The underevaluated impacts of the therapeutic revolution of hemophilia on women and girls.

The advent of new treatment options over the last decades has markedly improved the lives of male persons with hemophilia (PwH). However, this therapeutic revolution has not benefited women and girls with hemophilia (WGH) and symptomatic carriers of the disease to the same extent as their male counterparts. This inequity is primarily due to the exclusion of WGH from clinical trials and a failure to fully recognize their specific treatment needs. Additionally, the indirect impact of innovative therapies, when used for male PwH, on the lives of mothers, other relatives, and partners of these individuals has been largely overlooked until now. In addition to improving access of WGH and carriers to new hemostatic treatments and comprehensive hemophilia care, it is imperative to strive for alleviating the mental burden imposed on them by this chronic disease. The recently proposed concept of a "hemophilia-free mind," primarily focused on male PwH, should therefore also be applied to WGH, symptomatic carriers, and the predominantly female support network of PwH.

Postmortem diagnosis of severe factor X deficiency in a fetus with intracranial hemorrhage resulting in intrauterine death.

In patients with severe congenital factor X deficiency, spontaneous intracranial hemorrhage (ICH) is particularly frequent in early childhood. We describe a case of fetal death at 26 weeks due to massive ICH. Gene panel analysis of postmortem samples revealed homozygosity for a pathologic F10 gene variant (c.1210T>C, p.Cys404Arg), which impedes correct folding of the catalytic serine protease domain and, therefore, causes a significant reduction in FX levels. The parents, not consanguineous but of the same ethnic community, were found to be heterozygous for this variant and did not have any personal or family history of abnormal bleeding. To the best of our knowledge, this is the first reported case of severe FX deficiency resulting in ICH diagnosed through postmortem genetic analysis. It illustrates the importance of exploring the etiology of fetal or neonatal ICH, which may impact future pregnancies, and the treatment of a potential coagulopathy in the child.

Building a haemophilia-specific navigator in Epic® Electronic Health Records: Single-centre preliminary experience.

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.

How to translate and implement the current science of gene therapy into haemophilia care?

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.

Living with a "hemophilia-free mind" - The new ambition of hemophilia care?

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.

Adoption of emicizumab (Hemlibra®) for hemophilia A in Europe: Data from the 2020 European Association for Haemophilia and Allied Disorders survey.

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.

Patient selection for hemophilia gene therapy: Real-life data from a single center.

BACKGROUND: While the number of individuals with hemophilia who are expected to be or have already been included in gene therapy trials has been regularly reported, the number of unscreened or excluded individuals, in addition to the reasons for exclusion, is mostly not reported. METHODS: We conducted an eligibility assessment of all people with severe hemophilia for gene therapy trials in one large Belgian hemophilia treatment center based on patient selection criteria of gene therapy trials and patients' profiling. RESULTS: Among 87 adult patients with severe hemophilia A and B, 11 aged ≥65 years and two women were excluded from analysis. Six patients were excluded because of inhibitor development. One patient exhibited active hepatitis C infection, one had insufficient exposure to factor VIII, and five had uncontrolled comorbidities, while two were enrolled in other trials and two abused alcohol. Overall, 43 patients were not screened owing to psychosocial factors. Among 14 patients accepting gene therapy, six had adeno-associated virus type 5 neutralizing antibodies and one had liver fibrosis. The number of patients who would accept gene therapy in the absence of strict clinical trial requirements was estimated at 36 (41.4%), irrespective of any exclusion criteria. CONCLUSION: The majority of individuals with severe hemophilia could not be enrolled in gene therapy trials, almost half of them because of partly modifiable psychosocial reasons (49.4%). The proportion of candidates should substantially increase in the future, as eligibility criteria are likely to change and as more data on long-term efficacy and safety of gene therapy will become available.

Primary prophylaxis of venous thromboembolic disease with direct oral anticoagulants in patients with severe inherited thrombophilia.

Direct oral anticoagulants (DOACs) are widely used in several indications, but data on their efficacy and safety in individuals affected by severe inherited thrombophilia, yet without any personal history of thrombosis, is lacking. Severe inherited thrombophilia abnormalities, especially antithrombin deficiency, confer a higher risk of developing venous thromboembolism (VTE) than is the case in the general population. In this article, we propose primary prevention with low-dose DOACs for certain patients with severe inherited thrombophilia but without any personal history of VTE, while taking into consideration the type of thrombophilia, family history, comorbidities, and bleeding risk.

An exceptional case of severe combined inherited thrombophilia successfully treated with rivaroxaban.

: We herein report the case of a young patient who presented with premature thromboembolic venous disease secondary to combined heterozygous G20210A prothrombin mutation, dual homozygosity for Factor V Leiden, and severe protein S deficiency. This association has never been reported to date and is likely to be exceptional, even in populations wherein these thrombophilia traits are more common. Long-term antithrombotic prophylaxis with rivaroxaban has proven successful in preventing clinical recurrence under prolonged treatment.

Cerebral venous thrombosis revealing Behçet's disease in a Moroccan patient: A case report and literature review.

Behçet's disease is an inflammatory disease, the origin of which still remains unclear, and it has multiple manifestations, one of them being thrombosis. In this report, we describe the case of a 24-year-old Moroccan patient who presented with headache persisting for more than 2 weeks, which was found to be caused by cerebral venous sinus thrombosis. His medical history of recurrent oral and genital ulcerations, epididymitis and one episode of pericarditis led to the diagnosis of Behçet's disease. We could observe an almost complete relief of symptoms with colchicine therapy, and anticoagulation with warfarin was started for secondary prevention of thrombosis.