Role of platelets in regulating fibrinolysis

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Upon injury to a blood vessel, a blood clot forms at the site of injury to prevent catastrophic loss of blood. When repair to the tissue has ensued, the blood clot is removed by a system called the fibrinolytic system. The balance between blood clot formation (coagulation) and blood clot breakdown (fibrinolysis) is crucial, as imbalances can lead to clotting disorders such as heart attacks and strokes or to bleeding disorders such as hemophilia. Our research concerns platelets, which are cell fragments that circulate in the blood and are essential for proper blood clot formation. They are responsible for the first plug at the wound site, and they help to coordinate the blood clotting process. Specifically, we are interesting in the role that platelets play in coordinating the balance between blood clot formation and breakdown. Our current focus is a protein called TAFI (thrombin-activatable fibrinolysis inhibitor) which helps to regulate this balance. It was once thought that TAFI was only present in plasma, which is the fluid portion of blood. However, it appears that there is also a distinct portion of TAFI within the platelet that can be released when platelets become activated at the site of injury. No one knows what the purpose of this platelet form of TAFI is, or if it is different in its properties from plasma TAFI. We propose to answer these questions. First we will try and isolate platelet TAFI in pure form. From there, we can study its characteristics and compare them to those of plasma TAFI. Next, we will assess if platelet TAFI affects the attachment of platelets to injured blood vessel walls and the subsequent formation and breakdown of blood clots. We will do this both in model vessels in test tubes or in mice in which we have specifically deleted either platelet or plasma TAFI. Our studies will provide important new information on how blood clotting and blood clot breakdown are regulated.