Adeno-associated virus-based gene therapy for hemophilia-addressing the gaps.

Adeno-associated virus-based gene therapy for hemophilia has emerged as a revolutionary treatment option, offering potential correction of clotting factor deficiency through a single intravenous infusion of functional genes directed to hepatocytes. With 3 gene therapies recently approved, this approach shows promise in transforming the lives of individuals with hemophilia. However, the complexity of gene therapy and the lack of standardization of methods in different components of this therapy can lead to unique challenges for clinical implementation.

Amelioration of a von Willebrand disease type 2B phenotype in vivo upon treatment with allele-selective siRNAs.

Treatment options for the bleeding disorder von Willebrand disease type 2B (VWD2B) are insufficient and fail to address the negative effects of circulating mutant von Willebrand factor (VWF). The dominant-negative nature of VWD2B makes functionally defective VWF an interesting therapeutic target. Previous in vitro studies have demonstrated the feasibility of allele-selective silencing of mutant VWF using small interfering RNAs (siRNAs) targeting common single nucleotide polymorphisms (SNPs) in the human VWF gene, an approach that can be applied irrespective of the disease-causing VWF mutation.

Type of D-dimer assay determines the diagnostic yield of computed tomography in patients suspected for pulmonary embolism.

Background: Pulmonary embolism (PE) is a life-threatening condition with high morbidity and mortality. The diagnosis of PE is challenging due to nonspecific symptoms, making reliable diagnostic tools essential. This study addresses the clinical impact of interassay variability in D-dimer measurements on the utilization and diagnostic yield of computed tomography pulmonary angiography (CTPA).

Replacement therapy in pregnant women with von Willebrand disease during delivery: Factor levels and pharmacokinetics.

Limited data are available on VWF activity (VWF:Act) and factor VIII (FVIII:C) levels during delivery after VWF/FVIII concentrate administration in women with von Willebrand disease (VWD). We aimed to evaluate treatment with a specific VWF/FVIII concentrate on factor levels in women with VWD during delivery and the postpartum period. A retrospective single-center study was conducted between January 1, 2008, and August 1, 2022.

Prophylaxis in von Willebrand disease with von Willebrand factor concentrate and nonfactor therapies.

This manuscript summarizes the current status of prophylaxis and novel potential therapies to prevent bleeding in patients with von Willebrand disease (VWD). VWD is the most common inherited bleeding disorder, which is associated mainly with mucocutaneous bleeding and bleeding during surgical and dental interventions. More severely affected VWD patients, mostly those with type 2 and type 3, can also suffer from joint, muscle, and gastrointestinal bleeds.

Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model.

Background: Inhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI.

The severe von Willebrand disease variant p.M771V leads to impaired anterograde trafficking of von Willebrand factor in patient-derived and base-edited endothelial colony-forming cells.

Background: von Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (VWF). The p.M771V VWF variant leads to a severe bleeding phenotype in homozygous patients.

Psychometrics of patient-reported outcomes measurement information system in von Willebrand disease, inherited platelet function disorders, and rare bleeding disorders.

Background: Patient-reported outcomes measurement information system (PROMIS) measures can be used to measure patient-reported outcomes. PROMIS measures, including computer adaptive tests (CATs) and short forms, have demonstrated the ability to adequately assess outcomes in patients with hemophilia. It is, however, unclear if PROMIS measures are suitable for patients with von Willebrand disease (VWD), inherited platelet function disorders (IPFDs), and rare bleeding disorders (RBDs).

Exposure-Response Relationship between VWF/FVIII Activity and Spontaneous Bleeding Events Following Recombinant VWF Prophylaxis in Severe VWD.

 Recombinant von Willebrand factor (rVWF, vonicog alfa, Takeda Pharmaceuticals USA) is indicated in adults diagnosed with von Willebrand disease (VWD). In this study, the exposure-response (ER) relationship between VWF activity (VWF:RCo) or factor VIII activity (FVIII:C) and spontaneous bleeding events (BEs) was evaluated in adults with severe VWD receiving rVWF prophylaxis for up to 1 year.  This secondary analysis included 23 patients receiving rVWF prophylaxis in the open-label, phase 3 prophylaxis trial (NCT02973087).

Early Postoperative Changes in Von Willebrand Factor Activity Are Associated With Future Bleeding and Stroke in HeartMate 3 Patients.

Hemocompatibility-related adverse events (HRAEs), particularly gastrointestinal bleeding, remain a frequent complication after left ventricular assist device (LVAD) implantation. The current study sought to describe and analyze whether early (<60 days) postoperative von Willebrand factor (VWF) activity assays predict the risk of gastrointestinal bleeding and stroke. A prospective single-center study including 74 HeartMate 3 device recipients between 2016 and 2023 was undertaken.

Predictive performance of pharmacokinetic-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Background: Pharmacokinetic (PK)-guided dosing is used to individualize factor (F)VIII and FIX replacement therapy.

Objectives: This study investigates the reliability and feasibility of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Methods: In this multicenter, prospective cohort study, people of all ages with hemophilia received prophylactic treatment with factor concentrates based on individual PK parameters.

Tachyphylaxis and reproducibility of desmopressin response in perioperative persons with nonsevere hemophilia A: implications for clinical practice.

Background: Desmopressin is frequently used perioperatively in persons with nonsevere hemophilia A. However, increase in factor (F)VIII:C after desmopressin use is interindividually highly variable. Tachyphylaxis has only been reported in test setting for persons with hemophilia A, with a remaining response of approximately 70% after a second dose compared with that after a first dose.

Diagnosis and treatment of von Willebrand disease in 2024 and beyond.

Manuscript Background And Aim: The diagnosis and clinical care of patients with von Willebrand disease (VWD) has continued to evolve since the characterization of the von Willebrand factor (VWF) gene in 1985. This condition is almost certainly the most common inherited bleeding disorder, and the major symptomatic burden of the disease is experienced by females during their reproductive years. Diagnosis relies on the identification of a personal and family history of excessive mucocutaneous bleeding, and laboratory features consistent with quantitative and/or qualitative abnormalities of VWF.

Effect of etranacogene dezaparvovec on quality of life for severe and moderately severe haemophilia B participants: Results from the phase III HOPE-B trial 2 years after gene therapy.

Introduction: For people with haemophilia B (PwHB), bleeding may occur despite prophylaxis, negatively affecting health-related quality of life (HRQoL). The pivotal phase 3 HOPE-B trial investigating the adeno-associated virus gene transfer product, etranacogene dezaparvovec (EDZ), demonstrated sustained factor IX (FIX) activity and bleed protection in PwHB with baseline FIX levels ≤2%.

Aim: Assess how EDZ affects HRQoL in HOPE-B trial participants.

The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A.

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 non-neutralizing 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 study between 2018 and 2019 were included.

Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial.

Background: Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B.

Methods: The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis.

Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

Introduction: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated.

Aim: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients.

Patients with moderate hemophilia A and B with a severe bleeding phenotype have an increased burden of disease.

Background: Patients with moderate hemophilia express varying bleeding phenotypes.

Objectives: To assess the burden of disease in patients with moderate hemophilia and a mild or severe phenotype incorporating the thrombin generation profile.

Methods: This sub-study of the 6th Hemophilia in the Netherlands study, analyzed data of adults with moderate hemophilia A or B.