Evaluating the Safety and Efficacy of Targeting the Contact Pathway to Prevent Device Associated Thrombosis.

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Project Summary Our research project is designed to test our central hypothesis that the interaction between the contact activation system of blood coagulation and the surfaces of medical devices contributes to pathologic mechanisms including inflammatory responses and device associated thrombosis. Despite the use of anticoagulation and antiplatelet agents, many widely used vascular devices induce thrombus formation. Anticoagulation can mitigate thrombus formation, though not completely, and thus thrombosis is a persistent risk with significant clinical consequences including thromboembolism, device failure, stroke and even death. While current forms of anticoagulation can lessen these risks, they universally increase the risk of bleeding, paradoxically contributing to patient morbidity and mortality. Our group has extensively evaluated the contact pathway factors XI (FXI) and XII (FXII) which appear to be complicit in the development of device-associated thrombosis, yet dispensable for hemostasis. Our central hypothesis is that mechanical devices induce and propagate local blood coagulation and thrombus propagation in a FXIIa-dependent manner. Building on our prior successes, in AIM 1 we will utilize in vitro and non-human primate models, along with samples from patients with peripherally inserted central catheters (PICCs) as a model medical device to define the interaction of the contact pathway and device surfaces in the blood microenvironment. Using a novel inhibitor of FXII-mediated activation of FXI, in AIM 2 we will determine the role of contact activation in the development of device-associated thrombosis in patients with peripherally inserted central catheters (PICCs). PICCs are frequently used in ambulatory medical patients who require regular administration of intravenous medications, but are plagued by high rates of thrombosis leading to local symptoms, thromboembolism and delays in medical care. Paradoxically, the treatment of catheter associated thrombosis with modern forms of anticoagulation leads to significant morbidity from major bleeding, and to date trials of traditional anticoagulants to prevent CAT have not shown a favorable risk/benefit profile. There is an unmet medical need to develop safer more effective therapies in this space. Taken together, these analyses will be the first to define the mechanisms of by which activation of FXI and FXII by device surfaces contributes to device-associated thrombosis in humans. The data generated from this analysis will provide new mechanistic insights applicable to numerous medical devices used in modern health care practices and has large translational relevance in identifying safe and druggable targets within the contact activation system.