Emicizumab for preventing intracranial hemorrhage in infants with severe hemophilia A: a cost-effectiveness analysis.

Intracranial hemorrhage (ICH) and resulting neurological disability are severe complications for a subset of infants with severe hemophilia A (HA). While prophylactic factor replacement reduces bleeding risk, it is typically delayed until after age 1 due to risks associated with central venous access placement. Emicizumab, a subcutaneous activated factor VIII (FVIII) mimetic, has demonstrated safety and efficacy in preventing ICH in infants under 12 months in the HAVEN 7 trial.

A literature review of major surgery experience with emicizumab in people with hemophilia A without factor VIII inhibitors.

People with hemophilia A have a total or partial deficiency of factor (F)VIII, causing spontaneous and/or traumatic bleeding into the joints, muscles, and soft tissues. Major surgery may be required to restore joint mobility or treat the symptoms of common comorbidities in people with hemophilia A. Additional factor replacement is recommended during the perioperative period; collated information on the experience of emicizumab-treated people with hemophilia A during major surgery is currently lacking.

2025 Clinical Trials Update on Hemophilia, VWD, and Rare Inherited Bleeding Disorders.

Clinical trial programs for inherited bleeding disorders feature an array of innovative prophylaxis options: engineered clotting factor concentrates, FVIIIa mimetics, gene therapies, and biologics to bolster thrombin generation (rebalancing agents). Increasingly, non-hemophilia bleeding disorders and a broader demographic (females, children, and infants) are being incorporated into study populations. Ongoing clinical trials broadly address three themes: (1) indication expansion for licensed therapeutics in previously uninvestigated patient subgroups or clinical scenarios, (2) evaluation of efficacy and safety among other bleeding disorders such as von Willebrand disease, platelet function defects, and rare clotting factor deficiencies, and (3) longitudinal assessment of approved treatments particularly with regard to longer-term efficacy outcomes such as musculoskeletal health and treatment-specific safety outcomes including thrombotic risk and liver health.

The eTHINK Study: Cognitive and Behavioral Outcomes in Children with Hemophilia.

Objective: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care.

Study Design: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible.

Benefits and risks of non-factor therapies: Redefining haemophilia treatment goals in the era of new technologies.

Introduction: Over the last decades progress in haemophilia treatment has been remarkable and prophylaxis with clotting factor concentrates in haemophilia A and B has been established as the standard of care in individuals with haemophilia and a severe bleeding phenotype. Besides clotting factor products with prolonged half-life non-factor therapies were developed which enable prophylaxis via subcutaneous administration. Factor VIIIa mimetics like emicizumab facilitate the coagulation pathway and are used in routine clinical practice for indivdiduals with haemophilia A.

Antithrombin lowering in hemophilia: a closer look at fitusiran.

Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin (AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements.

Evaluation of venous thromboembolism risk factors reveals subtype heterogenicity in children with central venous catheters: a multicenter study from the Children's Hospital Acquired Thrombosis consortium.

Background: Acutely ill and medically complex children frequently rely on central venous catheters (CVCs) to provide life-sustaining treatment. Unfortunately, catheter-related thrombosis (CRT) is a serious and common complication. Little is known why some with a CVC develop CRT and others develop venous thromboembolism unrelated to the CVC (non-CRT).

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: facilitating research through infrastructure, workforce, resources and funding.

Background: The National Hemophilia Foundation (NHF) conducted extensive, inclusive community consultations to guide prioritization of research in coming decades in alignment with its mission to find cures and address and prevent complications enabling people and families with blood disorders to thrive.

Research Design And Methods: With the American Thrombosis and Hemostasis Network, NHF recruited multidisciplinary expert working groups (WG) to distill the community-identified priorities into concrete research questions and score their feasibility, impact, and risk. WG6 was charged with identifying the infrastructure, workforce development, and funding and resources to facilitate the prioritized research.

Surgical outcomes in people with hemophilia A taking emicizumab prophylaxis: experience from the HAVEN 1-4 studies.

Many people with hemophilia A (PwHA) undergo surgery in their lifetime, often because of complications of their disease. Emicizumab is the first bispecific monoclonal antibody prophylactic therapy for PwHA, and its efficacy and safety have been previously demonstrated; however, there is a need to build an evidence base on the management of PwHA on emicizumab undergoing surgery. Data from the HAVEN 1-4 phase 3 clinical trials were pooled to provide a summary of all minor and major surgeries in PwHA with or without factor VIII (FVIII) inhibitors who were receiving emicizumab prophylaxis.

Hemophilia A/B.

Adeno-associated virus (AAV)-mediated gene transfer has successfully raised, and in some cases transiently normalized, FVIII or FIX activity levels in adults with severe hemophilia. Raising FVIII/IX levels, particularly greater than ∼15 IU/dL (mild deficiency), corresponds to a marked decrease in spontaneous and provoked bleeding, dramatic reduction in factor concentrate use, and improved quality of life (QoL). Limited understanding of innate and adaptive immune system responses and hepatocyte transgene expression and stress responses to AAV-mediated gene transfer contribute to the variability in initial and long-term factor protein expression.

Kaposiform Lymphangiomatosis: Pathologic Aspects in 43 Patients.

Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

Introduction: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL).

Aim: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment.

Methods: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1).

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

Background: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose.

Methods: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5  × 10 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10 vg per kilogram.

Symptomatic pulmonary embolus after catheter removal in children with catheter related thrombosis: A report from the CHAT Consortium.

Background: Appropriate timing of central venous catheter (CVC) removal, in relation to start of anticoagulation, in children after the diagnosis of a CVC-related thrombosis (CRT) is not well established.

Objectives: This retrospective cohort study evaluated the incidence of symptomatic pulmonary embolism (PE) after CVC removal using data from the multi-institutional Children's Hospital-Acquired Thrombosis (CHAT) Consortium Registry.

Patients/methods: The CHAT Registry consists of data from children aged 0-21 years with a hospital-acquired venous thromboembolism.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

Objectives: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU.

Design: Case-control study.

Setting: ICUs from eight children's hospitals throughout the United States.

Phage display broadly identifies inhibitor-reactive regions in von Willebrand factor.

Background: Correction of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD).

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

Introduction: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher.

Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors.

Health care resource utilization and costs among adult patients with hemophilia A on factor VIII prophylaxis: an administrative claims analysis.

Standard of care for bleed prevention in patients with severe congenital hemophilia A is continuous prophylaxis with factor VIII (FVIII), typically administered intravenously 2-3 times per week in the home setting. Nonfactor prophylaxis and gene therapy are emerging novel prophylaxis strategies for hemophilia A, and it is important to compare their health economics with that of FVIII prophylaxis. Current data on resource utilization and costs in the adult hemophilia A prophylaxis population are limited, and a structured approach to analyze annual costs in these patients using administrative claims data has not been previously reported.

Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders.

Introduction: Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders.

Decreased platelet surface phosphatidylserine predicts increased bleeding in patients with severe factor VIII deficiency.

Background: Bleeding phenotypes among individuals with severe factor VIII (FVIII) deficiency are variable, even with routine prophylactic FVIII administration. Activated platelets, in addition to their role in primary hemostasis, play a major role in coagulation by providing a phospholipid surface to which coagulation factors bind.

Objectives: The aim of this study was to determine whether platelet function is associated with past and/or future bleeding in patients with severe FVIII deficiency on prophylaxis.

Discussing investigational AAV gene therapy with hemophilia patients: A guide.

Gene therapy has the potential to overcome many of the limitations of prophylactic hemophilia therapies. Several clinical trials evaluate investigational adeno-associated virus (AAV)-mediated gene transfer approaches for the treatment of hemophilia A and B. The practical application of these approaches is nuanced by differences in AAV serotypes, transgene modifications, manufacturing, dosing, administration, and approach to follow-up.

2021 clinical trials update: Innovations in hemophilia therapy.

Therapies engineered to prolong clotting factor protein circulation time, manipulate the balance of pro-coagulant and anti-coagulant proteins, or introduce new genetic material to enable endogenous factor protein production dominate the clinical trial landscape of hemophilia. The availability of clotting factor concentrates and the establishment of primary prophylaxis have dramatically improved health outcomes for hemophilia patients. But, the burden of hemostatic therapy remains significant, and many barriers to consistent longitudinal use of prophylaxis exist.