Research Focus

Hemophilia A and B are rare X-linked bleeding disorders defined by deficiencies of blood coagulation glycoproteins factor VIII and factor IX, respectively. Individuals with these disorders are at increased risk for spontaneous or trauma-induced bleeding including joint bleeds, muscle bleeds, intracranial hemorrhage, or bleeding with surgery. These individuals require replacement of the deficient factor protein by intravenous infusions in order to prevent and treat bleeding episodes. However, 30% of individuals with severe hemophilia A (factor VIII deficiency) and 3% with hemophilia B (factor IX deficiency) will develop neutralizing antibodies, called inhibitors, against the infused factor. Inhibitors significantly impair an individual’s ability to treat bleeds, which negatively impacts disease morbidity and mortality. Despite advancements in hemophilia management, immune tolerance induction (ITI) remains the primary strategy for inhibitor eradication. ITI is a time-intensive and often burdensome process that consists of frequent and scheduled intravenous infusions of high doses of factor. Yet, only ~70% of individuals with hemophilia A achieve successful “tolerance” with ITI and up to 30% of those individuals will have a relapse of their inhibitor. In hemophilia B, therapeutic options for tolerance induction are severely limited due to the development of IgE-mediated hypersensitivity reactions or anaphylaxis with the emergence of anti-factor IX IgG antibodies. Moreover, individuals with hemophilia B and inhibitors can develop nephrotic syndrome mediated by immune complex deposition. A small subset of individuals with hemophilia B and inhibitors without hypersensitivity or anaphylactic responses undergo ITI, however only ~30% achieve successful tolerance.

Knowledge Gaps

In the past several decades, there have been remarkable therapeutic advancements for the management of hemophilia that have dramatically improved quality of life including FDA-approved extended half-life factor replacement products, non-factor therapies, and gene therapy. However, the presence of inhibitors still dictates an individual’s access to extended half-life factor products & gene therapy as well as the hemostatic options available for management of acute bleeds on non-factor therapies. Although it has been established that the immunologic response to factor proteins is dependent on CD4 T cell activation of B cells within the splenic microenvironment, a fundamental understanding of the molecular processes, critical cell types, and localization that mediate this response are poorly defined. Additionally, the mechanisms that dictate ITI outcomes in hemophilia A and B remain elusive.