Hemophilia A is an X chromosome-linked inherited bleeding disorder with an incidence of 1 in 5,000 male births. It results from mutations of the F8-gene coding for coagulation factor VIII (FVIII) causing low plasma levels or activity of the FVIII protein. Patients with hemophilia A suffer from lifelong bleeding tendencies including spontaneous or traumatic bleeding episodes. Most patients receive protein replacement therapy with plasma-derived or recombinant FVIII, administered by intravenous infusion. The main complication regarding this therapy is the formation of neutralizing anti-FVIII antibodies that occurs in approximately 30% of patients with severe hemophilia A. Such antibodies neutralize the infused FVIII protein, leading to increased hemophilia A morbidity and mortality. To overcome this complication, the standard approach to induce FVIII-specific tolerance is the so-called immune tolerance induction therapy (ITI). ITI involves repetitive injections of high doses of FVIII with or without bypassing agents. This approach is reminiscent of an immunological phenomenon described almost 50 years ago termed “high-zone tolerance”, which denotes the empiric observation that repetitive application of large antigen doses often induces immune tolerance. However, approximately 20-40% of patients undergoing ITI do not achieve long-lasting peripheral tolerance.

The invention provides a biomarker that allows continuous monitoring of the patients‘ responses to the aforementioned therapy. It also serves as a risk assessment tool to monitor FVIII inhibitor development.