Hemophilia A is an inherited insufficiency of Factor VIII (FVIII), one of the critical clotting factors. The gold standard for the management of moderate-to-severe hemophilia A is prophylaxis using regular replacement therapy with clotting factor concentrates. Compared with conventional treatment, extended half-life products reduce the burden of frequent factor replacement injections. Of note, up to 30% of patients with hemophilia A receiving prophylactic factor infusions develop “inhibitors,” neutralizing anti-FVIII autoantibodies. Therapeutic options for patients with hemophilia A and inhibitors include the immune tolerance induction (ie, eradication of inhibitors) and the management of acute bleeds with bypassing agents and/or emicizumab. Emicizumab is a biphasic monoclonal antibody mimicking activated FVIII, approved for patients with hemophilia A with/without inhibitors. Gene therapy is an emerging therapy for hemophilia A, essentially curing patients with hemophilia A or transforming them to a milder phenotype by establishing continuous endogenous expression of FVIII after one-time treatment.
Prophylaxis using regular replacement therapy with clotting factor concentrates is the gold standard for the management of moderate to severe hemophilia A.
Extended half-life products can reduce the burden of frequent factor replacement injections.
Up to 30% of patients with hemophilia A on prophylaxis therapy develop “inhibitors,” neutralizing anti-Factor VIII (FVIII) autoantibodies.
Therapeutic options for hemophilia A with inhibitors include the immune tolerance induction (ie, inhibitor eradication) and the management of acute bleeds with bypassing agents and/or emicizumab.
Emicizumab is a biphasic monoclonal antibody mimicking activated FVIII, approved for patients with hemophilia A with/without inhibitors.
Hemophilia A is a clotting disorder characterized by an inherited insufficiency of Factor VIII (FVIII), one of the critical clotting factors of the coagulation cascade [
]. As a cofactor of Factor IX (FIX), FVIII plays an indispensable role in increasing the optimal activation of Factor X (FX), required for both the intrinsic and extrinsic coagulation cascades [
]. The lack of FVIII therefore prevents FX from adequately mediating the transformation of prothrombin to thrombin. Thrombin subsequently mediates the transformation of fibrinogen to fibrin, an insoluble protein, which in combination with platelets forms the clot itself. Therefore, the interruption of the clotting cascade at the level of FVIII can lead to serious hemorrhage.
The Centers for Disease Control and Prevention asserts that the prevalence of hemophilia A, although considered rare, has been grossly underestimated [
], with a report finding the prevalence may be as high as 1 in 5000 male births [ ]. Because of its X-linked recessive inheritance pattern, the misconception that women cannot present with hemophilia A persists; this has been disproven, as up to 50% of female carriers of the gene may present with FVIII levels low enough to qualify for mild hemophilia [
Hemophilia A can be further classified into mild, moderate, and severe subtypes, depending on the concentration of functional FVIII in the patient’s plasma: mild if 5% to 40%, moderate if 1% to 5%, and severe if less than 1% of normal [
]. Individuals with mild hemophilia generally do not experience spontaneous bleeding and can even tolerate invasive medical procedures with delayed bleeding; those with severe hemophilia, however, not only experience profuse bleeding with trauma but may also suffer from spontaneous joint and muscle bleeds [
To prevent bleeding, particularly hemarthrosis that would lead to arthropathy and disability, prophylaxis with regular administration of therapeutic products is strongly recommended [
, ]. Fortunately, during the past few years, there has been unprecedented progress in the development of novel therapeutics as well as acknowledged paradigm shifts in the principles of hemophilia care [ ]. Herein, we review recent advances in the management of hemophilia A including newer clotting factor concentrates (CFCs) with extended half-life and emicizumab, an innovative nonfactor replacement therapy.