Novel mechanisms of platelet aggregation: Roles of non-classical beta-3 integrin ligands and fibronectin in thrombosis and hemostasis

Platelets are small cells in the blood that are responsible for clot formation at the site of bleeding. Platelets adhere to an injured site of the blood vessel and clump together in a process called aggregation, forming a platelet plug. However, the same process may lead to thrombosis and blockage of blood flow in the vessel. This is the leading cause of death worldwide, particularly when this blocks blood flow in the vessels of the heart and brain; researchers have tried to make anti-thrombotic therapies to help treat these diseases. Current theory indicates that two proteins in the blood, von Willebrand Factor (VWF) and fibrinogen (Fg), can attach to a molecule on the platelet surface called beta 3 integrin (GPIIbIIIa); this attachment crosslinks different platelets and is required for platelet aggregation. However, using our unique intravital microscopy models, with which we can see in real-time the flow of blood and cells through vessels in live animals, we demonstrated that thrombus formation and vessel blockage occurred in mice lacking these two (VWF and Fg) key molecules. This unexpected finding indicates that other protein(s), besides VWF and Fg, are also capable of making platelets aggregate and blocking blood vessels. We found that this protein(s) binds to the beta 3 integrin and that this requires several other molecules, such as Calcium ions (Ca++), thrombin, and proteins from the blood and from inside platelets. We have begun to identify what other plasma and platelet proteins (e.g. fibronectin, Protocadherin 11X, Occludin, dystroglycan) contribute to this process and want to see how these proteins may be useful as new targets for anti-thrombotic therapies. On the other hand, these proteins may be of therapeutic potential to control bleeding in afibrinogemic, hypofibrinogemic and VWF deficient patients.

NI, Heyu

St. Michael's Hospital

Canadian Blood Services-CIHR Partnership Operating Grant Program

Ontario

$398,871