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Background: People with hemophilia often experience pain and suffer from comorbidities related to their bleeding disorder. Consequently, unemployment due to disability is prevalent among people with hemophilia. Objectives: To explore associations between unemployment due to disability and treatment while adjusting for known risk factors for unemployment. Methods: Collecting data from 20 hemophilia centers from 15 European countries, the Age-related DeVelopments ANd ComorbiditiEs in hemophilia study recruited 785 participants aged 40 years and over with hemophilia A or B. A comprehensive electronic case report form included items related to patient characteristics, demographic information, past and current treatment regimens, and medical history, including a lifelong history of comorbidities. Baseline data from the Age-related DeVelopments ANd ComorbiditiEs in hemophilia study was analyzed using descriptive statistics and logistic regression models. Results: Employment status was available for 756 of 785 participants aged 40 to 88 years (median, 53 years). We used regression analysis to compare people with hemophilia who were fully employed with those who were unemployed due to disability. This analysis included 424 participants. Using multivariable logistic regression, we found that age (odds ratio [OR], 1.07; P < .01), severe hemophilia (OR, 10.81; P < .01), current smoker (OR, 2.53; P < .01), and psychiatric disorder (OR, 4.18; P = .02) were associated with increased odds of unemployment due to disability. In contrast, prophylactic treatment (OR, 0.44; P = .01) was associated with decreased odds. Conclusion: Our analysis suggests that by maintaining factor levels above a critical threshold (3%-5%), prophylactic treatment for people with hemophilia could help avoid unemployment due to disability. While prophylaxis is more costly and can be burdensome, the benefits to material well-being and quality of life could be substantial.

Whole-genome sequencing (WGS) is revolutionizing clinical bacteriology. However, bacterial typing remains investigated by reference techniques with inherent limitations. This stresses the need for alternative methods providing robust and accurate sequence type (ST) classification. This study optimized and evaluated a GridION nanopore sequencing protocol, adapted for the PromethION platform. Forty-eight Escherichia coli clinical isolates with diverse STs were sequenced to assess two alternative typing methods and resistance profiling applications. Multi-locus sequence typing (MLST) was used as the reference typing method. Genomic relatedness was assessed using Average Nucleotide Identity (ANI) and digital DNA-DNA Hybridization (DDH), and cut-offs for discriminative strain resolution were evaluated. WGS-based antibiotic resistance prediction was compared to reference Minimum Inhibitory Concentration (MIC) assays. We found ANI and DDH cut-offs of 99.3% and 94.1%, respectively, which correlated well with MLST classifications and demonstrated potentially higher discriminative resolution than MLST. WGS-based antibiotic resistance prediction showed categorical agreements of ≥ 93% with MIC assays for amoxicillin, ceftazidime, amikacin, tobramycin, and trimethoprim-sulfamethoxazole. Performance was suboptimal (68.8–81.3%) for amoxicillin-clavulanic acid, cefepime, aztreonam, and ciprofloxacin. A minimal sequencing coverage of 12× was required to maintain essential genomic features and typing accuracy. Our protocol allows the integration of PromethION technology in clinical laboratories, with ANI and DDH proving to be accurate and robust alternative typing methods, potentially offering superior resolution. WGS-based antibiotic resistance prediction holds promise for specific antibiotic classes.

Background: Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. Objective: To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. Design: The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. Methods: This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1–5%; severe, FVIII

Deep vein thrombosis (DVT) is common in the general population, with an annual incidence of 1 to 2 per 1000 people. Inferior vena cava agenesis (IVCA) increased the risk of developing DVT and is found in approximately 5% of young adults (20-40-year-olds) diagnosed with unprovoked proximal DVT. IVCA can be caused by a defective embryological process, or be a result of intrauterine or perinatal thrombosis. Its estimated incidence in the general population ranges from 0.0005% to 1%, usually involving a partial absence of one of the four segments of the inferior vena cava (IVC). The management during the extended phase of patients with DVT associated with IVCA is not yet harmonized, as it is poorly described in the literature. Patients with IVCA are considered to be at high risk of DVT occurrence, prompting physicians to continue extended anticoagulation, often using vitamin K antagonists. In this retrospective study, we present a cohort of 11 patients diagnosed with IVCA following a DVT, who subsequently received extended treatment with a direct oral anticoagulants. These findings offer reassuring insights into the extended utilization of direct oral anticoagulants, demonstrating both antithrombotic efficacy and a favorable safety profile.

Background: The bypassing agent, activated prothrombin complex concentrate [aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA], is indicated for the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A. Objectives: To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice. Design: FEIBA Global Outcome (FEIBA GO; EUPAS6691) was a prospective, observational study. Methods: Investigators determined the treatment regimen and clinical monitoring frequency. The planned patient observation period was 4 years. Data are from the safety analysis set (patients who received ⩾1 aPCC infusion). Results: Overall, 50 patients received either aPCC prophylaxis ( n = 37) or on-demand therapy ( n = 13) at screening [hemophilia A, n = 49; hemophilia B, n = 1; median (range) age, 16.5 [2–71] years). Mean ± standard deviation overall annualized bleeding rate and annualized joint bleeding rate for patients receiving prophylaxis were 6.82 ± 11.52 and 3.77 ± 5.71, respectively, and for patients receiving on-demand therapy were 10.94 ± 11.27 and 6.94 ± 7.39, respectively. Overall, 177 and 31 adverse events (AEs) were reported in 28 of 40 and 10 of 13 patients receiving prophylaxis or on-demand therapy, respectively. Two serious AEs were considered possibly related to aPCC: acute myocardial infarction due to coronary artery embolism in one patient receiving prophylaxis. No thrombotic microangiopathy was reported. No AEs resulted in death. Conclusion: This study demonstrated the long-term, real-world effectiveness and consistent safety profile of aPCC as on-demand therapy and prophylactic treatment in patients with hemophilia and high-responding inhibitors. Trial registry: FEIBA Global Outcome Study; EUPAS6691 https://www.encepp.eu/encepp/viewResource.htm?id=32774

Background: Advances in treatment have enabled patients with haemophilia A to live longer and therefore may be subjected to comorbidities associated with ageing, in addition to disease-associated morbidities. There have been few reports to date on efficacy and safety of treatment specifically in patients with severe haemophilia A and comorbidities. Objective: To explore the efficacy and safety of damoctocog alfa pegol prophylaxis in patients with severe haemophilia A aged ⩾40 years with comorbidities of interest. Design: A post hoc analysis of data from the phase 2/3 PROTECT VIII study and its extension. Methods: Bleeding and safety outcomes were analysed in a subgroup of patients aged ⩾40 years with ⩾1 comorbidity receiving damoctocog alfa pegol (BAY 94-9027; Jivi ® ) prophylaxis. Results: Thirty-four patients with severe haemophilia A were included in this analysis, with a mean age of 49.4 years at time of enrolment. The most prevalent comorbidities were hepatitis C ( n = 33; chronic, n = 23), hepatitis B ( n = 8) and hypertension ( n = 11). Four patients had human immunodeficiency virus. All received damoctocog alfa pegol prophylaxis for the entire study [median (range) time in study = 3.9 (1.0–6.9) years]. During the main study and extension, median total annualised bleeding rates (ABRs) (Q1; Q3) were 2.1 (0.0; 5.8) and 2.2 (0.6; 6.0), respectively; median joint ABRs were 1.9 (0.0; 4.4) and 1.6 (0.0; 4.0), respectively. Mean adherence with prophylaxis schedule was greater than 95% throughout the study. No deaths or thrombotic events were reported. Conclusion: Efficacy, safety and adherence of damoctocog alfa pegol were confirmed in patients aged ⩾40 years with haemophilia A and one or more comorbidities, with data for up to 7 years supporting its use as a long-term treatment option in this group.

Background: The marine environment hosts the vast majority of living species and marine microbes that produce natural products with great potential in providing lead compounds for drug development. With over 70% of Earth’s surface covered in water and the high interaction rate associated with liquid environments, this has resulted in many marine natural product discoveries. Our improved understanding of the biosynthesis of these molecules, encoded by gene clusters, along with increased genomic information will aid us in uncovering even more novel compounds. Results: We introduce MariClus (https://www.mariclus.com), an online user-friendly platform for mining and visualizing marine gene clusters. The first version contains information on clusters and the predicted molecules for over 500 marine-related prokaryotes. The user-friendly interface allows scientists to easily search by species, cluster type or molecule and visualize the information in table format or graphical representation. Conclusions: This new online portal simplifies the exploration and comparison of gene clusters in marine species for scientists and assists in characterizing the bioactive molecules they produce. MariClus integrates data from public sources, like GenBank, MIBiG and PubChem, with genome mining results from antiSMASH. This allows users to access and analyze various aspects of marine natural product biosynthesis and diversity.

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.

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.

Abstract Background A large fraction of genes contains upstream ORFs (uORFs) in the 5′ untranslated region (5’UTR). The translation of uORFs can inhibit the translation of the main coding sequence, for example by causing premature dissociation of the two ribosomal units or ribosome stalling. However, it is currently unknown if most uORFs are inhibitory or if this activity is restricted to specific cases. Here we interrogate ribosome profiling data from three different stress experiments in yeast to gain novel insights into this question. Results By comparing ribosome occupancies in different conditions and experiments we obtain strong evidence that, in comparison to primary coding sequences (CDS), which undergo translational arrest during stress, the translation of uORFs is mostly unaffected by changes in the environment. As a result, the relative abundance of uORF-encoded peptides increases during stress. In general, the changes in the translational efficiency of regions containing uORFs do not seem to affect downstream translation. The exception are uORFs found in a subset of genes that are significantly up-regulated at the level of translation during stress; these uORFs tend to be translated at lower levels in stress conditions than in optimal growth conditions, facilitating the translation of the CDS during stress. We find new examples of uORF-mediated regulation of translation, including the Gcn4 functional homologue fil1 and ubi4 genes in S. pombe. Conclusion We find evidence that the relative amount of uORF-encoded peptides increases during stress. The increased translation of uORFs is however uncoupled from the general CDS translational repression observed during stress. In a subset of genes that encode proteins that need to be rapidly synthesized upon stress uORFs act as translational switches.

Abstract 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.

Abstract 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.

Recent advances in biomedicine are opening the door to new approaches, and treatment and prevention are being transformed by novel medicines based on genetic engineering, innovative cell-based therapies and tissue-engineered products, and combinations of a medical device with embedded cell or tissue components. These advanced therapy medicinal products (ATMPs) hold one of the keys to making a reality of genuinely personalised medicine. There are an estimated 450 companies across the globe working on the development of gene therapies and more than 1,000 clinical trials underway worldwide, and some 20–30 new ATMPs filings are expected in Europe annually over the next 5 years. But challenges confront the sector, complicating the translation from research into patient access. Scientific, clinical development and regulatory issues are compounded by limited experience with clinical and commercial use, limited manufacturing know-how, high costs, and difficulties in accessing development funding and investment. Pricing and reimbursement and market access issues are an additional challenge, particularly in Europe, where unfamiliarity with the technology and uncertainty over the use of real-world evidence induce caution among clinicians, health technology assessment bodies and payers. There is a need for a review of the suitability of the regulatory and market access framework for these products, focused development of data, public/private partnerships, and fuller collaboration governments, doctors, insurers, patients, and pharmaceutical companies. This paper makes specific recommendations for all stakeholders, ranging from early dialogue on potential products, linking of clinical data and patient registries or standardisation of control frameworks, to a comprehensive approach to evidence generation, assessment, pricing, and payment for ATMPs.

Introduction: In early 2021, the European Collaborative Haemophilia Network (ECHN) conducted a survey to determine whether the paradigms of care across the European region have changed with the introduction of novel therapies for people with hemophilia. Methods: We conducted a survey in 19 ECHN centers from 17 countries in the European region. The aim was to track recent changes in the hemophilia treatment landscape, determine the impact of these changes on hemophilia treatment centers and comprehensive care centers in the region, and to look into the future of care as applied to people with hemophilia. The survey was structured to include three key areas: demographics and organization; current challenges and opportunities; and future directions. Discussion: Our survey provides a snapshot of the current approach to hemophilia treatment that highlights a move toward preventive, rather than reactive care, but that also raises a number of key concerns related to costs and accessibility (particularly as related to novel therapies), time limitations for clinical research, and ongoing issues regarding human resources (particularly in terms of new doctors entering the field) and availability of laboratory resources as the use of novel therapies (some with unique modes of action and unusual adverse events, some with specialized monitoring requirements) becomes commonplace. Conclusion: While our survey suggests that specialized care will continue to play a central role in the management of hemophilia, the standards and protocols, as well as the centers themselves, will have to continue to evolve if they are to continue to provide the highest level of care. To meet this requirement, there is a clear need for engaging, ongoing education programs for healthcare professionals working in the field of hemophilia that can be adjusted to the changing landscape of hemophilia therapy and monitoring.

Abstract Background The Hemophilia Joint Health Score (HJHS) was developed and validated to detect arthropathy in children. Additional evidence is required to show validity in adults. We studied the convergent and discriminant construct validity of the HJHS version 2.1(HJHSv2.1) in adults with hemophilia. A secondary aim was to define age‐related normative adult HJHSv2.1 reference values. Methods We studied 192 adults with hemophilia, and 120 healthy adults in four age‐matched groups—18 to 29, 30 to 40, 41 to 50, and >50 years—at nine centers. Trained physiotherapists scored the HJHS and World Federation of Hemophilia (WFH) joint score. Health history, the Functional Independence Scale of Hemophilia (FISH), Hemophilia Activities List (HAL), and Short‐Form McGill Pain Questionnaire (SF‐MPQ) were also collected. Results The median age was 35.0 years. Of participants with hemophilia, 68% had severe, 14% moderate, and 18% mild disease. The HJHS correlated strongly with WFH score (Spearman’s rho [rs] = .95, P

Abstract Introduction Health-related quality of life evaluation is recognized as an important outcome in the assessment of boys with haemophilia. In fact, reliable health-related quality of life data are even more critical in developing countries to advocate for government agencies to develop national haemophilia care programmes. However, validated tools are not yet available in sub-Saharan African countries. Aims The purpose of this study was to complete the cultural adaptation and validation of the Canadian Haemophilia Outcomes-Kids’ Life Assessment Tool version2.0 (CHO-KLAT2.0) in Côte d’Ivoire. Methods The process included four steps: a linguistic adaptation, cognitive debriefing interviews with children and their parents, a validity assessment with the Pediatric Quality of Life Inventory (PedsQL) as a comparator, and a test-retest reliability assessment. Results The initial Ivoirian version of the CHO-KLAT2.0 was developed through a linguistic adaptation performed in close collaboration with members of the local medical team and haemophilia community. Cognitive debriefings were completed with five boys and their parents, with the final Ivoirian version of the CHO-KLAT2.0 developed in September 2017. The validation process included 37 boys with haemophilia (mean age: 11.4 years; 34 with severe and three with moderate forms of haemophilia, all treated on demand) and their parents. Among the child-reported population (n = 20), we observed a mean CHO-KLAT2.0 score of 51.3 ± 9.2; there was a moderate correlation between the CHO-KLAT2.0 and PedsQL scores (r = 0.581; p = 0.007) and an inverse correlation of the CHO-KLAT2.0 and PedsQL scores with the global rating of the degree to which the boys were bothered by their haemophilia. The mean parent proxy CHO-KLAT2.0 score (n = 17) was 53.5 ± 9.8. Among the parents, we found no significant correlation between the Ivoirian CHO-KLAT2.0 and PedsQL scores or between the parent-reported scores and the parent global ratings of bother. The test-retest intraclass correlation coefficient was 0.879 (95% CI: 0.673; 0.954) for the child-reported questionnaires and 0.880 (95% CI: 0.694; 0.955) for the proxy-reported questionnaires. Conclusions A cross-culturally adapted and validated version of the CHO-KLAT2.0 for Côte d’Ivoire is now available that enables baseline values to be obtained and intervention outcomes (namely, prophylaxis) to be measured in Ivoirian boys with haemophilia.

Background. The optimal duration of antithrombotic therapy (ATT) after patent foramen ovale (PFO) closure remains under debate. This study sought to compare the clinical outcome of patients receiving antithrombotic agents for a short (6 months) versus extended (>6 months) period after the procedure. Methods. This was a retrospective cohort study using a propensity score matching analysis on 259 consecutive patients (131 males, 43 ± 10 years) undergoing PFO closure due to cryptogenic stroke, with complete follow-up (median duration of 10 [4–13] years). The outcome was compared between patients receiving short-term (Group short, N = 88) versus extended ATT (Group long, N = 171). Results. The PFO closure device was successfully implanted in all cases, with 3% of minor complications. After propensity score matching, there were no differences between Groups short and long in the rate of stroke (0.3 vs. 0.4% patient-year, p=1.00), bleeding (2 vs. 2% patient-year, p=0.17), and device thrombosis (0.3 vs. 0.1% patient-year; p=0.60). Univariate analysis showed that short-term ATT was not associated with an increased risk of recurrent stroke (HR: 1.271 [95% CI: 0.247–6.551], p=0.775) or prosthesis thrombus (HR: 0.50 [95% CI: 0.070–3.548], p=0.72). Kaplan–Meier analysis revealed similar overall survival in Group short and long (100 vs. 99 ± 1%, respectively; p=0.25). Conclusions. Short-term (6 months) ATT after PFO closure did not impair the clinical outcome, with a preserved low rate of recurrent stroke (0.3% patient-year) and device thrombosis (0.2% patient-year) at 10-year follow-up.

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.

A man with severe hemophilia A (HA) without factor VIII (FVIII) inhibitors was admitted for total arthroplasty of his elbow. The patient was being treated with emicizumab, with his last administration given 8 days before surgery. Preoperatively, he received a bolus of 4000 international units (IU) of recombinant (r)FVIII. Throughout the operation, a continuous infusion of 4 IU/kg/h was administered and maintained over 24 hours. On the first postoperative day, the FVIII infusion rate was reduced to 225 IU/h for 4 days and stopped on the fifth day. Under this treatment, no bleeding complications occurred. Emicizumab is known to interfere with a wide range of coagulation assays, thereby challenging replacement therapy monitoring before, during, and after surgery. In this case study, we report on the assessment of FVIII levels at different time points using various reagents. We conclude that for both hematologists and non-hematology clinicians, it is crucial to be aware of emicizumab interferences with routine coagulation tests so as to avoid misinterpretation. In addition, laboratory specialists must be familiar with this treatment in order to select appropriate coagulation tests and provide rapid and reliable result interpretations.

Abstract 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.

Abstract 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.

Platelet membrane glycoprotein VI (GPVI) is increasingly recognized as an important receptor for thrombus formation and growth. Numerous arguments have been published indicating that GPVI plays a major role in thrombosis without being essential for physiological hemostasis. In humans, GPVI deficiencies are rarely reported. These are most often deficiencies occurring in the context of autoimmunity and, more rarely, genetic deficits. The purpose of this review is to compile data on the quantitative and qualitative genetic abnormalities of GPVI.

Key Clinical Message These cases of people with hemophilia (PWH) illustrate the importance of understanding the patient's expectations and desires and adapting treatment to meet these needs, in addition to traditional clinical targets. Population PK modeling and FVIII products with improved PK profiles provide the opportunity to individualize care and improve long‐term outcomes.

Abstract Background Little data is available on awareness of hemophilia carrier condition or associated bleeding risk and management in Sub-Saharan African countries. This study sought to identify hemophilia carriers in Côte d’Ivoire in order to collect data on demographics, bleeding phenotype, and laboratory results. Another purpose was to provide Ivorian hemophilia carriers with counseling on their risk of bleeding and of having children with hemophilia. A 12-month prospective study was conducted involving Ivorian hemophilia carriers recruited trough pedigree analysis pertaining to 81 hemophilia patients followed-up at the Yopougon Hemophilia Treatment Center in Abidjan. They were assessed using in-depth interviews, pedigree analysis, and laboratory testing. Results Sixty-one subjects comprising 27 obligate and 34 possible carriers were recruited. None had previously been assessed, with 64% unaware of their carrier status despite a familial history of hemophilia in 69%. The most frequently reported bleeding symptom was menorrhagia (31%). Prolonged bleeding was reported after vaginal delivery in 19.6%, post-surgery in 4.9%, and post-dental extraction in 4.9%. Only one carrier was treated with tranexamic acid, with no other hemostatic therapy recorded. The median (range) clotting FVIII was 0.85 IU/mL (0.24–1.90 IU/mL) and FIX 0.60 IU/mL (0.42–1.76 IU/mL) in hemophilia A and B carriers, respectively. HA carriers had a FVIII

Hemophilia B is a bleeding disorder caused by a deficiency of coagulation factor IX (FIX). Treatment with FIX replacement products can increase FIX activity levels to minimize or prevent bleeding events. However, frequent dosing with standard-acting FIX products can create a high treatment burden. Long-acting products have been developed to maintain bleed protection with extended dosing intervals. Recombinant factor IX–albumin fusion protein (rIX-FP) is a long-acting product indicated for the treatment and prophylaxis of bleeding events and perioperative management in adult and pediatric patients. This review outlines data from all previously treated patients in the Prophylaxis and On-Demand Treatment using Longer Half-Life rIX-FP (PROLONG-9FP) clinical trial program and summarizes real-world data evaluating the use of rIX-FP in routine clinical practice. In the PROLONG-9FP program, rIX-FP demonstrated effective hemostasis in all patients at dose regimens of up to 21 days in patients aged ≥ 18 years and up to 14 days in patients aged < 12 years. rIX-FP has a favorable pharmacokinetic profile and an excellent safety and tolerability profile. Extended dosing intervals with rIX-FP led to high levels of adherence and reduced consumption compared with other FIX therapies. Data from real-world practice are encouraging and reflect the results of the clinical trials.

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.

The protease activity in inflammatory bowel disease (IBD) and irritable bowel syndrome has been studied extensively using synthetic fluorogenic substrates targeting specific sets of proteases. We explored activities in colonic tissue from a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model by investigating the cleavage of bioactive peptides. Pure trypsin- and elastase-like proteases on the one hand and colonic tissue from rats with TNBS-induced colitis in the acute or post-inflammatory phase on the other, were incubated with relevant peptides to identify their cleavage pattern by mass spectrometry. An increased cleavage of several peptides was observed in the colon from acute colitis rats. The tethered ligand (TL) sequences of peptides mimicking the N-terminus of protease-activated receptors (PAR) 1 and 4 were significantly unmasked by acute colitis samples and these cleavages were positively correlated with thrombin activity. Increased cleavage of β-endorphin and disarming of the TL-sequence of the PAR3-based peptide were observed in acute colitis and linked to chymotrypsin-like activity. Increased processing of the enkephalins points to the involvement of proteases with specificities different from trypsin- or chymotrypsin-like enzymes. In conclusion, our results suggest thrombin, chymotrypsin-like proteases and a set of proteases with different specificities as potential therapeutic targets in IBD.

Background. Acquired hemophilia A (AHA) is a rare condition, due to the spontaneous formation of neutralizing antibodies against endogenous factor VIII. About half the cases are associated with pregnancy, postpartum, autoimmune diseases, malignancies, or adverse drug reactions. Symptoms include severe and unexpected bleeding that may prove life-threatening. Case Study. We report a case of AHA associated with bullous pemphigoid (BP), a chronic, autoimmune, subepidermal, blistering skin disease. To our knowledge, this is the 25th documented case of such an association. Following treatment for less than 3 months consisting of methylprednisolone at decreasing dose levels along with four courses of rituximab (monoclonal antibody directed against the CD20 protein), AHA was completely cured and BP well-controlled. Conclusions. This report illustrates a rare association of AHA and BP, supporting the possibility of eradicating the inhibitor with a well-conducted short-term treatment.

We here present the successful initial treatment and secondary prophylaxis of superficial venous thrombosis secondary to Behçet’s disease by a novel anticoagulant drug, rivaroxaban (Xarelto®). To our knowledge, this is the first case of using an oral direct inhibitor of FXa in this setting. Our findings are promising; the outcome was favourable without any adverse effect noted. We propose that the patients with Behçet’s disease and venous thrombosis might benefit from the advantages of the new anticoagulant drug.

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

Since 1981, the number of factor VIII units to infuse into patients with hemophilia A in order to achieve adequate circulating factor VIII levels has been calculated using the formula: [body weight(kg)×desired factor VIII increase(%)]/2, assuming a factor VIII recovery value of 2 for all patients. This study’s aim was to evaluate the impact of several morphometric parameters and various coagulation factor concentrates on factor VIII recovery. The analysis included 201 hemophilia A adults (>18 years of age) who were carefully selected from eight pharmacokinetic clinical trials using three recombinant factor VIII concentrates (Advate®, Kogenate® FS, or ReFacto AF®/Xyntha®). Regression tree analysis was used to identify factor VIII recovery predictors. The median factor VIII recovery was 2.16 for all patients. Using regression tree analysis, patients were separated into three groups on the basis of body mass index: below 20.3 kg/m2, between 20.3 and 29.5 kg/m2, and 29.6 kg/m2 or more. Each group had a significantly different median factor VIII recovery (P

In patients with haemophilia (PWH) (from Greek “blood love”), the long-term consequences of repeated haemarthrosis include cartilage damage and irreversible arthropathy, resulting in severe impairments in locomotion. Quantifying the extent of joint damage is therefore important in order to prevent disease progression and compare the efficacy of treatment strategies. Musculoskeletal impairments in PWH may stem from structural and functional abnormalities, which have traditionally been evaluated radiologically or clinically. However, these examinations are performed in a supine position (i.e., non-weight-bearing condition). We therefore suggest three-dimensional gait analysis (3DGA) as an innovative approach designed to focus on the functional component of the joint during the act of walking. This is of the utmost importance, as pain induced by weight-bearing activities influences the functional performance of the arthropathic joints significantly. This review endeavors to improve our knowledge of the biomechanical consequences of multiple arthropathies on gait pattern in adult patients with haemophilia using 3DGA. In PWH with arthropathy, the more the joint function was altered, the more the metabolic energy was consumed. 3DGA analysis could highlight the effect of an orthopedic disorder in PWH during walking. Indeed, mechanical and metabolic impairments were correlated to the progressive loss of active mobility into the joints.

Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.