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Globally, intron 22 inversions (Inv22s) of the factor VIII gene (F8) are the most frequent pathogenic variants and account for 45–50% of severe hemophilia A (SHA) cases, while intron 1 inversion (Inv1) explains 1–5% of SHA cases. The detection of both inversions by an inverse shifting-polymerase chain reaction (IS-PCR) is the first choice worldwide for the diagnosis of patients and carriers of SHA. To improve its sensitivity and reproducibility in the visualization of PCR products, we approached the IS-PCR with fluorescent capillary electrophoresis instead of agarose electrophoresis. Based on the original protocol, we modified two primers by 5'-end labeling with FAM™ fluorescent dye for the detection of the PCR products by capillary electrophoresis. Additionally, the "fast enzymes" BclI and T4-Ligase were incorporated for work saving in the genomic digestion and ligation reactions, respectively. Once we accomplished the standardization and verified the reproducibility of the modified IS-PCR method, we applied it for the diagnosis of a cohort of SHA patients and carriers. The modified IS-PCR by fluorescent capillary electrophoresis for PCR product detection is more sensitive than agarose electrophoresis. The method was also improved by using the new rapid enzymes to save time in the whole process. [ABSTRACT FROM AUTHOR]

Introduction: Valoctocogene roxaparvovec is an adeno‐associated virus vector serotype 5 (AAV5)‐mediated gene therapy approved for severe haemophilia A (HA). Aim: To report the safety and efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795). Methods: Males ≥18 years with severe HA (factor VIII [FVIII] ≤1 international unit [IU]/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti‐AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6 × 1013 vg/kg; n = 7) and 6 (4 × 1013 vg/kg; n = 6) years. Results: In the last year, one participant in each cohort reported treatment‐related adverse events (AEs): grade 1 (G1) hepatomegaly (6 × 1013), and G1 splenomegaly and G1 hepatic steatosis (4 × 1013). During all follow‐up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6 × 1013 (n = 5) and 4 × 1013 (n = 4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was ‐0.001 and ‐0.07 IU/dL/week for the 6 × 1013 and 4 × 1013 cohorts, respectively. Two participants (6 × 1013) resumed prophylaxis in year 7: one after a non‐treatment‐related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity. Conclusions: The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis. [ABSTRACT FROM AUTHOR]

Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Classical hemophilia A, an X-linked recessive disorder, is characterized by an inability to produce factor VIII in normal quantities. This condition, also leading to factor IX deficiency, underpins the bleeding disorder known as hemophilia A. Among the complications of this illness, spontaneous retroperitoneal hematoma is rare but can be associated with congenital coagulopathies such as von Willebrand disease or hemophilia A. This type of spontaneous internal bleeding has been the subject of a limited number of studies. Case Report: A 38-year-old man with a known diagnosis of hemophilia A presented to the Emergency Department exhibiting acute pain in the right lower abdomen. A computed tomography scan of the abdomen identified a rightsided retroperitoneal mass, suspected to be a hematoma. Within 7 h after admission, the patient experienced significant drops in the hemoglobin level and platelet count. He was administered packed red blood cells, fresh frozen plasma, and platelet transfusions prior to transfer to the Intensive Care Unit. There, he was treated with factor VIII and recombinant factor VIIa, coupled with stringent monitoring. Following clinical and laboratory findings and stabilization, he was discharged with specific medications, and a follow-up appointment was scheduled. Conclusions: Spontaneous retroperitoneal hematoma in patients with hemophilia A is a rare and grave emergency. This case underscores the need for precise diagnostic approaches, tailored management strategies, and vigilant surveillance to prevent and mitigate the potentially life-threatening complications associated with spontaneous hemorrhage in this population. [ABSTRACT FROM AUTHOR]

Introduction: An investigation of the suitability of reagents for measuring FVIII products in a one‐stage clotting assay (OSA) showed variations in their FVIII activity (FVIII:C). Most studies have focused on the activated partial thromboplastin time (APTT) reagent rather than FVIII‐deficient plasma (F8DP), even though the APTT‐based OSA is comprised of APTT reagents and factor‐deficient plasma. Aim: A single‐centre study was conducted to clarify variations in measurements of FVIII products in an OSA using a total of 12 reagent combinations, including four APTT reagents and three types of F8DP. Methods: FVIII:C in nine types of FVIII product‐spiked plasma was measured using an OSA with four different APTT reagents and three types of F8DP. Results: F8DP‐dependent variations were found in addition to differences derived from APTT reagents. Variations in target recovery (TR) were observed for NovoEight®, Eloctate®, and Jivi®. Reduced TR for Jivi was found only for Pathromtin SL in combination with congenital F8DP (F8DP‐3). This lower TR was not observed with alternative manufacturing lots of F8DP‐3. The reduced TR for Jivi might be related to impaired contact activation due to lower factor XI activity in F8DP‐3. Conclusion: In addition to APTT reagents, variations in F8DPs used for OSAs can also affect FVIII:C results. F8DPs as well as the APTT reagent used for OSA should be chosen with caution, and laboratories should evaluate reagents for F8DPs as they currently do for APTT reagents, especially when lot changes occur. [ABSTRACT FROM AUTHOR]

BACKGROUND Nearly half of all Americans have hypertension, and Black adults experience a disproportionate burden. Hypercoagulability may relate to hypertension risk, and higher levels of factor VIII increase thrombosis risk. Black adults have higher factor VIII and more hypertension than other groups. Whether higher factor VIII associates with incident hypertension is unknown. METHODS The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study measured certain biomarkers in a sex-race stratified sample of 4,400 REGARDS participants who attended both visits. We included BioMedioR participants, excluding those with prevalent hypertension, missing factor VIII level, or covariates of interest. Modified Poisson regression estimated risk ratios (RR) for incident hypertension by higher log-transformed factor VIII level per SD (SD of log-transformed factor VIII, 0.33). Weighting was applied to take advantage of REGARDS sampling design. RESULTS Among the 1,814 participants included (55% female, 24% Black race), the median follow-up was 9.5 years and 35% (2,146/6,138) developed hypertension. Black participants had a higher median (IQR) factor VIII level (105.6%; 87.1%–126.9%) than White participants (95.6%; 79.8%–115.9%; P  < 0.001). The age- and sex-adjusted Black–White hypertension RR was 1.45 (95% CI 1.28, 1.63). Higher factor VIII was not associated with more hypertension (final model RR 1.01; 95% CI 0.94, 1.07). CONCLUSIONS In a prospective study of Black and White adults without prevalent hypertension, factor VIII was not associated with greater hypertension risk. [ABSTRACT FROM AUTHOR]

Multiple Coagulation Factor Deficiency (MCFD) is an uncommon haematological disorder characterised by simultaneous deficiency of multiple clotting factors, which leads to an increased risk of bleeding and compromised haemostasis. The present series aimed to provide a comprehensive analysis of MCFD, shedding light on its aetiology, clinical manifestations, and potential therapeutic interventions in a case-by-case manner, highlighting the individualised treatment options that are needed for many of these cases. A prospective combined clinical and laboratory study was performed on all patients who presented with bleeding tendencies and were subsequently diagnosed with MCFD. Clinical records and laboratory data of all these patients were reviewed to identify commonalities and variations among affected individuals. Haematological assays were performed to quantify the extent of coagulation factor deficiencies. The present series identified a diverse cohort of eight individuals (2 females and 6 males) with MCFD, showcasing variability in age of onset, severity of symptoms, and potential underlying genetic mutations. Clotting factor assays revealed deficiencies of Factor V and Factor VIII (F5F8D), Vitamin K-dependent clotting factor deficiency, and failure of synthesis of clotting factors of hepatic origin. Clinically, patients presented with a spectrum of bleeding phenotypes, ranging from mild to severe, requiring tailored therapeutic strategies. The present series provides an overview of some of the presentations of MCFD, emphasising the need for a multidisciplinary approach in its diagnosis and management. Clinicians should be vigilant in recognising the varied clinical presentations of MCFD and consider genetic testing for precise diagnosis and management. [ABSTRACT FROM AUTHOR]

Introduction: Prior to the advent of recombinant factor products, the treatment of haemophilia was mainly based on the administration of direct blood products like whole blood, Fresh Frozen Plasma (FFP), and cryoprecipitates. This led to a high incidence of transfusion-transmitted infections like Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus (HIV) . Aim: To study the seroprevalence of Hepatitis B and Hepatitis C in people with haemophilia at Assam Medical College. Materials and Methods: This cross-sectional observational study was conducted at Assam Medical College, Dibrugarh, Assam on 73 haemophilia patients in the month of November 2023. Ethical clearance and informed consent were obtained. Demographic details and treatment-related history were taken, and blood samples were analysed to assess the seroprevalence of Australian antigen (HBsAg) and anti-HCV. The prevalence of Hepatitis B and C was studied with respect to the severity of the disease and treatment received. Statistical analysis was performed using Statistical Packages for Social Sciences (SPSS) version 17.0, and the level of significance was set at (p<0.05). Results: Out of the 73 patients included in the study, 62 participants (84.9%) had haemophilia A, while rest 11 (15.1%) had haemophilia B. The participants were distributed based on the severity of the disease into mild, moderate, and severe categories. Out of the 73 patients, 14 patients (19.2%), 20 patients (27.4%), and 39 patients (53.4%) belonged to the mild, moderate, and severe categories, respectively. Most of the patients belonged to the age of less than 30 years and highest number of patients in the age group of 11-20 years (35.7%). The overall positivity for Hepatitis B and C among all haemophilia patients was 1.4% and 5.5%, respectively. The prevalence of both Hepatitis B and C was higher in patients who had the severe form of haemophilia. Out of the 35 patients who received only recombinant factors, only one showed seropositivity for anti-HCV, whereas three patients were detected to be anti-HCV positive and one patient to be HBsAg positive among 38 patients who received both factors and FFP/ cryoprecipitates in their lifetime. Conclusion: Haemophilia patients are at a higher risk of developing transfusion-transmitted infections, which can cause multiple life-threatening complications. These complications can be easily prevented by early screening and early initiation of treatment. People with the severe form of the disease, especially those with a history of receiving direct blood products, are more prone to developing these infections. However, with the advent of recombinant factors, the incidence has come down. [ABSTRACT FROM AUTHOR]

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration–time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration–time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week. [ABSTRACT FROM AUTHOR]

Hemophilia A/B are caused by deficiency or lack of coagulation factors VIII (FVIII) or factor IX (FIX), respectively, in plasma. A person with hemophilia develops bleeding in the joints and muscles at an early age, which, if left untreated, leads to early arthropathy. Preventive treatment can be achieved by regular (prophylactic) administration of FVIII/FIX. In 1958, this was implemented on a small scale in Sweden with FVIII in patients with severe hemophilia A, and in those with hemophilia B in 1972 when FIX became available. However, there were problems with human immunodeficiency virus and hepatitis infection from contaminated blood products. In the 1990s, recombinant FVIII and FIX concentrates were introduced. The major remaining problems then were the development of inhibitors, and the need for a venous route for the injections in very young children. High-titer inhibitors were treated by immune tolerance induction according to a modified model of the original Bonn high-dose protocol. A central venous line, i.e., Port-A-Cath, has enabled early prophylaxis in many children with poor venous access and has enabled the early start of home treatment with adequate injection frequency. Scoring systems for X-rays, magnetic resonance imaging, and function of joints were developed early in Sweden and have been widely disseminated worldwide, partly with modifications. Extended half-life products with half-life increased three to five times have been developed, which can provide superior bleed protection when dosed once-weekly and can maintain therapeutic trough levels when administered less frequently. The ultimate prophylaxis therapy in the future may be gene therapy. [ABSTRACT FROM AUTHOR]

The management of hemophilia A has undergone a remarkable revolution, in line with technological advancement. In the recent past, the primary concern associated with Factor VIII (FVIII) concentrates was the risk of infections, which is now almost resolved by advanced blood screening and viral inactivation methods. Improving patients' compliance with prophylaxis has become a key focus, as it can lead to improved health outcomes and reduced health care costs in the long term. Recent bioengineering research is directed toward prolonging the recombinant FVIII (rFVIII) coagulant activity and synthesising higher FVIII yields. As an outcome, B-domain deleted, polyethylene glycolated, single-chain, Fc-fused rFVIII, and rFVIIIFc-von Willebrand Factor-XTEN are available for patients. Moreover, emicizumab, a bispecific antibody, is commercially available, whereas fitusiran and tissue factor pathway inhibitor are in clinical trial stages as alternative strategies for patients with inhibitors. With these advancements, noninfectious complications, such as inhibitor development, allergic reactions, and thrombosis, are emerging concerns requiring careful management. In addition, the recent approval of gene therapy is a major milestone toward a permanent cure for hemophilia A. The vast array of treatment options at our disposal today empowers patients and providers alike, to tailor therapeutic regimens to the unique needs of each individual. Despite significant progress in modern treatment options, these highly effective therapies are markedly more expensive than conventional replacement therapy, limiting their access for patients in developing countries. [ABSTRACT FROM AUTHOR]

Factor VIII and IX clotting factor concentrates manufactured from pooled plasma have been identified as potent sources of virus infection in persons with hemophilia (PWHs) in the 1970s and 1980s. To investigate the range and diversity of viruses over this period, we analysed 24 clotting factor concentrates for several blood‐borne viruses. Nucleic acid was extracted from 14 commercially produced clotting factors and 10 from nonremunerated donors, preserved in lyophilized form (expiry dates: 1974–1992). Clotting factors were tested by commercial and in‐house quantitative PCRs for blood‐borne viruses hepatitis A, B, C and E viruses (HAV, HBV, HCV, HEV), HIV‐ types 1/2, parvoviruses B19V and PARV4, and human pegiviruses types 1 and 2 (HPgV‐1,‐2). HCV and HPgV‐1 were the most frequently detected viruses (both 14/24 tested) primarily in commercial clotting factors, with frequently extremely high viral loads in the late 1970s–1985 and a diverse range of HCV genotypes. Detection frequencies sharply declined following introduction of virus inactivation. HIV‐1, HBV, and HAV were less frequently detected (3/24, 1/24, and 1/24 respectively); none were positive for HEV. Contrastingly, B19V and PARV4 were detected throughout the study period, even after introduction of dry heat treatment, consistent with ongoing documented transmission to PWHs into the early 1990s. While hemophilia treatment is now largely based on recombinant factor VIII/IX in the UK and elsewhere, the comprehensive screen of historical plasma‐derived clotting factors reveals extensive exposure of PWHs to blood‐borne viruses throughout 1970s‐early 1990s, and the epidemiological and manufacturing parameters that influenced clotting factor contamination. [ABSTRACT FROM AUTHOR]

Introduction. The SERPINE1 c.-820G (4_5), MTHFR gene variants, and unfavourably altered fibrin clot features, have been suspected to be associated with embolic stroke of undetermined source (ESUS). We investigated the SERPINE1 c.-820G (4_5) gene variants alone and coexisting with MTHFR c.665C > T and c.1286A > C gene variants in relation to thrombophilic factors and plasma fibrin clot properties in Polish patients with ESUS. Patients and methods. Unrelated consecutive patients with ESUS (n = 206) were genotyped by TaqMan assay. Thrombophilia screening was performed four weeks or more after a thrombotic event while off oral anticoagulation. Factor VIII (FVIII) activity was determined by a coagulometric assay, while lipoprotein(a) was determined using immunoturbidimetry. We determined fibrin clot permeability (Ks) and clot lysis time (CLT). Apparently healthy individuals without a family history of stroke or venous thromboembolism (n = 30), and patients with a history of atrial fibrillation (n = 25) or carotid artery disease-related stroke (n = 21), served as controls. Results. Among ESUS patients, the SERPINE1 c.-820G (4_5) minor allele frequency was 0.57. There were no differences in common factors associated with thrombophilia among ESUS patients regarding SERPINE1 variants. The overall prevalence of FVIII > 150IU/dL was 26% (n = 53) and elevated FVIII predominated in SERPINE1 variants carriers (n = 45; 84.9%), including 36 (68%) carriers of MTHFR variant. Moreover, 4.3-fold higher Lp(a) levels along with 50% reduced Ks and 46% prolonged CLT were found in patients with mutant SERPINE1 combined with mutant homozygotes in the MTHFR c.665C > T variant compared to the wild type SERPINE1 combined with mutant homozygotes in the MTHFR c.665C >T (P < 0.001). Conclusions. The SERPINE1 c.-820G (4_5) variants carriers have increased FVIII levels, while the SERPINE1 c.-820G (4_5) mutant homozygotes coexisting with MTHFR c.665C > T have more prothrombotic fibrin clot features and elevated Lp(a). Our study underlines the cumulative effect of genetic risk factors in patients with ESUS that might require specific antithrombotic therapy. [ABSTRACT FROM AUTHOR]

Introduction: Web‐Accessible Population–Pharmacokinetic Service–Haemophilia (WAPPS‐Hemo) data are available to study factor‐concentrate usage, defined as the required weekly dose to achieve a 3% trough (WD3T), across standard and extended half‐life (SHL/EHL) products. Aim: To provide baseline usage data including (i) differences across plasma‐derived (pdSHL) versus recombinant (rSHL) products, (ii) SHL versus EHL, and (iii) effect of age and positive inhibitor history. Methods: PK profiles (n = 14,416 patients, 0.3–85.2 years) and linear mixed effects models were used to estimate usage versus age, controlling for significant factors, using 95% confidence intervals to perform comparisons across all ages and posthoc tests to assess the differences. Results: Average usage was significantly higher for pdSHL versus rSHL in patients with a positive inhibitor history (PIH; 1.9–2.5 times higher), for SHL versus EHL (4–10 times), and was significantly associated with age. Conclusion: Baseline usage patterns from 2017 to early 2023 provide a benchmark for assessing the impact of emerging technologies in haemophilia. [ABSTRACT FROM AUTHOR]

Introduction: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear. Aim: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real‐world setting. Methods: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures. Results: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0–30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0–4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0–12.0) and 4.2 (3.0–6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures. Conclusion: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full‐dose emicizumab is ill affordable. [ABSTRACT FROM AUTHOR]

Introduction: Studies of treatment preferences in haemophilia have been conducted in many countries. This study is the first to examine treatment characteristic preferences among people with haemophilia (PWH) and their caregivers, and physicians in Japan. Aim: To examine current treatment preferences of PWH and their caregivers, plus those of physicians at haemophilia treatment centres (HTCs) and non‐HTCs for different treatment characteristics in Japan. Methods: Physicians listed on a survey panel were invited to participate in the survey and to refer PWH and caregivers to participate in the survey. Web‐based surveys were conducted to examine physician and PWH/caregiver background, prophylaxis background, prophylaxis goals, understanding of haemophilia treatment products, important information sources, preferences while choosing prophylaxis products, understanding of the patient's condition, and potential product switching. A discrete choice experiment exercise was included in the survey. Results: A total of 107 physicians and 44 PWH/caregivers participated in the study. Key treatment goals of physicians included optimisation of haemophilia management. PWH/caregivers were focused on quality of life and reduced treatment burden. Consistent differences in haemophilia treatment strategies at HTCs and non‐HTCs were observed for prescribed treatments, preferences in choosing prophylaxis products, understanding of patients' condition, and reasons for potential product switch. Conclusion: Our study utilises real‐world survey data and presents preferences for haemophilia treatment characteristics among physicians, PWH and their caregivers in Japan, which could encourage improvements in individualised treatment and disease management. Alignment between treatment approaches at HTCs and non‐HTCs could facilitate improvements in the quality of care for PWH across Japan. [ABSTRACT FROM AUTHOR]

Background: Mesenteric arterial thrombosis is an extremely rare thrombotic event, especially during pregnancy, that can cause rapid fatal consequences unless the patient receives early definitive treatment. Case presentation: We report the case of a 34-year-old female presenting in her seventh week of gestation with severe abdominal pain who was promptly diagnosed with mesenteric artery occlusion amidst incipient miscarriage. The patient underwent a successful mesentery artery embolectomy, recovered and was later diagnosed with elevated factor VIII activity. Conclusion: The diagnosis of mesenteric ischemia should be considered in pregnant women presenting with severe abdominal pain and any prior predisposing factors. Our case highlights the pivotal role of the emergency physician in maintaining a high index of suspicion coupled with timely and determined action. The prognosis of this high mortality condition depends on prompt diagnosis, early definite management and successful multidisciplinary cooperation. [ABSTRACT FROM AUTHOR]

Introduction: A prospective, non-interventional study (270-902) followed 294 adults with severe hemophilia A (SHA) receiving prophylactic factor VIII (FVIII). From these participants, 112 rolled over into a single-arm, multicenter, phase 3 trial (GENEr8-1; NCT03370913) that evaluated efficacy and safety of valoctocogene roxaparvovec, a gene therapy that provides endogenous FVIII in individuals with SHA. Participants from 270-902 who did not roll over provide an opportunity for a contemporaneous external control. Therefore, the comparative effectiveness of valoctocogene roxaparvovec vs FVIII prophylaxis was evaluated using propensity scoring (PS). Methods: This post hoc analysis compared 112 participants from GENEr8-1 (treated cohort) to 73 participants in 270-902 who did not enroll in GENEr8-1 (control cohort). The primary analysis used standardized mortality ratio weighting to re-weight baseline characteristics of the control cohort to better match the treated cohort. Mean annualized bleeding rates (ABR) for treated and all bleeds were compared between cohorts along with the proportion of participants with zero bleeds (treated and all bleeds). Sensitivity and scenario analyses were also conducted. Results: PS adjustments reduced differences in baseline characteristics between cohorts. Mean treated (4.40 vs 0.85; P < 0.001) and all (5.01 vs 1.54; P < 0.001) ABR were significantly lower, and the proportions of participants with zero treated bleeds (82.1% vs 32.9%; P < 0.001) and all bleeds (58.0% vs 28.5%; P < 0.001) were significantly higher in GENEr8-1. Conclusions: PS-adjusted analyses were consistent with prior intra-individual comparisons. Compared with participants receiving prophylactic FVIII, the participants receiving valoctocogene roxaparvovec experienced lower ABR, and a higher proportion had zero bleeds. Trail Registration: ClinicalTrials.gov identifier, NCT03370913. Plain Language Summary: Hemophilia A is a bleeding disorder where blood is unable to clot properly because of a missing protein called factor VIII (FVIII). Individuals with hemophilia A have an increased risk of prolonged bleeding episodes that can be deadly. To prevent bleeding, people with severe hemophilia A need to routinely inject treatment into the skin or vein (prophylaxis). While effective, some people find the time and effort needed to maintain frequent injections difficult, since some forms of the prophylaxis must be administered in a hospital setting. Valoctocogene roxaparvovec is a gene therapy where a single injection provides instructions to the liver of individuals with hemophilia A to make the missing protein (FVIII). Then, their own liver cells can produce FVIII protein and prevent bleeding episodes. The valoctocogene roxaparvovec clinical trial compared the number of treated bleeding episodes participants had prior to gene therapy, while using prophylaxis, with the number of treated bleeding episodes after gene therapy. On average, after gene therapy, participants had 4.1 fewer treated bleeding episodes per year. In this study, mathematical models were used to explore how differences in participant's physical characteristics, such as body weight or medical history, might influence the effectiveness of gene therapy. Even when considering differences in the participants' physical characteristics, the gene therapy reduced treated bleeding episodes by 3.6 events per year. This study confirms results originally presented from the valoctocogene roxaparvovec clinical trial and reinforces confidence in the ability of valoctocogene roxaparvovec to reduce bleeding outcomes for participants with hemophilia A. [ABSTRACT FROM AUTHOR]

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

Introduction: Consensus over the definition of recombinant factor VIII (rFVIII) product classification in haemophilia A is lacking. rFVIII products are often classified as standard half‐life (SHL) or extended half‐life (EHL); despite this, no universally accepted definition currently exists. One proposed definition includes half‐life, area under the curve, and technology designed to extend half‐life; however, the International Society on Thrombosis and Haemostasis defines activity over time as the most intuitive information for building treatment regimens and the World Federation of Hemophilia describes rFVIII product classification in terms of infusion frequency. Aim: To summarise published data on the clinical and pharmacokinetic criteria used to define rFVIII product classification. Methods: PubMed and EMBASE database searches of English‐language articles (2002–2022) were conducted using search strings to identify the relevant population, intervention, and outcomes (e.g., clinical and pharmacokinetic parameters). Articles then underwent title/abstract and full‐text screens. Results: Among 1147 identified articles, 62 were included. Half‐life was the most widely reported outcome with no clear trends or product groupings observed. No clear groupings emerged among other outcomes, including infusion frequency, consumption, and efficacy. As activity over time was reported in few articles, further investigation of its relevance to rFVIII product classification is warranted. Conclusion: The findings of this systematic literature review suggest that parameters other than half‐life might be important for the development of a comprehensive and clinically relevant rFVIII product classification definition. There seems to be an opportunity to consider parameters that are clinically meaningful and useful for shared decision‐making in haemophilia A treatment. [ABSTRACT FROM AUTHOR]

Background: The healthcare systems in Asia vary greatly due to the socio‐economic and cultural diversities which impact haemophilia management. Methods: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. Findings: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under‐diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. Conclusion: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi‐stakeholder involvement are needed. [ABSTRACT FROM AUTHOR]

Recent advancements have focused on enhancing factor VIII half-life and refining its delivery methods, despite the well-established knowledge that factor VIII deficiency is the main clotting protein lacking in hemophilia. Consequently, both viral and non-viral delivery systems play a crucial role in enhancing the quality of life for hemophilia patients. The utilization of viral vectors and the manipulation of non-viral vectors through targeted delivery are significant advancements in the field of cellular and molecular therapies for hemophilia. These developments contribute to the progression of treatment strategies and hold great promise for improving the overall well-being of individuals with hemophilia. This review study comprehensively explores the application of viral and non-viral vectors in cellular (specifically T cell) and molecular therapy approaches, such as RNA, monoclonal antibody (mAb), and CRISPR therapeutics, with the aim of addressing the challenges in hemophilia treatment. By examining these innovative strategies, the study aims to shed light on potential solutions to enhance the efficacy and outcomes of hemophilia therapy. [ABSTRACT FROM AUTHOR]

Introduction: Intracranial hemorrhage (ICH), a serious complication in persons with hemophilia A (PWHA), causes high rates of mortality and morbidity. Identified ICH risk factors from patient data spanning 1998– 2008 require reassessment in light of changes in the current treatment landscape. Aim and methods: PWHA identified in the ATHNdataset were evaluated retrospectively to assess incidence of ICH and determine the association between ICH risk and key characteristics using time-to-event analyses (Cox proportional-hazards models, survival curves, and sensitivity analyses). Results: Over a median follow-up time of 10.7 patient-years, 135 of 7837 PWHA over 2 years of age in the ATHNdataset (1.7%) experienced an ICH. Stratification by prophylaxis status and inhibitor status resulted in an incidence rate (IR) ratio (IRR) (IR+/IR−) of 0.63 (95% confidence interval [CI], 0.43– 0.94; P=0.020) and 1.76 (95% CI, 0.97– 3.20; P=0.059), respectively. Characteristics associated with greater risk of developing ICH include being aged 2– 12 years; being covered by Medicaid; having had HIV, hepatitis C, or hypertension; and never having received factor VIII or prophylactic treatment. In multivariable analysis with interaction, the estimated hazard ratio for PWHA never receiving prophylaxis was 7.67 (95% CI, 2.24– 26.30), which shrunk to 2.03 (95% CI, 1.30– 9.12) in bootstrapping analysis and 3.09 in the highest-penalty ridge-regression analysis but was still significant. Inhibitor status was found not to be statistically associated with ICH in all analyses. Conclusion: These results align with previous studies demonstrating that prophylaxis confers a protective effect against ICH. Previously, inhibitor positivity had been shown to increase risk for ICH; however, this study did not corroborate those findings. [ABSTRACT FROM AUTHOR]

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti‐haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective. [ABSTRACT FROM AUTHOR]

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear‐cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non‐factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person‐centred, holistic, multi‐disciplinary approach to support and optimise long‐term physical functioning and overall quality of life. [ABSTRACT FROM AUTHOR]

Introduction: After decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several other clinical programs testing adeno‐associated viral (AAV) vector gene therapy are at various stages of clinical testing. Discussion: Multiyear follow‐up in phase 1/2 and 3 studies showed long‐term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low‐grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long‐term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non‐viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B. Conclusions: AAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy. [ABSTRACT FROM AUTHOR]

Introduction: The advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development. Discussion: More recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life‐threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non‐factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors. Conclusion: This review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors. [ABSTRACT FROM AUTHOR]

Background: Low-dose pharmacokinetic (PK)-guided extended half-life (EHL) factor VIII (FVIII) prophylaxis can reduce the bleeding risk in hemophilia A (HA) patients. An increase in physical activities for promoting musculoskeletal health may enhance the benefits of prophylactic therapy. Objectives: To determine the clinical impact of moderate- to vigorous-intensity physical activities in HA patients during low-dose PK-guided EHL FVIII prophylaxis. Patients/Methods: This prospective study enrolled patients with moderate/severe HA (baseline FVIII levels ≤ 5 IU/dL) who had received low-dose PK-guided EHL FVIII prophylaxis for ≥ 6 months. An individualized exercise protocol was introduced to each participant, targeting a 65% increase in the maximum predicted heart rate for ≥ 150 min/week, while continuing low-dose PK-guided EHL FVIII prophylaxis for 6 months. Before and after implementing the intervention, annualized bleeding rates (ABR), annualized joint bleeding rates (AJBR), Hemophilia Joint Health Scores (HJHS), skeletal muscle mass, hemophilia-specific quality-of-life (QoL) scores and annualized FVIII consumption were compared. Results: Of 13 participants (mean age ± standard deviation [SD]: 20.1 ± 6.8 years), ABR, AJBR, and HJHS were significantly reduced (mean differences [MD] ± SD: −5.7 ± 2.6 bleeds/year, −4.2 ± 2.6 joint bleeds/year, and −4.3 ± 3.2 marks, respectively; P < 0.05) after applying the 6-month exercise protocol. Skeletal muscle mass and QoL scores had also improved (P = 0.001), while FVIII usage had decreased (MD ± SD: −129.1 ± 208.7 IU/kg/year; P < 0.05). Conclusions: The combination of moderate- to vigorous-intensity physical activities with low-dose PK-guided EHL FVIII prophylaxis improves bleeding prevention, musculoskeletal status and QoL in patients with moderate/severe HA. By minimizing FVIII consumption, this strategy helps optimize hemophilia care in countries with budget constraints. ClinicalTrials.gov NCT05728528. [ABSTRACT FROM AUTHOR]

Objectives: Anti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including nonneutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities. Methods: All persons with hemophilia A (mild (FVIII > 5-40 IU/dL)/moderate [FVIII 1-5 IU/dL)/severe (FVIII < 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA). Results: In total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24-60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor. Conclusion: In this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIIIspecific antibodies is associated with clinically relevant inhibitors. [ABSTRACT FROM AUTHOR]

Cerebral venous sinus thrombosis (CVST) has no identified cause in 15% of cases. Elevated factors (F) VIII and FXI have been associated with thromboembolism, but data on CVST are limited. We hypothesized that elevated plasma FVIII and FXI predispose to first and recurrent CVST. In 50 CVST survivors aged < 60 years, following anticoagulant cessation and in 50 controls, we determined plasma FVIII and FXI, along with fibrin clot properties: lysis time, permeability, maximum D-dimer (D-Dmax), and maximum rate of D-dimer increase (D-Drate). We recorded CVST recurrence during a follow-up of 58.5 (55.0–60.0) months. Plasma FVIII was 22.7% higher in CVST than in controls, with elevated FVIII > 150% in 13 (26%) vs. 4 (8%) patients, respectively (p = 0.02). Median FXI tended to be higher in CVST vs. controls (110.5 [99.0-117-0]% vs. 104.5 [97.0-116.0]%, p = 0.07), while FXI > 120% was observed more commonly in the former group (12 [24%] vs. 4 [8%], respectively, p = 0.03). Patients with FVIII > 150% were less likely to achieve complete recanalization compared with the remainder (2 [15.4%] vs. 28 [75.7%], respectively; p < 0.001). Eight patients (16%) experienced CVST recurrence. They had higher baseline FXI, but not FVIII, as compared with the remainder (125.5 [114.5–140.0]% vs. 107.5 [102.0-117.0]%, respectively, p = 0.01). Patients with FXI > 120% were four times more likely to have recurrent CVST (5 [62.5%] vs. 7 [16.7%], respectively; p = 0.01). Plasma FXI > 120% could represent a novel risk factor for first and recurrent CVST. Given advances in anti-FXI agents, CVST might be another indication for this emerging treatment. [ABSTRACT FROM AUTHOR]

Introduction: The increased life expectancy of patients with haemophilia A (HA) has led to a growing prevalence of cardiovascular risk factors and events. There is still scarce evidence on the safety and appropriate duration of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) in HA patients. Aim: We describe our experience on the clinical management of Italian HA patients after ACS. Methods: Nine patients with congenital HA treated with DAPT after a revascularization procedure performed for ACS have been enrolled and followed at the Angelo Bianchi Bonomi Haemophilia and Thrombosis Center in Milan between 2005 and September 2022. The safety and efficacy of DAPT with or without FVIII prophylaxis were assessed. Results: Ten ACS events occurred in the nine HA patients (four mild and five severe). All events were treated with percutaneous transluminal coronary angioplasty with deployment of 1 to 3 drug‐eluting stents followed by DAPT for 1–12 months. All patients except one were treated with FVIII prophylaxis during DAPT aimed at achieving FVIII trough levels ≥20–30 IU/dL. DAPT was effective in all cases in preventing early ACS recurrence, with only a late recurrence. We observed two clinically relevant non‐major bleeds (one in a patient without FVIII prophylaxis) and three minor bleeds. No venous thrombosis occurred. Conclusion: The long‐term secondary antithrombotic prevention consisting of DAPT and FVIII prophylaxis achieving a trough level of 20–30 IU/dL can be effective and safe in HA patients. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant porcine factor VIII (rpFVIII; susoctocog alfa) is predicted to provide functional FVIII activity in patients with congenital haemophilia A with inhibitors (CHAWI). Aims: To evaluate the efficacy and safety of rpFVIII in patients with CHAWI undergoing invasive procedures. Methods: This phase 3, multicentre, single‐arm, open‐label study (NCT02895945) enrolled males aged 12–75 years with severe/moderately severe CHAWI who required surgical/invasive procedures. Patients received a loading dose of rpFVIII 1–2 h before surgery. The primary outcome was the proportion of all procedures with a 'good' or 'excellent' response (treatment success) on the global haemostatic efficacy assessment score. Results: Of the eight dosed patients, five completed the study. Six of seven surgeries (85.7%; 95% confidence interval, 42.1–99.6) achieved treatment success; five were rated 'excellent', one was rated 'good'. Seven surgery‐related bleeding episodes occurred in three patients during the study, with none requiring additional surgical intervention. Overall, six of eight patients experienced 17 treatment‐emergent adverse events. Three patients developed de novo inhibitors to rpFVIII. Five patients reported anamnestic reactions, three to both human (h) FVIII (i.e., alloantibodies to exogenous FVIII detected with anti‐hFVIII assays) and rpFVIII, and two to hFVIII only. Four serious adverse events were considered related to rpFVIII (three anti‐rpFVIII antibody positive; one anamnestic reaction to hFVIII and rpFVIII). Conclusion: Good haemostasis was achieved with rpFVIII during the immediate perioperative period. The study was terminated early because the study sponsor and health authorities determined that the risk of anamnestic reactions outweighs the benefits in this study population. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant porcine FVIII (rpFVIII) (Obizur, Susoctcog‐alfa, Takeda, Japan) is licensed for the treatment of bleeding in acquired Haemophilia A (AHA). The summary of product characteristics state that monitoring should be by one stage assay (OSA) rather than chromogenic assay (CSA). CSA have been shown to underestimate activity when rpFVIII is added to plasma in vitro. Methods: Samples from three AHA patients (n = 21) (pre‐ and post rpFVIII) were assessed using FVIII:C assays; OSA methods: Actin, Actin FS, Actin FSL and Pathromtin SL performed on CS5100i (Sysmex, Kobe, Japan); APTT‐SP, SynthASil and SynthAFax performed on ACL TOP (Werfen, Barcelona, Spain). CSA methods on CS5100i: Siemens Chromogenic Assay, Biophen FVIII:C, Technochrom FVIII:C; on ACL TOP: Rox Factor VIII, Coamatic Factor VIII and CRYOcheck Factor VIII. Results: OSA and CSA varied according to reagent used median OSA 61 IU/dL (range 41.5–81 IU/dL (ANOVA p < 0.0001)) median CSA 46.5 IU/dL (range of method specific medians 36.5–84 IU/dL (ANOVA p < 0.0001)). Amongst OSA, Actin FS was associated with the highest FVIII:C, APTT‐SP was associated with the lowest. Variation in CSA results by different methods was also seen with highest FVIII:C levels obtained using the Technochrom FVIII:C and the lowest levels obtained with Siemens Assay. Conclusion: The relationship between OSA and CSA was not consistent between method or patient. Previously there has been reports of underestimation by CSA in in vitro spiked samples. Investigation into concentration of phospholipids in the APTT reagents may explain some of these variations. [ABSTRACT FROM AUTHOR]

Purpose: To report a rare case of acute renal vein thrombosis (RVT) that was treated with endovascular thrombectomy and lysis, and discuss potential etiology and indications for catheter-directed management. Case report: A 21-year-old female athlete presented with sudden pain in her left flank and vomiting. A 3-phase computed tomography (CT) angiogram identified total occlusion of the left renal vein with no excretion from the swollen tender left kidney. Catheter-directed thrombolysis and thrombectomy were initiated 24 hours after onset of symptoms. Complete resolution of the RVT with normalized renal function was achieved. Post-operative Doppler ultrasound scan confirmed normal renal resistance and flow in the renal vein. The patient was discharged on Apixaban and remains well at 6 months. Combined hormonal contraception via an intra-vaginal ring and raised Factor VIII activity were the only identified risk factors. Conclusion: Acute complete RVT with impaired kidney function is rare. Combined hormonal contraception and increased Factor VIII activity were potential risk factors. Endovascular thrombectomy and lysis restored renal perfusion and function, and can be used effectively in the management of fit patients with acutely compromised kidney function from total renal vein obstruction. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Acquired hemophilia A (AHA) can present as life‐threatening bleeding during the postpartum period. Prompt treatment allows patients with AHA to achieve complete remission and have normal subsequent pregnancies. Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the production of autoantibodies against factor VIII (FVIII). AHA can present with severe bleeding, especially in postpartum patient. We report a 38‐year‐old woman who presented in an emergency department with severe postpartum hemorrhage 2 weeks after cesarean section. Her investigation showed an isolated prolongation of partial thromboplastin time (PTT), low factor VIII assay and a factor VIII inhibitor test, resulting in abnormal Bethesda units which consistent with AHA. This case report highlights the importance of early diagnosis and treatment of AHA. With timely and appropriate management, most patients can achieve a good outcome. [ABSTRACT FROM AUTHOR]

Prophylaxis is the gold standard for the management of hemophilia A patients. It has been shown that prophylaxis regulated with pharmacokinetic (PK) data reduces frequency of bleeding and cost of treatment. To determine the best prophylaxis regimen, PK dosing tools using the Bayesian method have been developed. We aimed to compare two PK dosing tools. Blood samples were drawn before, 4, 24, and 48 h after FVIII infusions from patients with severe hemophilia A and inhibitor negative. FVIII levels were measured by PTT-based one-stage assay method. PK parameters obtained using WAPPS and myPKFiT, which are web-accessible PK dosing tools using Bayesian algorithm, and daily prophylaxis dose estimated by the programs were compared. Forty-two hemophilia A patients [median age 13 years (IQR 8.9–16.4)] included in the study. There was no difference between the daily dose of FVIII given for prophylaxis and the dose recommended by the myPKFiT for the 1% trough level; whereas, a significant difference was found with the WAPPS. The half-lives of FVIII did not differ between the two dosing tools; however, significant differences were found in the estimated dose, clearances, and times to 1% trough level. There was no significant difference between PK data of patients who received Advate® and those who received non-Advate® factor concentrates. Choice of PK dosing tool can affect recommended FVIII dose. However, target trough levels should be individualized according to bleeding phenotype and daily activity of patient. [ABSTRACT FROM AUTHOR]

Introduction: The genetic variant responsible for haemophilia A (HA) significantly impacts endogenous coagulant factor VIII (FVIII:C) level, thus impacting DDAVP responsiveness. Blood group (BG) also impacts FVIII:C levels, but this is difficult to evaluate in a genetically heterogeneous population. Canada has a large cohort of mild‐moderate HA due to a single point variant: c.6104T>C, p.Val2035Ala—the Twillingate variant. Aim: To evaluate the impact of BG on endogenous FVIII:C levels and DDAVP responsiveness in a single genotype of mild‐moderate HA. Methods: This was a retrospective, single‐centre study. BG and FVIII:C levels were obtained for males with the Twillingate variant. One‐hour absolute and fold increases in FVIII:C post‐DDAVP were calculated. T‐tests and Mann–Whitney U tests were used to compare FVIII:C levels and DDAVP challenge variables between individuals according to BGs (O vs. non‐O). Results: Twenty males were included. There were significant differences between BGs (O vs. non‐O) in their lowest FVIII:C level at age <12 years (medians: 0.05 vs. 0.08 IU/mL; P =.05). Fifteen subjects underwent DDAVP challenges. Mean 1‐h FVIII:C were 0.29 (O BG) versus 0.41 IU/mL (non‐O BG); P =.04. There were no significant differences between BGs (O vs. non‐O) in mean absolute FVIII:C increase (0.20 vs. 0.27 IU/mL; P =.10) and FVIII:C fold increase (3.3‐fold vs. 3.8‐fold; P =.51). Conclusion: In HA subjects with an identical genotype, BG significantly impacts baseline FVIII:C levels and FVIII:C levels post‐DDAVP, but does not impact absolute and fold increases in FVIII:C with DDAVP. [ABSTRACT FROM AUTHOR]

Introduction: Patient‐reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under‐reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen. Aim: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA. Methods: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses. Results: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended‐half‐life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health‐related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores. Conclusion: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real‐world practice with ≤1 year's follow‐up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well‐being. [ABSTRACT FROM AUTHOR]

Introduction: With recent approval of the first two gene therapies for haemophilia A and B, educational materials about AAV‐based gene therapy are needed by the haemophilia community for a better understanding of this novel therapeutic approach and helping healthcare providers and patients making personalized choices amongst an increasing array of therapeutic options. Aim: To provide a comprehensive summary of the whole process of AAV‐based gene therapy from basic principles to clinical implementation through an illustrated review. Methods: The authors, with expertise in and knowledge about gene therapy for haemophilia A and B, reviewed relevant articles from PubMed database and translated them into illustrations. Results: The review is divided into eight illustrated sections providing an overview of gene therapy for haemophilia A and B from haemophilia basics and current treatment landscape, principles of the AAV‐based liver‐directed gene therapy, through exploring the efficacy and safety results of published phase III clinical trials, current and future challenges, to implementation in clinical practice, including the hub and spoke models and the patient journey. Conclusion: This illustrated review educates healthcare professionals on AAV‐based gene therapy for haemophilia A and B enabling them to further educate their peers and their patients. [ABSTRACT FROM AUTHOR]

Introduction: Regular, prophylactic intravenous (i.v.) FVIII can be challenging for some patients with haemophilia A. Subcutaneous (s.c.) FVIII administration could provide an alternative treatment option with greater convenience and without the complications associated with venous access. Aim: To assess the safety, pharmacokinetics (PK), bioavailability and efficacy of s.c. OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer. Methods: This was a single‐centre, prospective, open‐label, phase I/II study (NCT04046848). Previously treated male patients (≥18 years) with severe haemophilia A were eligible for the study. The primary objective of the study was to assess the safety (including immunogenicity) of OCTA101. Secondary objectives included assessments of PK, bioavailability, and the efficacy of prophylaxis. Results: Thirty patients were treated with OCTA101. FVIII inhibitors developed in five (16.7%) patients during daily prophylaxis with 40–60 IU/kg (three cases) and 12.5 IU/kg (two cases) OCTA101. The trial was therefore terminated. OCTA101 had a 2.5‐fold longer terminal half‐life compared with i.v. rFVIII, and bioavailability was 16.6%. Efficacy data at study termination indicated that daily prophylaxis with 40–60 IU/kg OCTA101 was efficacious in the absence of FVIII inhibitors. Conclusions: Despite promising PK and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors. The occurrence of inhibitors at two dose levels suggests that their development may be related to the subcutaneous route of administration. [ABSTRACT FROM AUTHOR]

Introduction: Patients with hemophilia A treated with coagulation Factor VIII (FVIII) products are at risk for developing anti‐FVIII antibodies. The ABIRISK Consortium aimed to provide knowledge on the formation and detection of anti‐drug antibodies against biopharmaceutical products, including FVIII. Accordingly, standardized and validated assays for the detection of binding (total) and neutralizing antibodies are needed. Aim: Two‐center validation of an ELISA for the detection of total FVIII‐binding IgG‐antibodies and Nijmegen‐Bethesda assays for the quantification of FVIII‐neutralizing antibodies according to consensus validation guidelines. Methods: Validation of assays at both sites was done according to published recommendations and included preanalytics, the determination of key assay parameters, including cut‐points, assay sensitivity, precision, and FVIII interference. Results: The validated assays reproducibly detected FVIII‐binding and ‐neutralizing antibodies with comparable performance in both laboratories. Floating screening cut‐points were established for both assays. Determined mass‐based sensitivity of both assays (all values ≤66 ng/mL) complied with the minimum sensitivity for the detection of anti‐drug antibodies as recommended by the FDA (<100 ng/mL). Intra‐ and inter‐assay coefficients of variation did not exceed 25%. Assay validation further revealed that pre‐analytical heat treatment led to potentially false‐positive ELISA results, while up to 0.15 IU/mL, residual FVIII showed no significant impact. Overall, good agreement of results was found for patient samples analyzed at both study sites. Conclusion: Comprehensive validation of different anti‐FVIII‐antibody assays in two laboratories gave novel insights into the impact of pre‐analytical sample treatment as well as the comparability of test results generated by the use of methodically different assays. [ABSTRACT FROM AUTHOR]

Introduction: Several well‐established clinical laboratory methods are available to measure von Willebrand factor (VWF) in plasma samples, but few data are available on their use for analysing recombinant VWF (rVWF). Aim: To evaluate how clinical diagnostic laboratories analyse rVWF and plasma‐derived VWF (pdVWF) spiked in vitro into VWF‐deficient plasma using quantitative protein and functional assays of VWF. Methods: Human VWF‐deficient plasma samples were spiked with rVWF (vonicog alfa; Takeda) or pdVWF/factor VIII (pdVWF/FVIII; antihemophilic factor/VWF complex [human], CSL Behring), each at final concentrations of 1.0, 0.6, 0.2, 0.1 IU/mL VWF:ristocetin cofactor activity (VWF:RCo) according to labelled VWF activity. The ISTH SSC secondary coagulation standard was used as a control. Participating laboratories received three sets of these blinded aliquots. Mean results per assay were compared with the expected potency based on the labelled VWF:RCo activity. Results: Among 39 laboratories, the most commonly established assay was VWF:RCo; 22 laboratories reported data from 2214 tests. Despite a trend to lower values, VWF:RCo activities for rVWF were in agreement with target concentrations (71%–109%), whereas VWF:platelet glycoprotein Ib (VWF:GpIb) and VWF collagen‐binding activity (VWF:CB) assays gave high recoveries (up to 132% and 127%, respectively). In contrast, pdVWF/FVIII was substantially underestimated by VWF:GpIb and VWF:CB assays (56%–86% recoveries), whereas the VWF:RCo assay gave recoveries of 47%–112% for pdVWF/FVIII. Conclusion: The results of VWF assays used in clinical laboratories differ between rVWF and pdVWF, particularly for VWF:GpIb and VWF:CB assays. These differences may arise from the higher multimeric structure of rVWF compared to pdVWF. [ABSTRACT FROM AUTHOR]

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Background: Von Willebrand factor (VWF) and factor VIII (FVIII) complex play a pivotal role in hemostasis. A deficiency or defect of VWF causes von Willebrand disease (VWD). Recombinant (r)VWF product has proved to be effective for hemostatic treatment of VWD, but limited information is available on their role in moderating thrombus formation under flow condition. We aimed to assess thrombus formation in the presence of rVWF combined with rFVIII or pegylated-extended half-life rFVIII (peg-EHL-rFVIII) in VWD whole blood under high shear flow. Methods: Perfusion chamber experiments under high shear (2,500 s− 1) combined with immunostaining were performed using patient's whole blood with type 1 VWD, mixed with rVWF (Vonvendi®; 1.6 IU/mL), rFVIII or peg-EHL-rFVIII (Advate® or Adynovate®; 1.0 IU/mL), or both. Similar experiments were also conducted with clinical medical devices (T-TAS®). Results: The addition of rFVIII did not augment thrombus formation assessed by surface coverage (SC) and thrombus height (TH), whereas rVWF enhanced these parameters (SC 19.1 ± 1.1% vs. 30.1 ± 4.1%, TH 2.2 ± 0.14 μm vs. 3.6 ± 0.40 μm, respectively). The co-presence of rVWF/rFVIII was comparable to plasma-derived VWF/FVIII (Confact®, VWF:FVIII ratio = 1.6:1.0) for increasing thrombogenicity in SC (32.5 ± 4.3% vs. 38.7 ± 5.5%) and in TH (5.0 ± 0.60 μm vs. 5.5 ± 0.64 μm), respectively. The pre-incubation time with rVWF and rFVIII appeared to have a little effect on the size of thrombus. Peg-EHL-rFVIII mediated thrombus formation to similar extent as rFVIII in the co-presence of rVWF. Similar results were obtained even with T-TAS. Immunostaining demonstrated that rFVIII and peg-EHL-rFVIII were similarly co-localized with rVWF in formed thrombi, indicating that pegylation did not interfere with molecular complexes. Conclusion: The effects of high-level rVWF and peg-EHL-rFVIII on thrombus formation were comparable to conventional therapeutic products in a patient's whole blood with VWD under high shear flow. [ABSTRACT FROM AUTHOR]

Emicizumab prophylaxis dramatically reduces bleeding events in patients with hemophilia A (PwHA) with or without factor VIII (FVIII) inhibitors. However, long-term dynamic changes in FVIII inhibitor titers during emicizumab prophylaxis remain to be investigated. We conducted a retrospective follow-up study of FVIII inhibitor titers after initiation of emicizumab prophylaxis in 25 PwHA carrying current or historical FVIII inhibitors. Nineteen PwHA had FVIII inhibitors at initiation of emicizumab prophylaxis (age: median 22 [range 4–60] years and inhibitor titer: 30 [1.0–1450] BU/mL). In 17 of the 19 patients, the inhibitor titers markedly decreased to a median of 1.2 (< 0.6–58) BU/mL at a median follow-up of 71 (38–111) months. In two patients, titers were slightly elevated after initiation of emicizumab but decreased in the long term. The remaining six patients had negative inhibitor status (< 0.6 BU/mL) when switched to emicizumab from FVIII prophylaxis. Five patients maintained negative titers. One patient had inhibitor recurrence, with a peak titer of 1.6 BU/mL that decreased to 0.9 BU/mL. In most cases, FVIII inhibitor titers can be expected to decrease spontaneously during emicizumab prophylaxis, but regular follow-up is necessary to manage breakthrough bleeds. [ABSTRACT FROM AUTHOR]

To report the long-term prophylaxis management of a child with type 3 von Willebrand disease by switching to Wilate (Octapharma AG), a plasma-derived, double virus-inactivated concentrate of freeze-dried of a 1 to 1 ratio of active Von Willebrand Factor and Factor VIII (pdVWF:pdFVIII) recently marketed as Eqwilate in France. This is a case report of 12.6-year-old boy with congenital Type 3 VWD who had a history of frequent bleeds. Prophylaxis started at the age of 38 months with FVIII-poor pdVWF concentrate (Wilfactin, LFB) and FVIII (Wilstart, LFB). Pharmacokinetics and thrombin generation assay were performed. Annualized bleeding rate was derived from the bleeding episodes documented in the medical record during a 24-month period before and after starting pdVWF:pdFVIII concentrate. Both product injections promptly raised the endogenous thrombin potential (ETP). However, the maximal concentration of formed thrombin was higher following pdVWF:pdFVIII injection. Due to a high bleeds frequency and better results regarding FVIII levels and thrombin generation, the prophylaxis regimen was changed to the same dose and frequency of pdVWF:pdFVIII concentrate (42 IU/kg per day, three times a week). During the last 24 months, annualized total, trauma, and spontaneous bleeding rates were 7.5, 4.5, and 3, respectively. These rates decreased to 2, 1.5, and 0.5 respectively during the next two years. The mother reported a marked improvement in the quality of life of his son and hers. Switch to pdVWF:pdFVIII concentrate for long-term prophylaxis in a young type 3 VWD patient was safe and effective in reducing bleeds. [ABSTRACT FROM AUTHOR]

Prophylactic treatment with emicizumab has become an important and effective bleeding prevention for people with hemophilia A (PwHA). Perioperative management of PwHA using emicizumab prophylaxis is still challenging due to a lack of experience. Medical records of perioperative management and outcomes were reviewed, and data were collected for adult PwHA receiving emicizumab and undergoing surgical procedures between August 2019 and July 2022 at the University Medical Center Ljubljana. Twelve surgical procedures were performed in eight PwHA (one with FVIII inhibitors) while on emicizumab prophylaxis. Three minor procedures included cataract surgery, cystoscopic lithotripsy, and percutaneous coronary intervention. Nine major surgeries included four osteosyntheses, necrectomy of chronic osteomyelitis with new ankle arthrodesis, two below-knee amputations, total knee replacement, and placement of ventriculostomy after a spontaneous intraventricular hemorrhage. No major bleeds, thrombotic events or deaths, or new inhibitors appeared. Our real-world experience demonstrates that minor and major surgeries can be performed safely in PwHA on emicizumab prophylaxis. Additional data are needed to optimize dosing/duration of additional hemostatic agents in diverse invasive procedures and complex clinical situations. [ABSTRACT FROM AUTHOR]

This paper presents a portable point-of-care testing (POCT) device to conduct simultaneous and on-site tests of ABO and Rh(D) forward blood typing and hemophilia diagnosis using only a small amount of human whole blood sample. The POCT device consisted of a spinning module, a measuring circuit, an interdigitated electrode (IDE) for hemophilia diagnosis, and three disposable microfluidic chips for bioassays with anti-A, anti-B, and anti-D, respectively, and measurement of the concentration of factor VIII. Agglutination will occur if red blood cells (RBCs) are exposed to the corresponding antibody. To evaluate the degree of RBC agglutination, a linear sweep voltage, ranging from − 0.5 to + 0.5 V, was applied to the electrodes of the microfluidic chip and the resulting current was measured. For different levels of agglutination, the measured I–V curves were explicitly discriminated, providing five clinical levels from non-agglutination (level 0) to strong agglutination (level 4). The quantitative norm obtained from cubic fitting function of each I–V curve served as the criterion to represent this agglutination level. The ABO blood type was determined by both agglutination levels of the blood sample reacting with anti-A and anti-B. The degree of agglutination with anti-D gave the Rh(D) type. Moreover, the concentration of factor VIII was detected for the determination of hemophilia. Without requiring expensive equipment, this POCT device is especially suitable for usage in emergency or natural disasters to provide quantitative testing in rescue and relief operations. [ABSTRACT FROM AUTHOR]

Background: Unfractionated heparin (UFH) is primarily monitored using activated partial thromboplastin time (APTT). However, the recent introduction of anti-activated factor X (anti-Xa) activity testing has provided a direct evaluation of Xa inhibition by anticoagulants. This study aimed to investigate discrepancies between APTT and anti-Xa activity during UFH monitoring in critically ill patients and explore their underlying causes. Methods: This study analyzed 271 pairs of laboratory test results from blood samples of 99 critically ill patients receiving continuous intravenous UFH. Theoretical APTT values were calculated using fitted curve equations from spiked sample measurements with anti-Xa activity. Samples were categorized into three groups based on the measurement of the APTT/theoretical APTT ratio: the lower group (< 80%), the concordant group (80–120%), and the upper group (> 120%). Results: The overall concordance rate between APTT and anti-Xa activity was 45%, with a 55% discrepancy rate. The lower group frequently showed apparent heparin overdoses, while coagulation factor activities in the lower and upper groups were higher and lower, respectively, than those in the concordant group. Particularly, the lower group exhibited higher factor VIII activity levels than the upper and concordant groups. Conclusions: Discrepancies between APTT and anti-Xa activity were frequently observed, influenced by changes in coagulation factors activity levels. The lower and upper groups were classified as pseudo-heparin-resistant and coagulopathy types, respectively. Accurate monitoring of heparin in critically ill patients is crucial, especially in cases of pseudo-heparin resistance, where APTT values may wrongly indicate inadequate heparin dosing despite sufficient anti-Xa activity. Understanding these discrepancies is important for managing heparin therapy in critically ill patients. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Introduction: The standard of care in severe haemophilia A is prophylaxis, which has historically aimed for a factor VIII (FVIII) trough level of ≥1%. However, despite prophylactic treatment, people with haemophilia remain at risk of bleeds that have physical and quality of life implications, and that impact everyday life. Aim: The aim of this review was to evaluate evidence supporting the relationship between targeting higher FVIII activity levels with prophylaxis and improved outcomes in people with haemophilia A. Methods: We conducted a narrative review that defined the unmet needs and treatment goals in people with haemophilia A, evaluated evidence to support targeting higher FVIII activity levels, and highlighted therapies that may support higher and sustained FVIII activity levels and improved outcomes for people with haemophilia A. Results: Despite recent advances in treatment, unmet needs remain, and people with haemophilia continue to experience joint and functional impairment, acute and chronic pain, and poor mental health. All these negatively impact their health‐related quality of life. Evidence suggests that FVIII activity levels of up to 50% may be needed to achieve a near‐zero joint bleed rate. However, achieving high FVIII activity levels with current standard and extended half‐life (EHL) FVIII replacement therapies is associated with a high treatment burden. Innovative treatment options may provide high sustained FVIII activity levels and improved patient outcomes. Conclusion: Evidence suggests that FVIII activity levels in people with haemophilia A should be sustained at higher levels to improve joint and patient outcomes and enable progression towards health equity. [ABSTRACT FROM AUTHOR]