Project 467239

Thrombosis is a pathological condition that occurs as a result of unregulated blood clotting that occludes blood vessels, leading to conditions such as heart attack and stroke. Despite the availability of drugs that either prevent blood clotting or encourage clot breakdown, thrombosis is responsible for 1 in 4 deaths in Canada. Current therapies are limited by the need to balance their therapeutic effectiveness with their associated risk of bleeding. As a result, more research is needed to explore the mechanisms of thrombosis to identify new targets for safe and effective therapy. A critical step in the clotting pathway is the accumulation of platelets at the site of blood vessel injury, which forms a plug that helps to stop bleeding. Platelet recruitment is mediated by the circulating protein von Willebrand Factor (vWF), a long string-like protein that adheres to the site of vessel injury and captures circulating platelets. However, recruitment of too many platelets can lead to thrombosis. ADAMTS13 is a protease that cuts vWF strings, shortening them and reducing their platelet-capturing activity. Due to its capacity to reduce platelet-recruitment, ADAMTS13 is currently being explored as a therapeutic to treat thrombosis. Our preliminary data shows that ADAMTS13 can be rapidly degraded by other proteases that are formed at sites of blood vessel injury, which may limit its antithrombotic activity. Therefore, the objectives of this project are to (a) engineer a degradation-resistant form of ADAMTS13 and (b) examine its capacity to prevent thrombosis in mouse models, using wild-type ADAMTS13 as a comparator. This work will provide critical insight into the regulation of ADAMTS13 activity and may yield a more potent novel therapeutic to treat thrombosis.