI were analysed using Pearson's correlation test. A multiple regression analysed the relationship between HR-QoL and BPI-PS, with age and haemophilia severity as confounding factors., Results: Within 185 respondents (97, 31 and 57 respectively severe, moderate and mild PwH), 67% (118/177) reported pain. In severe, moderate and mild PwH, respectively 86% (79/92), 71% (22/31) and 32% (17/54) reported pain. Median [IQR] BPI-PS, BPI-PI and EQ-HUI scores were respectively 1.5 [.0; 4.0], 1.6 [.0; 3.6] and .81 [.69; 1.00]. PwH reported pain interference with general activity (56% (99/176)), psychosocial factors such as mood (53% (93/175)), and sleep (51% (90/177)). Moderate correlations were found between EQ-HUI, BPI-PS and BPI-PI. After adjusting for age and haemophilia severity, BPI-PS explained 14% of HR-QoL variance., Conclusions: Pain is a major issue amongst PwH, including people with mild haemophilia. Pain interferes with activities, emotions, sleep and HR-QoL, arguing for a comprehensive biopsychosocial approach of pain., (© 2023 John Wiley & Sons Ltd.)

The World Federation of Haemophilia (WFH) is a global network of national member organizations (NMOs) that advocate, collectively and individually, to improve lives of people with inherited bleeding disorders. The WFH vision of "Treatment for All" speaks to a future in which all people with an inherited bleeding disorder will have access to care, regardless of their gender or where they live. Over the last several years, initiatives including the WFH Humanitarian Aid program, the World Bleeding Disorders Registry, and Guidelines for the Management of Haemophilia and von Willebrand disease have significantly changed how the WFH and its partners work to improve and sustain care for people with bleeding disorders. Following an extensive consultation that included over 200 stakeholders from 70 countries, a Theory of Change was developed, and strategic priorities identified, to clearly define the WFH's intended impact and point of accountability to its stakeholders, and to determine how and through who those goals will be achieved. Both should help the WFH better support its NMOs and healthcare providers around the world in their efforts to improve access to diagnosis and care, as new therapies revolutionize the treatment landscape and the fallout of the global pandemic continues to challenge the ways in which we work and connect. Global collaboration of all stakeholders, based on their resources, objectives and skills, will be required to achieve these goals and to ensure more people have reliable access to safe treatment and care, regardless of their bleeding disorder, gender, or where they live., (© 2022 John Wiley & Sons Ltd.)

Introduction: Haemophilia is characterized by bleeding complications resulting from clotting factor VIII (FVIII) or IX (FIX) deficiency. Identifying the causal pathogenic genetic variant denotes a vital aspect of haemophilia management., Aim: This study evaluated the accessibility and performances of genetic testing for haemophilia across Europe. The types of genetic analyses, techniques used, turn-around time (TAT) and costs were collected and analysed, as were data updating and quality control., Methods: Reported data were retrieved from open access resources, including international databases, Google, laboratory websites, PubMed and government organizations., Results: Overall, 51 genetic laboratories across 15 European countries providing recently updated molecular haemophilia testing were identified. Gene sequencing for small variants of both F8 and F9 genes was provided in most surveyed laboratories. Almost two-thirds of them offer analysis for inversions using a polymerase chain reaction (PCR) method and detection of copy number variation (CNV) using multiplex ligation-dependent probe amplification (MLPA). Cost and TAT were found to vary considerably. In total, 74% of laboratories exhibited a last modified date or change history. The same percentage of laboratories was in possession of an ISO 15189 standard accreditation, whereas only few of them recently performed external quality assessment schemes (EQA) for haemophilia., Conclusion: Despite several initiatives to improve access to genetic testing for haemophilia, such access must still be improved. Our study similarly revealed the large heterogeneity of the variants tested, techniques employed, TAT, cost and quality among the surveyed laboratories., (© 2022 John Wiley & Sons Ltd.)

Introduction: To assess activity limitations in people with haemophilia (PwH), the self-reported Haemophilia Activity List (HAL) is widely employed, despite several methodological limitations impacting the interpretation of categorical scores. Modern psychometric approaches avoid these limitations by using a probabilistic model, such as the Rasch model. The ACTIVLIM is a Rasch-built measurement of activity limitations previously validated in several clinical conditions like neuromuscular disorders., Aims: This study sought to develop the ACTIVLIM-Hemo, meaning an ACTIVLIM scale version specifically adapted to assess daily activity limitations in adult PwH., Methods: Daily activities were assessed as "impossible," "difficult" or "easy" by 114 PwH (median age of 44 years) with 63 of them reassessed after 12 days. The Rasch Rating Scale model was used to identify activities delineating a unidimensional and linear scale unbiased by demographic and clinical status. Concurrent validity was determined through correlation with the HAL sub-scores and sum score., Results: The ACTIVLIM-Hemo included 22 pertinent activities, with difficulties independent of demographic and clinical conditions, allowing a reliable measure of activity limitations (PSI = .92) expressed on a linear and unidimensional scale in PwH (7%-100 % range, ceiling effect of 1/114) with excellent test-retest reliability (ICC = .978). Spearman rank correlations between ACTIVLIM-Hemo and HAL sub-scores ranged between .623 and .869., Conclusions: The ACTIVLIM-Hemo is an easy-to-administer, valid and reliable alternative to HAL in assessing activity limitations in PwH. Its invariant scale can be used across conditions and time to compare the functional status of PwH over a wide measurement range., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

New treatment possibilities and modalities are now available globally for patients with haemophilia requiring surgery or invasive procedures. The first is the appropriate application of low-dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resources constraint environments. The increasing availability of CFC through humanitarian aid programs allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half-life CFC that are increasingly available in many countries represent valuable alternatives to standard half-life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half-life factor IX. Third, in the era of recently introduced nonfactor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low-dose administrations of CFC or bypassing agents. Additional factor VIII/IX or recombinant activated factor VII has proven to be safe and effective in association with emicizumab for major surgeries and it was effectively given at low doses in association with fitusiran (including activated prothrombin complex concentrate). No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents., (© 2022 John Wiley & Sons Ltd.)

Introduction: Recurrent bleeding in severe haemophilia B causes painful hemarthroses and reduces capacity for physical activity. Recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis results in low annualised bleeding rates, with the potential to improve patients' health-related quality of life (HRQoL)., Aim: To present a post hoc analysis of data from B-LONG describing change over time in patient-reported outcomes associated with pain and physical activity., Methods: Patients (≥12 years) who received weekly dose-adjusted or interval-adjusted rFIXFc prophylaxis and completed the Haemophilia-Specific QoL questionnaire for adolescents (Haemo-QoL) or adults (Haem-A-QoL) at baseline (BL) and end of study (EoS). Individual level changes in items of the 'Physical Health' and 'Sports and Leisure' domains, categorised as 'never/rarely/seldom' or 'sometimes/often/all the time', were analysed using McNemar's test to compare distribution of responses at EoS versus BL., Results: At EoS versus BL, a significantly greater proportion of patients did not experience painful swellings (64% vs. 44%; P = .004), painful joints (44% vs. 28%; P = .003) or pain when moving (54% vs. 41%; P = .026). Additionally, at EoS versus BL, patients were less likely to avoid participating in sports like football (30% vs. 8%; P = .002), avoid sports due to their haemophilia (47% vs. 27%; P = .007), or experience difficulty walking as far as they wanted (63% vs. 43%; P = .001). The proportion of patients who played sports as much as the general population was numerically increased (52% vs. 37%; P = .033) at EoS versus BL., Conclusion: Results of the analysis suggest that over time, rFIXFc prophylaxis is associated with significant improvements in pain and physical functioning. This contributes to previous evidence of overall HRQoL improvements in patients with haemophilia B treated with rFIXFc., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Background: Emicizumab, a bispecific monoclonal antibody administered subcutaneously, mimicking the action of activated coagulation factor VIII, has been approved in Europe for use in patients with severe hemophilia of all ages., Aims: To assess availability, acceptance, adverse events, efficacy and laboratory monitoring of emicizumab and the effect of the coronavirus disease 2019 (COVID-19) pandemic on its use., Methods: Online questionnaire sent to 144 hemophilia treatment centres (November 2020 to January 2021)., Results: Forty-six physicians from 21 countries responded, with a total of 3420 patients with severe HA under their care. Emicizumab was widely available, for 100% of inhibitor patients and 88% of non-inhibitor patients. No major adverse events were reported. Four reported deaths in patients on emicizumab were not thought to be related to emicizumab. An annualized bleeding rate (ABR) of zero was achieved in 73% of inhibitors patients. Haemostasis was satisfactory in the majority of minor (93.7%) and major (90.7%) surgical procedures performed while on emicizumab. Inhibitor titers were monitored in 78.4% of inhibitor patients on emicizumab, but chromogenic FVIII assay was only available in 73% of centres. The COVID-19 pandemic did not have a major impact on the adoption of emicizumab in most centres (64.9%)., Conclusion: Three years after its rollout in Europe, emicizumab is widely available. Clinical efficacy and safety were evaluated to be very good, keeping in mind the inherent limitations of the study. Unmet needs include establishment of treatment guidelines for surgery and breakthrough bleeding, limited expertise, especially in young children, and availability of laboratory assays., (© 2021 John Wiley & Sons Ltd.)

The performance of surgery and invasive procedures in patients with haemophilia is currently facing new challenges globally. The first is the appropriate application of low-dose protocols of clotting factor concentrates (CFC) achieving adequate perioperative haemostasis in resource constraint environments. The increasing availability of CFC through humanitarian aid programmes allows more invasive surgeries to be performed for which efficacy and safety data should be more widely collected and reported. Second, extended half-life CFC that are increasingly available in many countries represent valuable alternatives to standard half-life products in surgical patients allowing reduced number of infusions and lower consumption, in particular for extended half-life factor IX. Third, in the era of recently introduced non-factor prophylaxis, some minor surgical procedures can now be performed without additional haemostatic treatment, others with few low-dose administrations of CFC or bypassing agents. Additional factor VIII or bypassing treatment has proven to be safe and effective in association with emicizumab for major surgeries, and it was effectively given at low doses in association with fitusiran. No thrombotic complications have been reported in the surgical setting so far. A multidisciplinary team/facility remains crucial to manage major surgery in patients on prophylaxis with these new agents., (© 2020 John Wiley & Sons Ltd.)

Introduction: In sub-Saharan Africa, access to clotting factor concentrates (CFCs) is often extremely limited and published data on people with haemophilia on prophylaxis are almost not existent., Aims and Methods: To assess the feasibility, barriers and outcomes of a low-dose and low-frequency prophylaxis with extended half-life (EHL) recombinant Fc fusion FVIII and FIX in Ivorian children on a two-year period in the setting of the World Federation of Hemophilia's (WFH) humanitarian aid programme., Results: Twenty-five boys with haemophilia were included. Mean (SD) age at inclusion was 5.6 (2.5) years. The median [range] follow-up duration was 17 [11-24] months. Regimen of prophylaxis was 20 IU kg -1 1×/week in haemophilia A and every 10 days in haemophilia B. We observed a maximal reduction by 87.6% of the annual spontaneous joint bleeding rate and a slight decrease in the total HJHS scores (p = .047). Adherence problems related to parents' low education level and shortage in CFCs were the main issues to carry out the programme. Inhibitors occurred in 12.5%., Conclusion: This study confirms the feasibility and efficacy of low-dose and low-frequency prophylaxis in young Ivorian children with haemophilia treated with EHL CFCs donated through the WFH humanitarian aid programme. This work also highlights the crucial role of adherence and the need for appropriate education to achieve prophylaxis. Finally, it reminds the paramount objective of achieving self-sufficient, sustainable and available haemophilia replacement therapy for all worldwide., (© 2020 John Wiley & Sons Ltd.)

Introduction: The SARS-CoV-2 coronavirus-induced infection (COVID-19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The pathophysiology and management of the COVID-19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments., Objective: We propose practical guidance for the diagnosis and management of COVID-19 coagulopathy in persons with haemophilia., Results: Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence., Conclusions: These practical recommendations are based on the current literature on COVID-19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies., (© 2020 John Wiley & Sons Ltd.)

Background: Deep venous thrombosis (DVT) is a common postoperative complication in patients undergoing major orthopaedic surgery of the lower limbs, such as total hip or knee replacement (THR, TKR). Routine pharmacological thromboprophylaxis with low-molecular-weight heparin (LMWH) or a direct oral anticoagulant agent is strongly recommended in this setting. THR and TKR as well as ankle arthrodesis are frequently performed in people with haemophilia (PWH) and chronic haemophilic arthropathy. Pharmacological thromboprophylaxis in this population remains controversial., Methods: We report the results of a single-centre prospective study initiated in 2002 evaluating by systematic Doppler ultrasound the incidence of subclinical DVT in consecutive PWH referred for major orthopaedic surgery and not receiving pharmacological thromboprophylaxis., Results: We included 46 different PWH (39 Haemophilia A, 7 Haemophilia B, 27 severe, 15 moderate and 4 mild forms) undergoing 67 orthopaedic procedures. Most (89.5%) were performed with continuous infusion of clotting factor concentrates. Rehabilitation was usually started on day 1 post-op. No clinical DVT or pulmonary embolism was suspected. In total, there were 5 cases (3 severe, 1 moderate HA and 1 moderate HB) of subclinical DVT which were all distal. Two patients were treated with a short course (10-14 days) of LMWH. The overall incidence of DVT was 7.5%., Conclusions: These data provide imaging-based evidence that the risk of DVT following major orthopaedic surgery among PWH is low. Identified DVTs were distal and resolved spontaneously in most cases. Systematic pharmacological thromboprophylaxis in this specific population is probably for most patients not required., (© 2020 John Wiley & Sons Ltd.)

In approximately 90% of mild haemophilia A (HA) patients, a missense mutation can be identified using complete gene sequencing. In this study, multiplex ligation-dependent probe amplification analysis was performed as a second step in 10 French-speaking Belgian with mild HA presenting no detectable causal mutation by complete sequencing of the factor VIII (FVIII) (F8) gene's 26 exons and its 1.2 kb of contiguous promoter sequence. This gene dosage technique enabled the detection of exon 1 duplications of F8 in three apparently unrelated subjects. Using array-comparative genomic hybridization, breakpoint analysis delimited the duplication extent to 210 kb in the F8 intron 1 and VBP1 gene intragenic position. We postulated that the rearrangement responsible for this duplication, never before reported, could be attributed to a symmetrical tandem inversion duplication, resulting in a large 233 kb rearrangement of F8 intron 1. This rearranged intron should lead to the production of a small number of normal mRNA transcripts in relation to the mild HA phenotype. Our analysis of the entire F8 mRNA from index case 1, particularly the segment containing exons 1-9, revealed normal amplification and sequencing. Reduced plasma FVIII antigen levels caused by cross-reacting material is associated with a quantitative deficiency of plasma FVIII. Male patients were unresponsive to desmopressin (1-deamino-8-D-arginine vasopressin). All patients displayed identical F8 haplotypes, despite not being related, which suggests a possible founder effect caused by a 210 kb duplication involving F8 exon 1., (© 2015 John Wiley & Sons Ltd.)