Prophylaxis is the standard of care for people living with haemophilia (PwH) as it is able to prevent majority of bleeding episodes, including joint bleeds and life-threatening bleeds (i.e., intracranial haemorrhage). However, despite undeniable advantages, prophylaxis has limitations including need for frequent intravenous infusions and cost. Adherence to long-term treatment regimens based on multiple weekly intravenous injections of standard half-life products is challenging, and it is highly likely that injections are skipped or delayed with great impact on efficacy due to the rather rapid clearance of the drug from the body. The advent of extended half-life products allowed for greater flexibility and easier treatment personalization with the possibility to improve protection as well as to reduce number of intravenous injections. For people living with haemophilia A and inhibitors the advent of the first non-replacement therapy, emicizumab, made a turning point offering for the first time an effective prophylaxis with the additional advantage of a consistent steady state of haemostatic effect across different ages and body weights and of subcutaneous route of administration. However, during emicizumab prophylaxis breakthrough bleeds might occur due to the limited haemostatic potential which stays in the mild haemophilia range with some interindividual variability and not clearly definable FVIII equivalence. More recently the toolbox for haemophilia care has further expanded with several non-factor therapies that will offer the opportunity of effective prophylaxis to people with haemophilia B with inhibitors, subcutaneous prophylaxis for all PwH and the promise of protection in the non-haemophilia range.
There is a high prevalence of human immunodeficiency virus (HIV) infection among the haemophilia community due to treatment in the 1970s and 1980s with contaminated clotting factor. Lifelong treatment regimens for haemophilia and HIV are burdensome alone and pose a particular challenge for individuals living with both conditions. Adeno-associated virus (AAV)-based gene therapy restores endogenous factor expression and offers an alternative to routine prophylaxis for haemophilia that individuals living with haemophilia and HIV infection may find uniquely appealing to alleviate the treatment burden for at least one of their chronic conditions. The aim of this article is to provide guidance on clinical practice to health care professionals considering gene therapy as a treatment option for individuals with haemophilia and HIV. We compile available safety and efficacy evidence from participants living with HIV who participated in gene therapy trials for haemophilia. Then, based on this evidence, we provide several HIV-specific considerations for individuals with haemophilia and HIV comorbidity. As part of a shared decision-making approach, it is important to not only evaluate if gene therapy is appropriate but also to offer recommendations on what to expect when navigating the treatment journey. The available evidence to date indicates modern antiretroviral therapy (ART) regimens may not cause complications when combined with AAV-based gene therapies. Accordingly, HIV infection should not be considered a general contraindication for gene therapy to restore factor expression in haemophilia. However, a careful consideration of the individual's life context, especially hepatotoxic drug effects or interactions, is warranted.
The use of emicizumab prophylaxis among persons with haemophilia A (PwHA), both with and without inhibitors, has been increasing significantly in recent years. Nevertheless, clear recommendations remain lacking regarding the necessity and extent of perioperative adjunctive systemic haemostatic therapy for surgical procedures. Given the high frequency of dental interventions, minor oral surgical procedures, are of particular clinical relevance for these persons. This paper provides a review of the literature along with a retrospective analysis of a case series involving 10 PwHA who underwent invasive dental procedures across three centres. In cases involving permanent tooth extraction a single preoperative dose of rFVIII (for PwHA without inhibitors) or rFVIIa (for those with inhibitors) were used. The analysis indicated that extraction of primary teeth in children receiving emicizumab prophylaxis can be successfully performed without the concomitant use of systemic haemostatic agents. Only one postoperative bleeding event was observed, following a periodontal procedure, suggesting that type of procedure may pose a greater challenge in achieving adequate hemostasis due to larger bleeding area and limited possibility for the use of local haemostatic measures. A review of the literature showed that for minor oral surgical procedures, such as tooth extraction, either preoperative administration of haemostatic factor infusions or performing the procedure without factor use may be recommended. However, evidence-based data and recommendations regarding the safest management strategies remain insufficient. A multidisciplinary and individualized approach, incorporating assessment of the procedural bleeding risk, the patient's bleeding history, and strict use of local haemostatic measures remains essential.
Women with haemophilia can present manifestations and experience undiagnosed symptoms, which negatively affect their health-related quality of life (HRQoL). To evaluate the HRQoL in obligate carriers of haemophilia (OCH) versus women non-carriers of haemophilia (WNCH) in a Colombian population. Observational, cross-sectional study of women over 18 years. OCH were defined as daughters of a father with haemophilia, mothers of two or more sons with haemophilia, or mothers of one son with haemophilia and another affected relative. OCH were matched 1:1 with WNCH according to socioeconomic stratum and age. Women with other haematological pathologies, use of anticoagulants or antiplatelets, pregnancy or cognitive impairment were excluded. The Bleeding Assessment Tool (ISTH-BAT) was used to evaluate bleeding symptoms, and the SF-36 questionnaire was used to measure HRQoL. A total of 104 women were included (52 OCH and 52 WNCH), with a median age of 49 years (IQR 40.5-48.5). WNCH had higher educational levels and a lower proportion of homemakers (23.8% vs. 46.15%; p = 0.015). A total of 38.46% had abnormal bleeding (ISTH-BAT ≥ 6), which was more frequent in OCH (75% vs. 1.92%; p < 0.01), with menorrhagia being the most prevalent manifestation (90.38% vs. 44.23%; p < 0.01). OCH reported lower scores in all of the SF-36 domains, with greater involvement in physical role (65.38%), while the WNCH reported a lower score in mental health (17.31%). Compared with WNCH, OCH have a significantly more compromised HRQoL, which highlights the need for specific interventions to improve their physical and psychosocial well-being.
Haemophilia has historically been recognised as a disease occurring in males due to X-linked inheritance. Some haemophilia carriers (HC) with factor eight or nine levels within normal range > 40 IU/dL may not have bleeding manifestation and may never require treatment, however more than 30% of haemophilia carriers experience bleeding symptoms, including those with factor levels above 50 IU/dL. World Federation of Hemophilia (WFH) guidelines for the management of haemophilia, third edition, recommend that HC, irrespective of factor levels, should be registered with a haemophilia treatment centre (HTC) and those with reduced factor levels should be managed as their male counterparts with haemophilia. To identify the provision of access to care for HC amongst global HTCs, nurses from nine countries, across six continents, collected data in line with the WFH guidelines for the management of haemophilia and reflected on challenges to meeting these recommendations around the world. In 66% of HTCs, HC with normal and reduced coagulation factor levels are registered as patients within their HTCs. Differences in access to information, investigations, monitoring and treatment were observed between the participating HTCs. While this evaluation aimed to reflect global practice, the participating haemophilia treatment centres predominantly represent high-income healthcare systems. HC access to care remains inconsistent globally. Many of these gaps relate to different healthcare systems and resource limitations. Despite the majority of centres being large, from high income countries, the lack of demonstrable care around their management, highlights a gap in service provision for this underserved group.
Gene therapy for Haemophilia B has received FDA approval, offering patients a transformative therapeutic option. However, effective communication about the benefits, risks, long-term efficacy and follow-up of gene therapy remains essential for informed decision-making. This study aimed to explore the diverse expectations, concerns and perspectives of patients with Haemophilia B, their caregivers and healthcare professionals (HCPs) regarding gene therapy and to identify strategies for improving communication. A prospective qualitative study was conducted using semi-structured interviews with male patients aged ≥12 years with moderate or severe Haemophilia B (factor level ≤ 2%), their caregivers and HCPs (physicians, nurses, social workers, advanced practice providers and pharmacists). Interviews were audio-recorded, transcribed and analysed thematically. Thirty participants were interviewed, including 15 patients (mean age, 21.1 years), caregivers and 15 HCPs across the United States. Patients and caregivers emphasised five themes: (1) current challenges; (2) hope and optimism; (3) concerns and skepticism; (4) the complex emotional challenges of decision-making and (5) preferences for transparent, patient-friendly communication. HCPs identified four complementary themes: (1) variable patient knowledge; (2) the need for transparency in discussing 'curative' language; (3) factors influencing treatment decisions (trust, prior experiences and financial concerns) and (4) strategies to improve communication (clear language, visuals and testimonials). Stakeholders view gene therapy as both promising and uncertain. Targeted educational interventions, transparent communication and patient-centred decision discussions are essential to fill knowledge gaps and support informed consent in this transformative era of treatment for Haemophilia B.
The recently approved haemophilia A and B gene therapies via adeno-associated virus (AAV) showed a promising therapeutic response after a single injection, but there are still limitations, including the potential loss of transgene expression and restriction in adults. Conversely, genome editing by precise gene correction or targeted transgene insertion could be translated to children and even neonates. Pioneer studies with Zinc-Finger nucleases (ZFN) driving homologous directed repair (HDR) established the proof of concept for in vivo targeted integration. The advent of the much more versatile CRISPR-Cas9 technology boosted research in the haemophilia field, and preclinical data demonstrated that targeted gene insertion of the F8/F9 coding sequence, can represent a durable therapy both in adults and neonates. Although with modest efficiency, the effect can be boosted by exploitation of the hyperactive FIXPadua and/or integration at a "smart" target locus of a highly expressed liver-specific gene such as Albumin (Phase 1/2 trial). Moreover, targeted insertion has been achieved at the CCR5 locus to insert the FIXPadua via HDR in B lymphocytes, and this promising ex-vivo gene therapy entered a Phase 1/2 trial. Base and prime editors have also been successfully exploited in cellular models to precisely correct gene defects but their translational potential is limited by the many diverse haemophilia-causing genetic variants that need to be addressed. As these technologies mature, rigorous long-term follow-up and safety monitoring will be essential to offer patients a definitive cure for haemophilia.
Traditional haemophilia therapies act to replace the relevant missing clotting factor, are not interchangeable between haemophilia A and B and cannot be used in patients with high titre inhibitors. Novel non-replacement factor therapies (NFT) target other endogenous coagulation proteins or anticoagulants such as antithrombin (AT) and tissue factor pathway inhibitor (TFPI) to rebalance haemostasis. As such, pharmaceutical clinical trials of these molecules have enrolled patients with haemophilia A or B, with and without inhibitors. The requirement for monitoring the efficacy of NFTs is greatly reduced compared to replacement therapy and global assays such as thrombin generation assay (TGA) have been used extensively in clinical trials to indicate improvement to haemostasis. Comprehensive haemophilia care, including access to and laboratory monitoring of replacement and NFTs, is well established in high income countries, but there are profound global inequities in the diagnosis and treatment of haemophilia which still need to be remedied. The authors examine the challenges of haemophilia and von Willebrand diagnosis and monitoring of NFTs using conventional and global assays of haemostasis.
In this article, we have reviewed the most important modern conceptual developments for the treatment of the elbow in persons with haemophilia. Despite modern preventive strategies, subclinical bleeding can still occur, underscoring the need for constant vigilance. The elbow is particularly susceptible to synovitis due to its extensive synovial tissue and multiplanar movement, which increase exposure to recurrent bleeding episodes. Iron deposition in the joint initiates a complex inflammatory and apoptotic cascade that ultimately leads to changes in the synovial membrane. Point-of-care ultrasound has become an essential tool for detecting subclinical synovitis, but ensuring diagnostic accuracy remains critical. Comprehensive treatment also requires a highly specialised musculoskeletal expert with access to the full range of therapeutic options. When conservative measures fail, rapid deactivation of the synovial tissue is imperative, and synovectomy stands out as a simple but highly effective intervention. In addition, advances in haematological care now allow the entire range of orthopaedic reconstructive procedures on the elbow to be performed safely in patients with haemophilia. In this evolving context, the role of a coordinated and specialised multidisciplinary team has become more important than ever, as it ensures the full integration of medical, rehabilitative and surgical approaches to optimise long-term joint outcomes.
Over the recent years, the introduction of nonfactor replacement (NFR) prophylaxis for haemophilia has allowed to reduce the burden of treatment and to offer effective prophylaxis also for patients with inhibitors, with an excellent successful prevention of spontaneous bleeding, often approaching a median annual bleeding rates close to 0. However, patients on NRF prophylaxis require traditional replacement treatment for breakthrough bleeds and to manage especially major surgery. Real-world experiences with the use of emicizumab are accumulating, showing excellent outcomes, while these are still significantly limited data available with rebalancing agents (concizumab, marstacimab and fitusiran). The present overview is focused on surgical procedures with nonfactor replacement prophylaxis. Review of the literature and report of personal experiences with the use of emicizumab and replacement treatment during surgery. Combined used of emicizumab prophylaxis together with factor replacement in patients with Haemophilia A with and without inhibitors provided excellent results. Multiple elective orthopaedic procedures, oral and abdominal surgical interventions, and trauma surgery confirmed the feasibility of this combined approach, without significant side effects. The association of nonfactor prophylaxis with recombinant factors has provided safe, reproducible and effective results, with low rates of complications. However, the experience with rebalancing agents is still limited, and more real-world studies are needed to confirm the most appropriate approach.
Despite available prophylactic therapies for haemophilia A, breakthrough bleeding and consequent pain and joint damage still occur. To provide insights into the unmet treatment needs of people with moderate-to-severe haemophilia A in the US. For this descriptive, observational cohort study, eligible participants diagnosed with moderate-to-severe haemophilia A were enrolled in the PicnicHealth database on or before 3 October 2022. Three patient groups were established to identify: (1) treatment patterns; (2) clinical outcomes by therapy class (standard half-life [SHL] factor VIII [FVIII]; extended half-life FVIII [EHL]; emicizumab); (3) health-related quality of life (HRQoL) using the Patient-Reported Outcomes Measuring Instruments System (PROMIS)-29 survey and a supplemental pain survey. Patients switching treatment classes were included in multiple treatment groups. Of 211 participants in the 'treatment patterns population', 123 (58.3%) used SHL FVIII prophylaxis, 81 (38.4%) EHL FVIII prophylaxis, and 83 (39.3%) emicizumab prophylaxis. In the 'clinical outcomes population', 63 participants (70.8%) receiving SHL, 43 (61.4%) EHL and 36 (62.1%) emicizumab had ≥1 bleed at Year 1. Pain-related events within the past year occurred in 18 (12.8%), 16 (18.2%) and 10 (12.2%) participants, respectively. The most frequent patient-reported symptoms were 'sleep disturbance' (84.5%), 'inability to participate in social roles and activities' (69.7%) and 'fatigue' (66.9%). The most impacted PROMIS scores were anxiety and pain interference. Regardless of the prophylaxis product class used, most participants experienced ≥1 bleeding event per year and reduced QoL. Further treatment optimisation may be needed to prevent bleeding episodes and improve patient QoL.
This article contributes to the continuing conversation in Haemophilia about the UK Infected Blood Inquiry (IBI). Discussion within the journal to date has largely foregrounded professional and technical perspectives. This article aims to bring back into view two elements central to the Inquiry-patient voice and the roles of law and ethics-and consider what this means for how the lessons of the IBI are interpreted in clinical and public discourse. The article engages with published reflections and commentary to consider how responsibility has been framed, how consent has been understood, and what is at stake in the shaping of professional memory. The article shows how narrowed framings of consent, appeals to clinical authority, and selective uses of language risk marginalising those infected and affected. It argues that such narratives continue to shape how responsibility is allocated and how the Inquiry will be remembered within professional discourse. Accountability, transparency, and recognition must remain central as the implications of the Inquiry continue to unfold, and as processes of reconciliation begin.
Current guidelines recommend prophylaxis for patients with non-severe haemophilia with severe bleeding phenotype (SBPT) but there is no consensus how to define a SBPT and when to recommend prophylaxis in patients with non-severe haemophilia. A Delphi consensus procedure among the members of the Standing Committee Hemophilia of the German, Austrian and Swiss Society of Hemostasis and Thrombosis Research (GTH) was conducted. After defining 41 statements in a steering committee, 26 haemophilia experts participated. Statements were scored on a scale of 1-9, and agreement was defined as a score of ≥ 7. Consensus was defined as ≥ 75%, and strong consensus as ≥ 95% agreement. After 3 rounds of consent, five major and three minor criteria for SBPT, five recommendations for starting long-term and six recommendations for starting intermittent prophylaxis were consented. Major criteria included life-threatening bleeding in critical regions or organs, severe bleeding that occurs spontaneously, repeatedly, or after inadequate trauma, development of haemophilic arthropathy, presence of chronic synovitis, and Hb-relevant menstrual bleeding. Long-term prophylaxis should be recommended in patients with a residual factor activity < 3 IU/dL, in patients with a residual activity > 3 IU/dL and a SBPT, following intracranial haemorrhage after assessing the individual risk of recurrence, in cases of comorbidities and medications that cause a permanently increased bleeding tendency, and in the presence of risk factors for severe bleeding or arthropathy. Consensus was reached on criteria for SBPT and recommendations to initiate prophylaxis in patients with non-severe haemophilia that can be used in daily practice.
Patient registries capture disease related information and provide a valuable source for real-world data on rare diseases and their management. The Swiss Haemophilia Registry (SHR) was established in 2015 on the basis of a new Swiss federal human research act. It includes patients with inherited bleeding disorders, namely haemophilia A and B, von Willebrand disease (VWD), other rare bleeding disorders, and platelet function disorders. To describe the bleeding disorder landscape in Switzerland. The SHR is an observational, prospective, longitudinal, multi-centre national registry. Individual patient data is collected annually and includes patient demographics, comorbidities, bleeding events and treatment. By 2023, 929 patients were included in the SHR, with 60% diagnosed with haemophilia A, 17% with haemophilia B, and 15% with VWD. The cohort was predominantly male (87%), and 75% were adults. Median follow-up was 5.8 years (IQR 3.35-7.22). The prevalence of target joints in 2023 was 2%, with no affected children. Annual inhibitor prevalence in haemophilia patients was 1-2%. The SHR illustrates clearly the transition of prophylaxis products from plasma-derived to extended half-life factor products, and non-factor products, mirroring the global treatment evolution, and trends in individualised and patient-centred haemophilia management. The SHR provides real-world evidence on haemophilia care in Switzerland and documents major improvements in treatment and patient outcomes over the past decade. Future expansion will be more inclusive of VWD, rare bleeding disorders, and specifically women with bleeding disorders. This will enhance the value of the SHR as a comprehensive national resource.
The 2021 ASH/ISTH/NHF/WFH VWD diagnosis guidelines recommend Type 1 VWD diagnoses for patients with (a) VWF <0.30 IU/mL or (b) 'Low VWF' 0.30-0.50 IU/mL with the presence of abnormal bleeding. This recommendation recategorizes 'Low VWF' patients with abnormal bleeding into Type 1 VWD. To assess the impact of the 2021 VWD guidelines on the diagnosis and management of 'Low VWF' patients. A single centre retrospective study was conducted to review all patients presenting for VWD evaluation between January 2000 to September 2024, analyzing for clinical features, ISTH-BAT scores, VWF/FVIII levels, and management of bleeding. 149 patients, totalling 305 clinical encounters, were included in the study. Seventy five percent of patient encounters had a change in diagnosis from 'Low VWF' to Type 1 VWD after applying the 2021 VWD diagnosis guidelines. The use of VWF therapy (statistically significant, p = 0.04) and antifibrinolytics (not statistically significant, p = 0.52) increased in the post-guidelines period compared to pre-guidelines period. More than half saw increasing VWF levels with age, emphasizing the need to periodically re-evaluate/re-test patients with 'Low VWF'. Applying the 2021 VWD guidelines leads to improved diagnosis and management of symptomatic patients with 'Low VWF' as they are now classified as Type 1 VWD and receive optimal care with increased use of haemostatic therapy.
Valoctocogene roxaparvovec is an adeno-associated virus vector serotype 5 (AAV5)-mediated gene therapy for severe haemophilia A (HA). Report the final safety and efficacy results of the phase 1/2 trial of valoctocogene roxaparvovec. An open-label phase 1/2 trial (NCT02576795) enrolled adult males with severe HA (factor VIII [FVIII] ≤1 IU/dL) without FVIII inhibitors, anti-AAV5 antibodies, or liver dysfunction to receive 6 × 1013 or 4 × 1013 vg/kg valoctocogene roxaparvovec. Efficacy endpoints included FVIII activity (chromogenic), annualized bleeding rate (ABR) of treated bleeds, annualized FVIII infusion rate, and quality of life. Safety was assessed by adverse events (AEs). Year seven 6 × 1013 vg/kg cohort results were reported previously. Five of six 4 × 1013 vg/kg cohort participants completed the 7-year study. Mean FVIII activity peaked within year 1 for the 4 × 1013 cohort (week 52 FVIII, 21.1 IU/dL) and decreased to 4.2 IU/dL at the end of year 7. Across all follow-up, mean ABR declined 87% from baseline to 1.6 bleeds/year and mean annualized FVIII use declined 93% to 10.3 infusions/year. Overall, 3/5 of the 4 × 1013 participants remain off prophylaxis. Haemo-QOL-A Total Score was mostly stable from baseline. The last treatment-related AE (TRAE) of alanine aminotransferase elevation occurred in year 1. No serious TRAEs occurred after year 1. No participants had thromboembolic events or developed FVIII inhibitors. Over 7 years, valoctocogene roxaparvovec increased FVIII activity from baseline and improved haemostasis compared with FVIII prophylaxis for most participants. The 6 × 1013 vg/kg dose was more efficacious than 4 × 1013 vg/kg. No concerning long-term safety signals were identified.
Intracranial haemorrhage (ICH) is the most serious complication in infants and children with severe congenital bleeding disorders causing substantial mortality and long-term neurological morbidity. The neonatal period carries the highest risk, particularly in severe haemophilia and rare factor deficiencies. We review the epidemiology, risk factors, prevention, recognition, management, and long-term outcomes of ICH in children with congenital bleeding disorders. Current evidence from cohort studies, literature reviews, and recent clinical data addressing ICH in childhood is summarized, with attention to evolving prophylactic strategies. Neonatal ICH occurs in 2%-4% of infants with haemophilia and more frequently in severe FXIII and FX deficiency. Unrecognized bleeding disorders and traumatic delivery-especially with forceps or vacuum-substantially increase risk. Immediate factor replacement prior to diagnostic imaging improves survival and reduces neurological sequelae. After the neonatal period, risk remains elevated, particularly in children <1 year not receiving prophylaxis. Early initiation of prophylaxis, historically limited by challenges with intravenous access, markedly reduces ICH incidence. Emerging non-factor therapies (FVIII mimetics and rebalancing agents) enable earlier and more effective protection. Despite advances in care, 30%-40% of survivors experience long-term neurological impairments with outcomes influenced by bleed location, cerebral shift, age at time of ICH, and treatment delays. ICH remains a major threat to children with severe bleeding disorders. Prevention requires early identification of at-risk pregnancies, careful delivery planning, and timely diagnosis of bleeding disorders. Advances in prophylactic therapy offer the potential to significantly reduce ICH incidence and improve long-term outcomes.
Inhibition of tissue factor pathway inhibitor represents an advanced rebalancing strategy for hemophilia, applicable across hemophilia A and B irrespective of inhibitor status. Although concizumab has demonstrated efficacy in clinical trials, real-world data remain very limited. To evaluate the real-world effectiveness and safety of concizumab prophylaxis in an unselected national cohort of patients treated in routine clinical practice in France. This cross-sectional observational study included all patients receiving concizumab through compassionate-use or Early Access Programs across six French hemophilia centers. Retrospective data were collected from treatment initiation to a predefined cutoff (1, December 2025). Outcomes included bleeding rates, target joint status, surgical management, laboratory monitoring practices, adherence, and adverse events. Eleven patients were included, ten with hemophilia B with inhibitors and one with hemophilia B without inhibitors. Mean exposure to concizumab was 22.8 months. Compared with the pre-treatment period, concizumab prophylaxis was associated with a marked reduction in bleeding, including complete absence of bleeding in four patients and resolution of target joints in nine of ten patients. Nine surgical procedures, including two major surgeries, were performed under concizumab prophylaxis with concomitant rFVIIa without thrombotic complications. No thrombotic events or injection-site pain were reported. None of the patients discontinued concizumab prophylaxis. In this nationwide real-world cohort, concizumab prophylaxis was effective, well tolerated, and manageable in routine practice, including during surgical procedures. These data support its use as a valuable prophylactic option in carefully selected patients with hemophilia B and inhibitors, while underscoring the importance of individualized monitoring and thrombotic risk assessment.
Acquired haemophilia A (AHA) is a rare autoimmune disorder where the development of autoantibodies to factor (F)VIII neutralise its function, leading to bleeding. Emicizumab has been approved for treating AHA in Japan. This post-marketing study was performed to primarily examine the use and safety of emicizumab, and indirectly assess effectiveness, for AHA patients in clinical practice in Japan. This post-marketing surveillance study is being conducted in patients with AHA who receive emicizumab and immunosuppressive therapy (IST). For each patient, the observation period is from the first day of emicizumab to 4 weeks after the last administration, up to 24 months. The primary endpoint is adverse events (AEs). The first 51 patients who completed the survey were included in this interim analysis; 34 (66.7%) were male, and the median (range) age was 76.0 (33-91) years. Twenty-five (49.0%) patients experienced 63 AEs (45 serious). One thromboembolism occurred: cerebral infarction, unrelated to emicizumab. Nine (17.6%) patients died, due to infection (n = 4), haemorrhage (n = 3) and 'other' (n = 2), with no causal relationship with emicizumab in any case. Excluding the Week 1 emicizumab loading dose period, 8 (15.6%) patients received recombinant FVIIa while on emicizumab. All patients received IST from Day 1 (median initial prednisolone dose: 0.93 mg/kg). Median FVIII activity (one-stage assay) reached ∼60% in the patients who completed emicizumab treatment, and continued increasing after completion. This post-marketing study confirmed that emicizumab is well tolerated in patients with AHA, with no unexpected safety concerns. The benefit-risk profile of emicizumab remains favourable.
The therapeutic landscape for haemophilia is rapidly evolving beyond traditional factor replacement to include nonfactor therapies and adeno-associated virus (AAV) gene therapy. These innovations promise effective, long-term prophylaxis with reduced treatment burden but introduce new complexities in clinical management. This review provides a comprehensive analysis of these emerging treatments, focusing on key practical challenges. For nonfactor therapies-including emicizumab, concizumab, marstacimab and fitusiran-critical considerations for bleed management, surgical procedures, and transitioning between products, emphasizing that these agents are for prophylaxis only and require specific, often product-specific, concomitant factor or bypassing agent protocols for acute haemostasis. We further examine the safety profiles of these agents, with a focus on thrombotic risk, which can arise from drug-drug interactions, an excessive procoagulant effect, or the unmasking of baseline risk factors. Immunogenicity, while less frequent than with traditional factors, remains a consideration requiring ongoing pharmacovigilance. Finally, we address the central immunogenicity challenge in AAV gene therapy: managing cytotoxic T-cell-mediated hepatotoxicity that can threaten transgene expression. The role of corticosteroid immunomodulation-both prophylactic and reactive-is explored across clinical trials for haemophilia A and B, highlighting variable responses and the need for tailored strategies. This review synthesizes current evidence to help clinicians navigate this new therapeutic era, optimizing outcomes while mitigating the risks associated with these transformative treatments.