Project Summary This project evaluates the contribution of contact activation to the progression of vascular device-related blood coagulation and thrombus formation. The research will generate new knowledge supporting the development of novel anticoagulants that lack dose-limiting toxicity, are significantly safer, 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, 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 safety and outcome of vascular interventions, including permanent intravascular devices like stents and various forms of temporal extracorporeal organ support (ECOS). This project aims at identifying and characterizing the molecular mechanisms that drive propagation of vascular device surfaces-initiated thrombus formation under flow. Our preliminary data now suggest that coagulation factors (F)XII and XI of the contact activation pathway play important roles in not only the initiation but also the propagation of the thrombotic process. 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 detrimental bleeding side effects for patients. Each Aim will have 3 subaims that will translate our (A) molecular 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 primate 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.