The Role of Circulating Extracellular Vesicles in Hemophilia

Hemophilia is a rare inherited bleeding disorder caused by a deficiency of factor VIII or IX, leading to insufficient thrombin generation and impaired clot formation. While advances in replacement and nonfactor therapies have improved patient outcomes, challenges such as inhibitor development, joint disease, and breakthrough bleeding persist. Extracellular vesicles (EVs) are small membrane-bound particles released from all kinds of cells and have emerged as key mediators of coagulation, vascular integrity, and immune responses. In hemophilia, EVs provide procoagulant surfaces, carry tissue factor and phosphatidylserine, and may stabilize clot structure, partially compensating for deficient coagulation. Clinical studies further suggest that EV levels and composition are altered by factor replacement or bypassing agents, indicating their role as biomarkers of treatment response. Beyond their diagnostic potential, engineered EVs are being explored as innovative therapeutic tools capable of delivering clotting factors and modulating joint inflammation. This review outlines current knowledge on circulating EVs in hemophilia, emphasizing their mechanistic roles, clinical evidence, and therapeutic potential.