The Role of Coagulation Factor XII in Medical Device-induced Thrombosis

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Project Summary Blood-contacting medical devices, such as catheters, vascular grafts, and stents, are often required to treat cardiovascular diseases. A major cause of device failure is intraluminal blood clot formation, also known as thrombus formation or thrombosis. Thrombosis hinders blood flow and can lead to myocardial infarction or stroke, due to tissue death. Anticoagulants are used to prevent and reduce the incidence of thrombosis on medical devices. However, current therapies target important hemostatic factors, which often leads to detrimental bleeding side effects. Factor (F) XII is a coagulation factor that has been implicated in thrombosis, but has no known role in hemostasis. Therefore, it has been suggested FXII could be a safe target for the next-generation of anticoagulants and this has been supported by early studies. Despite the promise of FXII-targeted therapies, the mechanisms of FXII activation that lead to thrombosis on cardiovascular medical devices remain unknown. I hypothesize that thrombosis on medical devices is dependent on FXIIa-fibrin and FXII-platelet interactions at the blood-device interface. The proposed work aims to (1) determine the role of FXIIa in the modulation of fibrin formation and structure in medical device-induced thrombosis and (2) determine the role of device-activated platelets on FXII activation in medical device-induced thrombosis. Determining how FXII activation promotes thrombosis on medical devices will aid in the development of effective and safe FXII-targeted anticoagulants. FXII specific anticoagulants could reduce or eliminate morbidity and mortality in patients suffering from medical device-related thrombosis. The proposed work will investigate interactions between FXII and major components of a thrombus on medical device materials.