Inhibitors in Hemophilia: Treatment Challenges and Novel Options

Abstract

Hemophilia A (HA) and hemophilia B (HB) are rare congenital severe bleeding disorders, that may be controlled by proper administration of adequate prophylaxis with factor VIII (FVIII), and factor IX (FIX) concentrates, respectively, to prevent joint damage due to recurrent bleeding. However, approximately 30% of patients develop inhibitory antibodies that render factor replacement therapy ineffective. Due to the high variability of patients' bleeding tendency, there is a need to "individually tailor treatment" for this unique group of patients. While replacement therapy with FVIII or FIX can be used for treating HA or HB patients with low responding inhibitors, hemophilia patients with high-responding inhibitors are treated with bypassing agents. Unfortunately, the Bethesda assay applied for inhibitor measurement in most laboratories does not fully predict either bleeding tendency or therapy response. Immune tolerance induction (ITI) may eradicate most inhibitors, yet treatment is challenging during bleeding episodes. The role of bypassing agents and their various treatment strategies still deserves attention. Recently, new nonreplacement therapies have emerged for patients with hemophilia including patients with inhibitors. Adequate monitoring of bypassing therapy and of the new nonreplacement therapies in inhibitor patients is extremely challenging, thus global hemostatic assays are increasingly used to assess clot formation. This review aims to summarize the current treatment and monitoring challenges for inhibitor patients; in this perspective, we will discuss our institutional approach for optimal decision-making and individual therapy tailoring.

A novel, point‐of‐care, whole‐blood assay utilizing dielectric spectroscopy is sensitive to coagulation factor replacement therapy in haemophilia A patients

“…Haemophilia patients with inhibitors present unique treatment and monitoring challenges . There is limited ability, primarily using TEG and TGA, to monitor therapy with bypassing agents (recombinant FVIIa and activated prothrombin complex concentrates) in patients with inhibitors .…”

Development of inhibitors in hemophilia A: An illustrated review

“…Neutralizing alloanƟbodies (inhibitors) are the maintreatment-related complicaƟon in paƟents with severe HA. [5][6] CumulaƟve incidence of inhibitor development in paƟents with HA is 20%-35%.…”

Reprogrammed CD4+ T Cells That Express FoxP3+ Control Inhibitory Antibody Formation in Hemophilia A Mice

“…Inhibitors render factor replacement therapy ineffective and can present a high risk of morbidity and mortality (7). Immune tolerance induction (ITI) for the eradication of inhibitors via frequent and high dose exposure to FVIII concentrates for a prolonged period is expensive and not always successful, especially in severe hemophilic patients (8). Mechanisms for tolerance induction by ITI are not clearly known but may include T effector cell (T eff ) exhaustion/anergy, inhibition of FVIII-specific memory B-cell differentiation, or induction of regulatory T cells (Tregs) (9, 10).…”