Antithrombotic therapies, which primarily consist of antiplatelet and anticoagulant agents, have become the cornerstone therapies for a wide variety of cardiovascular diseases. Increasingly, combination antithrombotic therapies are used in the clinic, which affords increased antithrombotic protection. However, all currently employed anticoagulant agents indiscriminately inhibit blood clotting reactions at the injured vessel wall and throughout the body of a developing blood clot, resulting in increased bleeding risk for patients receiving these medications.
The generation of a fibrin blood clot is driven by coagulation factors present in the plasma. These factors assemble on negatively charged endothelial cell surfaces, to facilitate thrombin generation and promote blood clot formation. Platelets are also capable of presenting negatively charged surfaces to facilitate localised thrombin generation – a process referred to as platelet ‘procoagulant’ function. Recent progress in understanding the mechanisms by which platelets support blood coagulation have raised the possibility that selective inhibition of platelet procoagulant function may specifically reduce thrombin generation within a thrombus, with the possibility of less bleeding.
Over the last several years, studies from our laboratory have afforded important insight into the development of platelet procoagulant function, specifically its close resemblance to cell death pathways in nucleated cells. Our studies have demonstrated that procoagulant platelets are dying cells, undergoing a cell death process akin to necrosis, leading to PS exposure and thrombin generation. We have also found a novel role for an adaptor protein – 14-3-3z – in regulating platelet death necessary for blood clot growth and stability. We aim to determine whether therapeutic targeting of these pathways represents a safe and effective way of reducing thrombin generation in vivo without increasing bleeding risk.
1. Schoenwaelder SM, et al, Blood, 114(3): 663-666, 2009.