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Keywords: Haemophilia, Gene therapy, Decision making, Informed consent, Clinical trial

An AAV5 vector containing the factor IX Padua allele was administered to 54 men with hemophilia B. Factor IX expression increased to approximately 39% of normal, and the annualized bleeding rate was decreased to 1.5.

Despite the numerous and groundbreaking therapeutic advances made in the field of hemophilia over the past decades and particularly in recent years, hemophilia remains a disease that has a major impact on the daily lives of our patients, through the multiple complications and burdensome treatments it imposes. The disease burden is not only physical but also psychological and is difficult to evaluate solely by questionnaires and scores. In this article, we propose to examine the absence of psychological burden and of permanent thoughts about the disease and its complications in people with hemophilia as a new ambition that should guide hemophilia care and research in the future.

Prophylactic therapy with exogenous clotting factor concentrates in haemophilia A and B aims to achieve levels of circulating FVIII or FIX that are adequate for the prevention or reduction of spontaneous joint bleeding. Historically, a minimum trough level of at least 1% of the normal levels of circulating clotting factor has been targeted using standardised protocols. However, clearance of clotting factor varies between products and patients, and other pharmacokinetic (PK) parameters such as the frequency and magnitude of peaks may be important for ensuring optimal coverage. Thus, it is increasingly recognised that an individualised, PK-based approach to prophylaxis is necessary to achieve optimal protection. This review focuses on the clinical implications of using PK-guided, individualised prophylaxis in haemophilia to improve patient outcomes and considers practical methods of establishing patients’ PK parameters. The most useful PK parameters will depend on the aim of the specific treatment (e.g. preventing activity-related and traumatic bleeds or addressing subclinical bleeding). In clinical practice, lengthy and frequent post-infusion sampling for PK analysis is costly and a significant burden for patients. However, a Bayesian analysis allows for the estimation of different PK parameters (e.g. half-life, factor concentrations over time, etc.) with only a minimum number of samples (e.g. 4, 24 and 48 h for haemophilia A), by using the patient’s data to adjust a relevant population PK value towards the actual value. Numerous tools are available to aid in the practical use of Bayesian PK-guided dosing in the clinic, including the Web-based Application for the Population Pharmacokinetic Service hosted by McMaster University, Canada. The PK data can be used to determine the appropriate prophylaxis regimen for the individual patient, which can be monitored by assessment of the trough level at each clinic visit. Collection of PK data and subsequent PK-guided dosing should become standard practice when determining treatment strategies for people with haemophilia.

Acquired haemophilia A (AHA) is a rare and severe haemorrhagic autoimmune disease caused by autoantibodies directed against factor VIII (FVIII). Treatment is based on two principles, including haemostatic control to compensate FVIII inhibition and eradication of inhibiting antibodies using immunosuppressive therapy. Rapid recognition and proper management are essential to avoid excess morbidity and mortality. Effective and safe treatments can be challenging, given that AHA patients are often elderly, with multiple comorbidities. Emicizumab, a bispecific antibody that mimics the action of FVIII, has proven effective in managing patients with congenital haemophilia, with or without inhibitors. Likewise, its mode of action suggests theoretical efficacy in AHA patients. We herein describe two AHA cases with comorbidities that were treated effectively using emicizumab combined with immunosuppressive therapy. We have also reviewed the current literature regarding the promising use of emicizumab in this indication.

Michel Goldman and Cédric Hermans discuss thrombotic mechanisms in COVID-19 and rare adverse reactions to SARS-CoV-2 vaccinations.Michel Goldman and Cédric Hermans discuss thrombotic mechanisms in COVID-19 and rare adverse reactions to SARS-CoV-2 vaccinations.

Emicizumab, a bispecific antibody mimicking the action of factor VIII (FVIII), is currently the first and only approved and increasingly accessible disruptive treatment option for hemophilia A, a disease so far mainly treated with frequent intravenous infusions of FVIII concentrates or bypassing agents in case of inhibitor development. Other disruptive treatments are expected to follow, such as agents that rebalance coagulation and gene therapy with the ambition of curing hemophilia. While these treatment options represent major achievements or expectations, their adoption and implementation should consider their multiple direct and indirect, immediate or delayed, consequences on hemophilia care globally. It is these multiple changes, present and future, already visible or hypothetical, that this article intends to review and explore.

Background The D-dimer (DD) assay is an essential biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, which is likely related to age, cardiovascular risk factors, invasive thrombogenic procedures, over-correction of Factor VIII (FVIII) or FIX, or administration of new therapeutic agents mimicking FVIII or rebalancing coagulation. Objective This retrospective study sought to assess the basal DD levels in PWH treated prophylactically with FVIII, and to evaluate potential changes after switching to emicizumab. Method Patients over 18 years of age treated with emicizumab within a single center over the period 2017-2022 were included in the study. Result DD levels were measured in 40 adult PWH (37 severe/ three moderate / two with FVIII inhibitor) with a median age of 46 years (range: 19-82; Q1-Q3: 30,25-56,5), before and at least 3 months after emicizumab initiation. No significant changes were revealed, with DD median values of 257 ng/mL (range: 250-2876; Q1-Q3: 250-493,5) before and 250 ng/mL (range: 50-6205; Q1-Q3: 250-380,25) after the switch (p  =  0.9). Conclusion Most adult PWH on prophylaxis using FVIII display DD levels within the normal range, which remain unchanged after switching to emicizumab. In view of these reassuring results, monitoring of DDs at the start of emicizumab treatment does not appear necessary but could be considered when combined with other bypassing agents or high dose FVIII.

Gene-based therapy opens an entirely new paradigm in managing people with haemophilia (PWH), offering them the possibility of a functional cure by enabling continuous expression of factor VIII (FVIII) or factor IX (FIX) after transfer of a functional gene designed to replace the PWH’s own defective gene. In recent years, significant advances in gene therapy have been made, resulting in clotting factor activity attaining near-normal levels, as reflected by ‘zero bleeding rates’ in previously severely inflicted patients following a single administration of adeno-associated viral (AAV) vectors. While this new approach represents a major advancement, there are still several issues that must be resolved before applying this technology in clinical practice. First, awareness, communication, and education about the therapeutic potential and modalities of gene therapy must be further strengthened. To this end, objective, unbiased, transparent, and regularly updated information must be shared, in an appropriate way and understandable language with the support of patients’ organizations. Second, healthcare providers should adopt a patient-centred approach, as the ‘one size fits all’ approach is inappropriate when considering gene therapy. Instead, a holistic patient view taking into account their physical and mental dimensions, along with unexpressed expectations and preferences, is mandatory. Third, the consent procedure must be improved, ensuring that patients’ interests are maximally protected. Finally, gene therapy is likely to be first delivered in a few centres, with the highest expertise and experience in this domain. Thus, patients should be managed based on a hub-and-spoke model, taking into account that the key to gene therapy’s success lies in an optimal communication and collaboration both within and between haemophilia centres sharing their experiences in the frame of international registries. This review describes recent progress and explains outstanding hurdles that must be tackled to ease the implementation of this paradigm-changing new therapy.

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients’ quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5–1.8 times that of standard products for FVIII and 3–5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.