Current perspectives on non-factor therapies for hemophilia.

Hemophilia is an inherited bleeding disorder caused by deficiency of coagulation factor VIII or IX and results in impaired thrombin generation and recurrent bleeding. Prophylactic factor replacement remains the standard treatment; however, its limitations, including the burden of intravenous treatment, inhibitor development, and residual bleeding, necessitate alternative strategies. Non-factor therapies restore hemostatic balance independently of factor replacement. These agents include factor VIIIa-mimetic bispecific antibodies and rebalancing therapies that enhance thrombin generation by inhibiting anticoagulant pathways such as tissue factor pathway inhibitor or antithrombin. Regardless of inhibitor status, non-factor therapies reduce bleeding rates, provide sustained prophylactic efficacy, and improve quality of life in patients with hemophilia A or B. However, several significant challenges remain unresolved. Because these therapies modify physiological procoagulant and anticoagulant pathways, excessive rebalancing may increase thrombotic risk, particularly when additional factor concentrates or bypassing agents are used for breakthrough bleeding or surgery. Furthermore, standardized laboratory assays for assessing global hemostatic potential are lacking, and long-term safety, optimal patient selection, and perioperative management require further clarification. Therefore, this review summarizes current and emerging non-factor therapies for hemophilia, focusing on their mechanisms of action, clinical evidence, safety considerations, unmet needs, and future perspectives for safe implementation in clinical practice.