Contribution of platelets to fibrinolysis in health and disease

Kim, Paul Y | $243,270

Ontario McMaster University 2021 CIHR Project Grant

Maintaining the balance between blood clotting and removal is important. Upon vascular damage, blood clots must be formed to stop the initial blood loss. Afterwards, these clots are removed (fibrinolysis) in order to restore blood flow. Unwanted blood clots forming or failure to remove them leads to blocked blood flow (thrombosis). Typically, clot formation starts with clumping of small cells in the blood called platelets, which get activated near the wound. These platelet plugs are then stabilized by the formation of large mesh-like structure called fibrin. While the roles of platelets in clot formation are well understood, how they help break down the clots are not known. This is important to understand to find new ways to treat blood clotting diseases such as stroke, heart attack, and COVID-19. It is thought that clot breakdown starts at the surface of the clots. However, we have recently shown that platelets can promote fibrinolysis on itself. This is an interesting new finding since platelets are usually found near the core of the blood clot, suggesting that clot-breakdown can be initiated anywhere throughout the clot and not limited to the surface. In addition, we show that these processes are inhibited by a protein called TAFIa, which was thought to mainly have a role within circulation or near the surface of blood clots. We now want to first identify the molecules responsible for promoting fibrinolysis on platelets in test tubes, and then confirm these findings (a) using mice with altered clotting proteins, and (b) in human COVID‑19 patients by testing whether their platelets are better at starting clot breakdown compared with healthy people due to increased molecules of interest. Our findings may offer novel treatment strategies to rapidly promote blood flow restoration in blood clotting diseases, particularly COVID-19, where there is a lack of treatment options available.

With funding from the Government of Canada

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