Rescue of the endogenous FVIII expression in hemophilia A mice using CRISPR-Cas9 mRNA LNPs.

Gene editing provides a promising alternative approach that may achieve long-term FVIII expression for hemophilia A (HemA) treatment. In this study, we investigated correction of a mutant factor VIII (FVIII) gene in HemA mice. We first developed MC3-based LNPs for efficient mRNA delivery into liver sinusoidal endothelial cells (LSECs), the major site of FVIII biosynthesis.

Neurosurgical bleeding in platelet storage pool disorder: a case report.

Dense-granule deficiency (DGD) is an inherited platelet disorder due to the absence of dense granules essential for activation of platelets in the event of vascular injury. Decreased platelet dense granules can be detected by electron microscopy, while other tests of hemostasis, including platelet function analyzer (PFA®) closure times, may be normal. The present case report describes a patient with a lifelong history of mucocutaneous bleeding and excessive hemorrhage with resection of vestibular Schwannoma.

The importance and evolution of bleeding disorder registries.

Registries are excellent sources of data to address questions that are typically not evaluated in randomized clinical trials, including natural history, disease prevalence, treatment approaches and adverse events, and models of care. Global and regional registries can provide data to identify differences in outcomes and in haemophilia care between countries, economic settings, and regions, while facilitating research and data sharing. In this manuscript, we highlight five bleeding disorder registries: Country registries from Australia and China, Paediatric Network on Haemophilia Management (PedNet) data on children who have received emicizumab, data from the European Haemophilia Safety Surveillance (EUHASS) system, and data on women and girls with haemophilia from the World Federation of Haemophilia (WFH) registries.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B.

The World Federation of Hemophilia World Bleeding Disorders Registry: insights from the first 10,000 patients.

Background: The prevalence of hemophilia varies globally, with close to 100% of patients diagnosed in high-income countries and as low as 12% diagnosed in lower-income countries. These inequalities in the care of people with hemophilia exist across various care indicators.

Objectives: This analysis aims to describe the clinical care outcomes of patients in the World Bleeding Disorders Registry (WBDR).

Management of pregnant women who have bleeding disorders.

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta.

A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories.

Introduction: Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half-life.

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene ()-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and -mutational-heterogeneity.

Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study.

Patients with hemophilia A require exogenous factor VIII (FVIII) or nonfactor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector-based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain-deleted human F8 gene.

Prophylaxis with a recombinant factor VIII Fc in hemophilia A: long-term follow-up on joint health, efficacy, and safety from phase 3 studies in children and adults.

Background: Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance.

Objectives: To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies.

Dynamic and functional linkage between von Willebrand factor and ADAMTS-13 with aging: an Atherosclerosis Risk in Community study.

Background: von Willebrand factor (VWF) is a multimeric glycoprotein critically involved in hemostasis, thrombosis, and inflammation. VWF function is regulated by its antigen levels, multimeric structures, and the state of enzymatic cleavage. Population studies in the past have focused almost exclusively on VWF antigen levels in cross-sectional study designs.

Efanesoctocog alfa for the prevention and treatment of bleeding in patients with hemophilia A.

Introduction: Hemophilia A is an inherited bleeding disorder due to a deficiency of coagulation factor VIII (FVIII). Prevention and treatment of bleeding is traditionally through intravenous infusion of a FVIII concentrate. Modifications of recombinant FVIII (rFVIII) with an aim to prolong the half-life have been modest, thought because FVIII is dependent on plasma von Willebrand factor (VWF) for its half-life.

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point.

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

Background: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear.

Methods: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A.

How I approach bleeding in hospitalized patients.

Excessive bleeding is relatively common in adult inpatients, whether as the primary reason for admission or as a development during the hospital stay. Common causes include structural issues, medication effects, and systemic illnesses; occasionally, unexpected bleeding can develop as a result of an undiagnosed or newly acquired bleeding disorder. The first step in caring for the inpatient who is bleeding is to determine whether the bleeding symptom is truly new or whether the patient has a history of abnormal bleeding.