Platelets as Biosensors and Mediators of Aortic Aneurysm Growth

Project Summary Asymptomatic abdominal aortic aneurysms (AAA) can progress to rupture with an out-of-hospital mortality of 90%. Accelerated AAA growth is associated with platelet activation and platelet aggregates (thrombi) in aneurysmal segments. Antiplatelet drugs may limit AAA growth and rupture risk. A mechanistic explanation for these observations has never been elucidated. This project builds upon our discovery that platelets from patients with AAA are hyperactivated through selective surface receptors and that the antiplatelet drug aspirin partially inhibits AAA growth and rupture. This suggests a new link between platelet activation and aneurysm development, and implies aspirin may not be the best antiplatelet drug to suppress. aneurysm growth. Using an ex vivo system to recapitulate disturbed (turbulent) blood flow in aneurysmal arteries, localization of an olfactory receptor on the surface of the platelet membrane is a new and promising target to suppresses AAA growth. Discovering this pathway in platelets from patients with AAA exposed to turbulent blood flow is a conceptual advancement in our understanding of how platelets mechanically sense and respond to their external environment. Platelets therefore emerge as circulating biosensors, releasing proteins that are useful biomarkers for distinguishing fast from slow-growing aneurysms. This project offers the promise of the first medical therapy to treat AAA.