Optimizing liver health before and after gene therapy for hemophilia A.

Gene therapy for severe hemophilia A uses an adeno-associated virus (AAV) vector and liver-specific promoters that depend on healthy hepatocyte function to achieve safe and long-lasting increases in factor VIII (FVIII) activity. Thus, hepatocyte health is an essential aspect of safe and successful gene therapy. Many people living with hemophilia A have current or past chronic hepatitis C virus infection, metabolic dysfunction-associated steatosis or steatohepatitis, or other conditions that may compromise the efficacy and safety of AAV-mediated gene therapy.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis.

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).

Recombinant vs plasma-derived von Willebrand factor to prevent postpartum hemorrhage in von Willebrand disease.

von Willebrand disease (VWD) is a congenital bleeding disorder characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, postpartum hemorrhage (PPH) is common. Treatment options at delivery include plasma-derived VWF (pdVWF) and recombinant VWF (rVWF).

Inflammatory Bowel Disease and Thrombosis: A National Inpatient Sample Study.

 Thrombosis is more common in inflammatory bowel disease (IBD) patients than the general population, but disease-specific correlates of thrombosis remain unclear.  We performed a retrospective analysis of discharge data from the National Inpatient Sample between 2009 and 2014, using International Disease Classification codes to identify IBD and non-IBD patients with or without thrombosis. We used NIS-provided discharge-level weights to reflect prevalence estimates.

Case-based discussion on the implications of exogenous estrogens in hemostasis and thrombosis: the hematologist's view.

In the childbearing years, hormonal therapy or hormonal changes in the menstrual cycle or the puerperium may be complicated by bleeding or thrombosis; however, among women with congenital disorders of hemostasis and thrombosis, the risk of bleeding or thrombosis may be increased. In women with congenital bleeding disorders, heavy menstrual bleeding is the most common bleeding symptom, and postpartum hemorrhage occurs despite treatment. Given the limitations of current therapy and the associated medical and psychological burden in women with bleeding disorders, better treatment approaches are needed to improve health outcomes and quality of life.

Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy.

Inhibitor formation is among the most severe complications of hemophilia treatment. With a cumulative incidence of ∼30% in those with severe hemophilia A and ∼3% in those with severe hemophilia B, inhibitors are caused by a T-cell response directed against infused coagulation factor; these inhibitors neutralize factor VIII or IX activity and disrupt normal hemostasis. Inhibitor patients become unresponsive to standard factor treatment and, as an alternative, use bypass treatment (eg, recombinant factor VIIa or factor VIII inhibitor bypass activity).

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

Background: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

Methods: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies.

Hemophilia Liver Transplantation Observational Study.

Hepatitis C virus (HCV) infection is the leading cause of liver disease in hemophilia patients. In those with human immunodeficiency virus (HIV)/HCV coinfection, the rate of liver disease progression is greater than in HCV monoinfected individuals. Despite antiretroviral therapy, which slows HCV liver disease progression, some require transplantation.

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

Background: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood.

Objectives: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI.

Hepatic stellate cell-conditioned myeloid cells provide a novel therapy for prevention of factor VIII antibody formation in mice.

A major complication of factor VIII (F.VIII) infusion therapies for the treatment of hemophilia A is the formation of antibodies (inhibitors) against F.VIII, a T-cell-dependent, B-cell-mediated process.

Rationale for a randomized controlled trial comparing two prophylaxis regimens in adults with severe hemophilia A: the Hemophilia Adult Prophylaxis Trial.

A major goal of comprehensive hemophilia care is to prevent occurrence of bleeds by prophylaxis or regular preventive factor, one or more times weekly. Although prophylaxis is effective in reducing bleeding and joint damage in children, whether it is necessary to continue into adulthood is not known. The purpose of this article is to describe a Phase III randomized controlled trial to evaluate prophylaxis comparing two dose regimens in adults with severe hemophilia A.

Viral pathogens.

Despite continuous improvement in safety and purity of blood products for individuals with haemophilia, transmissible agents continue to affect individuals with haemophilia. This chapter addresses three viral pathogens with significant clinical impact: HIV, hepatitis C and parvovirus B19. Hepatitis C is the leading cause of chronic hepatitis and the major co-morbid complication of haemophilia treatment.

New-generation recombinant factor concentrates: bridge to gene therapy.

Despite our best efforts to deceive the immune system, outwit pathogens, and improve upon the design of nature, there continues to be a need to improve the margin of safety of treatment for those with bleeding disorders. The current approach includes: (1) recombinant factor concentrates free of added proteins; (2) 'designer' factor molecules that enhance function and reduce immunogenicity; and (3) modulation of the immune system to suppress immune response in those who develop inhibitors. The hope is that through advances in our understanding of the coagulation and immune systems, treatment of haemophilia in the new millennium will be safer and less immunogenic.

Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection.

Hepatitis C virus (HCV) is the major cause of chronic liver disease in hemophiliacs. To determine the effect of human immunodeficiency virus (HIV) on the natural history of HCV infection, we evaluated end-stage liver disease (ESLD) in 157 hemophiliacs (85 HIV positive and 72 HIV negative) with HCV infection for an average of 24 years. After adjusting for age at HCV infection, past or current hepatitis B surface antigen positivity, and history of alcohol abuse, we determined that the rate of ESLD was significantly greater among HIV-positive than among HIV-negative hemophiliacs (relative risk [RR], 3.