Toward optimal therapy for inhibitors in hemophilia

Abstract

Treatment of patients with hemophilia A and B has undergone significant advances during the past 2 decades. However, despite these advances, the development of antibodies that inhibit the function of infused clotting factor remains a major challenge and is considered the most significant complication of hemophilia treatment. This chapter reviews current tools available for the care of patients with inhibitors and highlights areas where progress is imminent or strongly needed. For management of bleeding, bypassing agents remain the mainstay of therapy. Recombinant factor VIIa and activated prothrombin complex concentrates are similarly effective in populations of patients with hemophilia and inhibitors; however, individuals may show a better response to one agent over another. Recent studies have shown that prophylaxis with bypassing agents can reduce bleeding episodes by ∼50%-80%. The prophylactic use of bypassing agents is an important tool to reduce morbidity in patients before they undergo immune tolerance induction (ITI) and in those with persistent high titer inhibitors, but cost and lack of convenience remain barriers. Because of the significant burden that inhibitors add to the individual patient and the health care system, inhibitor eradication should be pursued in as many patients as possible. ITI is an effective tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a return to a normal factor VIII response in ∼60% of patients. However, for the group of patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire

“…New treatments to promote immune tolerance to FVIII in individuals with an inhibitor or at increased risk for inhibitor development are therefore badly needed. 1 To facilitate their development, a better understanding of the anti-FVIII immune response, particularly in those who have developed a high-titer inhibitor refractive to ITI therapy, is required. Severe HA subject GS1-56A had failed ITI therapy and his high-titer inhibitor had persisted for .10 years.…”

“…1 Inhibitors occur more frequently in severe than in mild or moderate HA. [2][3][4] Inhibitor risk is associated with genetic and nongenetic factors.…”

Design and characterization of an APC-specific serpin for the treatment of hemophilia

“…14 In addition, because the replacement factor is effectively a foreign protein, treatment is often associated with formation of inhibitory antibodies, 15,16 which necessitates using a different class of therapeutics termed "bypassing agents." 17 Bypassing agents increase thrombin generation through mechanisms independent of the intrinsic Xase complex, the most commonly used of which are fVIIa (NovoSeven), prothrombin concentrates, and FEIBA. However, these agents suffer from short half-lives and result in variable responses in patients.…”

Expression and functional evaluation of biopharmaceuticals made in plant chloroplasts

“…This immune response to protein antigens can cause life-threatening anaphylaxis in severe cases [32]. Current clinical protocols of immune tolerance induction (ITI) require administration of high doses of blood clotting factor over a long period of time [33]. However, this clinical protocol is highly expensive and it does not guarantee the effective immune tolerance [1].…”