Project Summary This project evaluates the contribution of contact activation to the progression of vascular device-related blood coagulation and thrombus formation. Our work and findings to date have opened the window towards the development of safer antithrombotic strategies. Our research will generate new knowledge supporting the development of novel anticoagulants that lack dose-limiting toxicity, and cause less bleeding than current drugs, while also helping to identify medical conditions that could benefit from the therapeutic use of these contact activation inhibitors. Vascular devices such as stents, grafts, hemodialyzers and oxygenators can activate blood and often require the use of systemic antithrombotics to reduce the incidence or severity of device failure and thrombotic events. Currently marketed antithrombotic drugs can help reduce clot formation on vascular devices, but all increase the risk of bleeding. For instance, 30% of severely ill neonates that are treated with extracorporeal membrane oxygenation (ECMO) experience severe bleeding complications, including gastrointestinal, pulmonary and brain hemorrhage, which contribute to the high mortality rate of neonatal ECMO. These and other vascular device-associated thrombotic and treatment-associated bleeding complications signify the unmet medical need to improve the outcome of vascular interventions, including permanent intravascular devices like stents and various forms of temporal extracorporeal organ support. This program will now take a new direction to study the molecular mechanisms by which vascular devices activate FXII to initiate thrombus formation at the blood-biomaterial interface, and evaluate the utility of inhibiting the contact activation pathway in combination with anticoagulants or reduced platelet function. We focus on FXII and FXI because (1) there appears to be a causal relationship between contact activation and vascular device failure, and (2) targeting the contact activation pathway as a therapeutic approach is less likely to have bleeding side effects for patients. Each Aim will have 3 subaims that will translate our (A) mechanistic in vitro studies to (B) ex vivo blood flow studies of artificial surface-related thrombus formation and (C) in vivo studies of vascular device-related thrombus propagation in 2 distinct animal models. The potential significance of this translational project is that the knowledge generated will lead to verification of promising, safe, and druggable molecular targets within the contact activation pathway to both prevent and interrupt vascular device-related thrombosis. Our research may ultimately support the rationale for the development of selective contact activation inhibitors that could benefit a large number of patients exposed to vascular interventions and devices.