Abstract
While conventional prophylaxis with clotting factor concentrates (CFC) is the standard of care for hemophilia A and B, its challenges include frequent intravenous administration, factor level fluctuations, and potential inhibitor development. Rebalancing agents, including fitusiran (antithrombin-lowering small interfering ribonucleic acid), concizumab and marstacimab (tissue factor pathway inhibitor antagonists), are novel nonfactor therapies that restore hemostatic balance by targeting natural anticoagulants rather than replacing missing clotting factors. Clinical trials demonstrate that these three rebalancing agents provide effective prophylaxis for people with hemophilia (PwH) with or without inhibitors through subcutaneous administration. Rebalancing agents thus provide subcutaneous alternatives to current treatment regimens and offer effective prophylaxis for people with hemophilia B with inhibitors who previously had limited therapeutic options. Their novel mechanism of action may necessitate individualized dose optimization and unique approaches for managing breakthrough bleeds and surgeries. Those conditions require reduced dosing of CFC or bypassing agents to mitigate potential thrombotic risk. In addition, the use of rebalancing agents in pediatric patients (<12 years old) remains under investigation. While promising, successful implementation depends on individualized treatment approaches, appropriate monitoring protocols, and thorough patient education to improve current care for PwH.