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Over the last decade, the development of new treatments for haemophilia has progressed at a very rapid pace. Despite all the promising advances in protein products, the prospect offered by gene therapy of a single potentially lifelong treatment remains attractive for people with haemophilia. Transfer to the liver of coagulation factor VIII (FVIII) or factor IX (FIX) transgenes has indeed the potential to stably restore the dysfunctional coagulation process. Recombinant adeno‐associated virus (AAV)‐derived vectors are widely employed for liver‐directed gene therapy, given their very good efficacy and safety profile, shown in several preclinical and clinical studies. However, there are some limitations associated with AAV vectors, such as their predominantly episomal nature in the nucleus of target cells and the widespread pre‐existing immunity against the parental virus in humans. By contrast, HIV‐derived lentiviral vectors (LV) integrate into the target cell chromatin and are maintained as the cells duplicate their genome, a potential advantage for establishing long‐term expression especially in paediatric patients, in which the liver undergoes substantial growth. Systemic administration of LV allowed stable multi‐year transgene expression in the liver of mice and dogs. More recently, improved phagocytosis‐shielded LV were generated, which, following intravenous administration to non‐human primates, showed selective targeting of liver and spleen and enhanced hepatocyte gene transfer, achieving up to supra‐normal activity of both human FVIII and FIX transgenes. These studies support further preclinical assessment and clinical evaluation of in vivo liver‐directed LV gene therapy for haemophilia. [ABSTRACT FROM AUTHOR]

We encourage therapists to critically examine their own practice, as well as asking centre directors and therapy managers to see the value of a well-defined physiotherapy service within haemophilia. GLO:EVW/01mar21:hae14150-fig-0001.jpg PHOTO (COLOR): 1 Recommendation for reviewing provision of a local haemophilia physiotherapy service gl It remains unclear if new treatments (EHL's, non-substitutive therapies) will considerably reduce the frequency of bleeding in patients treated. Acute pain significantly impacts quality of life and is greater when present on a backdrop of ongoing persistent pain.6 An increase in age is also associated with a decrease in quality of life predominantly related to haemophilia-specific MSK complications, that is, joint disease. [Extracted from the article]

Haemophilia and inherited bleeding disorders in newborns and their carrier mothers pose unique challenges. The pattern of bleeding and the causes and risk factors for bleeding are decidedly different than an older child or an adult with haemophilia/inherited bleeding disorder. This document outlines the needs for further research and education, summarizes the state of the art background information and provides guidance regarding research, education and access to care issues in this population. [ABSTRACT FROM AUTHOR]

Record keeping among individuals who manage haemophilia at home is an essential tool of communication between patient and Haemophilia Treatment Center ( HTC). Complete records help HTCs monitor patients, their use of factor and ensure treatment is optimal. HTCs provide patients with a number of methods to track infusion practices. The study objectives were to: [1] determine the current methods of record keeping; [2] identify previous methods of record keeping; [3] understand the strengths and weaknesses associated with each method; and [4] gather suggestions for improvement. Survey methods were used to address the research objectives. Of the 83 patients in the Hamilton-Niagara region who received the survey distributed through the local HTC, 51 returned surveys were included into the analysis. Descriptive statistics were used. Results indicate individuals with haemophilia record infusion practices using: paper diaries, excel spreadsheets, hand-held PDAs and/or the online EZ-Log Web Client. The most popular method of record keeping was EZ-Log (45.1%) followed by paper diaries (35.2%). Advantages to using paper methods include the visual tracking of information and retaining hardcopies. The disadvantage was the inconvenience of physically submitting the records monthly. Advantages to using the online EZ-Log Web Client included ease of use and improved accuracy. The primary disadvantage was technical errors that were difficult to troubleshoot. Record keeping practices among individuals with haemophilia seem to vary according to personal preference and convenience. Respondents suggested that saving infusion history, incorporating barcode scanners or a copy and paste function could improve electronic methods. [ABSTRACT FROM AUTHOR]

Reports on the English translation of Erik von Willebrand's Swedish medical paper by professor Peter E. Wahlberg. Preservation of archaistic mode of writing.

ABSTRACT Introduction Aim Methods Results Conclusion 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.This paper comprehensively critiques, against this background, the recommendations of the ISTH clinical practice guidelines for the treatment of haemophilia.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.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.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. [ABSTRACT FROM AUTHOR]

A recent article published in Haemophilia reports the results of a survey of treatment center practices in the United States, and specifically the use of prophylaxis as treatment regimen [ ] . This article discusses the issues that may contribute to utilization of prophylactic regimens and issues to consider when determining treatment programs for pediatric patients. [ABSTRACT FROM AUTHOR]

On-demand or prophylactic home-treatment is currently the treatment of choice for haemophilia patients. To allow physicians to monitor the amount of factor concentrates administered, the patients document each factor injection in a paper-diary. Nevertheless, because of the fact that most patients visit their physicians only two to four times a year, there could be considerable delay in detecting medication problems. The aim of this pilot study was to assess whether an electronic documentation tool could successfully replace traditional paper-diaries for haemophilia A patients and enable the physician to have a timely overview of the patient’s treatment. An electronic, hand-held documentation tool, Haemoassist™, was developed. In this study, patients using prophylaxis and on-demand therapies documented their factor consumption both electronically and on paper-diaries. Documentations were compared and descriptively evaluated. Patients also completed a survey to evaluate the feasibility and gather their opinions on the Haemoassist™ system. Ten patients from two haemophilia treatment centres in Germany submitted a total of 548 records via hand-held device during the observation period, from March 2006 to February 2007. Comparison of electronic and paper-based records showed differing responses among patients with some patients entering more electronic and some others more paper-based documentations. In the questionnaires on feasibility and usefulness of Haemoassist™, three patients preferred the electronic tool, two patients wanted to continue using paper-based diaries, and one had no preference. The study shows that an electronic documentation system is feasible for haemophilia patients and provides the physician with the opportunity to more closely monitor patients. However, not all patients seem to be qualified for using an electronic tool, and the tool has to run reliably without major errors for ensuring reliability and acceptability. In the future, Haemoassist™ might support quality assurance in haemophilia treatment and improve guidance in the home-care setting. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor regarding the need of structured abstracts and explicit reporting of levels of evidence and author contributions published in the May 2004 issue of "Haemophilia."

Introduction: Hereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre‐clinical development and characterization of a high‐purity plasma‐derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency. Methods: A chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability. Results: The production process complied with good pharmaceutical manufacturing practice. It achieved 6000‐fold purification and 100‐fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%–96% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus‐reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma‐derived therapeutics. The freeze‐dried product remained stable between +2°C and +30°C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48 h at +18°C to +22°C. Conclusion: Targeted pre‐clinical development of the first highly‐purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra‐orphan medicinal products. [ABSTRACT FROM AUTHOR]

Better access to haemophilia treatment and care is currently changing the life of a great many patients with haemophilia or other inherited bleeding diseases in numerous developing countries. These changes are encouraging while stimulating local research initiatives and projects that deserve to be communicated through scientific publications. This paper addresses several opportunities and challenges, providing guidance to scientists, clinicians, researchers and health professionals from developing countries who are actively involved in multidisciplinary haemophilia care, while wishing to publish their reports in Haemophilia, the official, global, multidisciplinary journal of the World Federation of Haemophilia (WFH), the European Haemophilia and Allied Disorders (EAHAD) organization and the Hemostasis and Thrombosis Research Society (HTRS) of North America, focusing on inherited bleeding diseases. Several strategies and pathways designed to encourage, help and support successful publications from developing countries are herein discussed. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials in haemophilia product development are expanding rapidly however, the number of sites and expertise in the clinical trial conduct is limited. Guidance on the requirement for conducting clinical trials is required Aim: The aim of this paper is to outline generic requirements to participate in clinical trials in haemophilia Materials: This paper describes three elements which are the requirements for success conduct of haemophilia clinical trials. These are the study product, study participant, and the global regulatory and ethics framework Results and conclusion: In haemophilia clinical trials, requirements for participate in studies are many and include considerations of study product, study participant and ethical and regulatory framework. When these elements are in place, it is possible to conduct haemophilia clinical trials anywhere in the world. [ABSTRACT FROM AUTHOR]

Background: The Patient Reported Outcomes, Burdens and Experiences (PROBE) study aims to develop and validate questionnaire for assessing health status in patients with haemophilia and participants without bleeding disorders. Objective: To investigate the test‐retest properties of the PROBE questionnaire. Methods: The PROBE questionnaire covers four domains and is comprised of 29 questions. People with haemophilia (PWH) and participants without bleeding disorder were invited to participate in this study. All participants were asked to complete the PROBE questionnaire three times (paper‐based survey on two consecutive days: T1 and T2 and then a web‐based version: T3). Test‐retest properties and percentage agreement were analysed. Results: A total of 63 participants were enrolled in this study with a median age of 50 (range: 17‐76) years. Of these, 30 (47.6%) were PWH. On the questions common to PWH and participants without bleeding disorder, Kappa coefficients ranged from 0.69 to 1.00, indicating substantial to almost perfect agreement (T1 vs T2). For haemophilia‐related questions (T1 vs T2), Kappa coefficients ranged from 0.5 to 1.0. Of these, 5 of 11 items were in perfect agreement (Kappa = 1.0). The web‐based questionnaire (T3) showed substantial to almost perfect agreement with the paper version (T1 test‐retest properties were comparable between PWH and individuals without a bleeding disorder). Conclusions: The results suggest that PROBE is a reliable tool to assess patient‐reported outcomes for PWH and benchmark data in participants without bleeding disorder. The web‐based questionnaire and the standard paper‐based version can be used interchangeably. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia B is a debilitating hereditary coagulation disorder characterized by prolonged or spontaneous episodes of bleeding caused by a deficiency of endogenous factor IX. In Algeria, even though many studies are being carried out to evaluate the prevalence and management of haemophilia B, there is a paucity of locally published literature that can be used to understand the most recent information on the disease's epidemiology, diagnostic techniques and treatment options. Aims: The aim of this manuscript is to raise awareness among patients and family clinicians about current practices, recent developments and unmet needs related to haemophilia B in Algeria. Methods: A comprehensive literature search was conducted through online scientific databases to review publications regarding haemophilia B in Algeria. Exclusions of the review include case studies, interregional comparisons, abstract‐only papers and studies outside the range of 2012–2022. Results: The findings discussed relate to the epidemiology of haemophilia B in Algeria, the clinical diagnostic process, disease symptoms, the benefits of molecular and genetic testing, advancements in prophylactic care, as well as unmet needs hindering the progression of optimal haemophilia B management. Conclusion: These findings are crucial to encourage the maintenance of national registries with updated epidemiological data, facilitate early and timely detection of disease symptoms, improve the provision of diagnostic facilities and enhance the overall treatment landscape for better patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: People with haemophilia rely on specialists for their care, yet the specific dosing regimens of treatments prescribed by these specialists have not been widely studied. Aim: The objective of this study is to describe trends in clinician prescribing practices for the management of haemophilia in the United States (US). Methods: We administered surveys to members of the Hemostasis and Thrombosis Research Society via paper surveys at its in‐person annual symposia in 1999 and 2015, and an online survey in 2021. The surveys collected information on haemophilia treatments including factor dosing, inhibitor therapy and gene therapy. Results: Clinicians treating haemophilia for more than 50% of their practice time have increased from 37.5% of respondents in 1999 to 46.3% in 2021. Clinicians prescribing factor concentrates at >40 units/kg for routine bleeding events increased from 0% in 1999 to 29.3% in 2021 in haemophilia A (HA) and from 22.5% to 87.8% in haemophilia B (HB). In 2021, the clinicians reported prescribing emicizumab to treat HA patients (>89.5% paediatric, >85.7% adult) with or without inhibitors at least some of the time. Approximately 78.0% of respondents reported that they expected to recommend gene therapy at least some of time. Conclusion: These data indicate changing trends in prescribing practices among US haemophilia specialists during the past 22 years. Preference for high doses of factor (>40 units/kg) has increased during this period. Emicizumab prophylaxis has been prescribed for patients with and without HA inhibitors. Clinicians expect gene therapy to have value for some haemophilia patients. [ABSTRACT FROM AUTHOR]

Introduction: In the era of electronic medical records, pen‐and‐paper‐based physician‐administered bleeding assessment tools (BAT) remain under‐utilized in the clinical setting, as they are noted to be time‐consuming. Aim: The current study reviews the use of an electronic self‐administered bleeding assessment tool (eBAT) prospectively in a paediatric haematology clinic and in comparison with a physician administered BAT (pBAT). Materials and Methods: This was reviewed and approved in the current form because the aims statement includes the method regarding comparison of 2 groups. So no additional section required. Results: A total of 94 BAT response pairs were available for analysis. The median time required for patients or parents to complete the eBAT was 8 min, with less than a third of the patients requiring over 10 min. The median bleeding scores noted in this study were 4 for both the BATs, with strong positive correlation between the eBAT and the physician administered bleeding questionnaire. The eBAT had a sensitivity of 93.8% (95% CI 82.8%–98.7%), a specificity of 34.8% (95% CI 21.4%–50.3%), a positive predictive value (PV) of 60.0% (95% CI 54.5%–65.2%) and a negative PV of 84.2% (95% CI 62.5%–94.5%) for identifying a bleeding disorder. Conclusions: Findings indicate that eBAT is a valid and time‐efficient screening tool for evaluating patients' bleeding symptoms, which can improve clinical applicability of BATs by reducing time for bleeding history review. [ABSTRACT FROM AUTHOR]

Introduction: Tailored prophylaxis is the current treatment regimen for patients with severe haemophilia A. Recently, published guidelines describe two possible approaches, based on clinical characteristics or estimation of pharmacokinetic parameters. However, both have strengths and weaknesses, and their characteristics need to be integrated to optimize treatment appropriately. In this paper, we present a model that considers together the characteristics of prophylaxis and the relevance of each. Methods: The age at initiation of prophylaxis, number of bleeding events, treatment regimen, therapeutic adherence, FVIII trough levels, and joint status were analyzed in 59 patients followed at La Paz University Hospital between January 2000 and December 2019. Results: The mean duration of primary prophylaxis of 113.37 ± 57.79 months. Eighty‐three percent (n = 49) had no joint status involvement at the end of follow‐up (HJHS and HEAD‐US = 0). The median ABR was 0.7 (IQR 0.2 –1.0) and 54.2% presented trough levels of FVIII during follow‐up >1 IU/dL. 72,9% engaged in some type of physical activity and overall adherence was over 85% in all patients evaluated. The regression analysis performed, considering all these factors, showed that the initiation of prophylaxis before 21 months of age was the most relevant protective factor against the appearance of joint involvement (OR 88.33 p.031 CI 95% 1.49‐5224.40) Conclusion: Early initiation of prophylaxis was the most relevant factor in the protection of joint status. More comprehensive analysis models adapted to the characteristics of each population, are needed to adequately individualize treatment. [ABSTRACT FROM AUTHOR]

Introduction: The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a patient‐reported outcome tool that assesses quality of life and disease burden in people with haemophilia (PWH). Aim: To assesses the test–retest reliability of PROBE when completed using the mobile phone application. Methods: We recruited PWH, including carriers, and individuals with no bleeding disorders who attended haemophilia‐related workshops or via social media. Participants completed PROBE three times (twice on the app: T1 and T2, and once on the web, T3). Test–retest reliability was analysed for T1 versus T2 (app to app, time period one) and T2 versus T3 (app to web, time period two). Results: We enrolled 48 participants (median age = 56 [range 27–78] years). Eighteen participants (37.5%) were PWH and seven (14.6%) were carriers. On general health domain questions, we found almost perfect agreement, except for a question on the frequency of use of pain medication in the last 12 months [Kappa coefficient (κ).72 and.37 for time period one and two, respectively] and any use of pain medications (κ.75) for time period two. For haemophilia‐related questions, we found substantial to perfect agreement, except for the questions on the number of joint bleeds in the previous 6 months for time period one (κ.49) and the number of bleeds in the previous two weeks for time period two (κ.34). Conclusions: The results demonstrate the reliability of the PROBE app. The app can be used interchangeably with the paper and web platforms for PROBE administration. [ABSTRACT FROM AUTHOR]

Introduction: Due to advances in treatments, people with haemophilia (PWH) are living longer. They are not as active as the general population due to joint damage and lack confidence to be active due to concerns about further bleeds and pain. There is a need to facilitate healthy aging through promotion of physical activity (PA) and exercise. Changing patient beliefs and increasing physical literacy and confidence to move are thought to be key to helping PWH become more active. Aim: This paper describes the development of an exercise and behaviour change intervention to improve confidence to exercise in PWH. Methods: The 4‐stage Medical Research Council framework for complex intervention development was used. Results: Stakeholders included 17 PWH and 7 physiotherapists working in haemophilia. Seven online focus group meetings were held. The final intervention is a hybrid 12‐week physiotherapist led progressive exercise programme. Classes are 45 min including Pilates, High intensity interval training and balance elements, together with discussion sessions focusing on PA recommendations, the types and benefits of different exercise styles and the effects of PA, together with the effects of aging for PWH. The COM‐B model of behaviour change was used to develop the intervention. Conclusion: Co‐design helps to produce an intervention that understands the stakeholders needs. Through this process the intervention developed to incorporate not only increasing PA but also confidence to exercise. The use of behaviour change theory identified the behaviour techniques included in the intervention and aims to increase physical literacy in this population. [ABSTRACT FROM AUTHOR]

An editorial is presented on the treatment of haemophilia. Topics mentioned include the changing landscape of haemophilia treatment with inhibitors, the new type of surgical operation in a patient with haemophilia and the international practice of the physicians in treating haemophilic patients with inhibitors.

This paper is based on the assumption that psychosocial services can add important mental and social dimensions to the traditional concepts of help and medicine. Peer support which has been established world-wide for people with haemophilia and their families is invaluable and irreplaceable. However the role of the professional psychosocial worker is underutilized in most countries, mostly because of lack of financial resources. This paper will argue that skilled workers can assist individuals and groups to reach their full potential in a variety of creative and non-threatening ways. Psychosocial workers have strict codes of conduct and requirements relating to accreditation to ensure accountability in their work. They can work in a variety of individual roles and have a wide range of individual mandates within work settings. [ABSTRACT FROM AUTHOR]