Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

Abstract

The development of coagulation factor VIII (FVIII) inhibitory antibodies is a serious complication in hemophilia A (HA) patients after FVIII replacement therapy. Inhibitors render regular prophylaxis ineffective and increase the risk of morbidity and mortality. Immune tolerance induction (ITI) regimens have become the only clinically proven therapy for eradicating these inhibitors. However, this is a lengthy and costly strategy. For HA patients with high titer inhibitors, bypassing or new hemostatic agents must be used in clinical prophylaxis due to the ineffective ITI regimens. Since multiple genetic and environmental factors are involved in the pathogenesis of inhibitor generation, understanding the mechanisms by which inhibitors develop could help identify critical targets that can be exploited to prevent or eradicate inhibitors. In this review, we provide a comprehensive overview of the recent advances related to mechanistic insights into anti-FVIII antibody development and discuss novel therapeutic approaches for HA patients with inhibitors.

Hemophilia throughout the life cycle

“…In contrast to severe hemophilia A, patients with moderate/mild have a lower but life-long risk of inhibitor development 42 . In hemophilia B, inhibitors occur primarily in patients with F9 deletions, frameshifts, and nonsense mutations, resulting in truncated or absent factor IX protein.…”

Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab

“…Up to 30% of patients with severe HA develop anti-FVIII antibodies. In such cases, traditional clotting factor replacement treatments may be less effective [ 14 ]. Moreover, testing for inhibitors is not widely or easily available, and once HA patients develop inhibitors, their access to hemophilia care is hampered by the complexity of care with bypassing agents [ 15 ].…”