Grant: Doctoral: Vanier Canada Graduate Scholarships

Statistics Canada acknowledges stroke and heart disease as two of the three leading causes of death in Canada. A major contributor is blood clots, or thrombi, that block the normal flow of blood. In the clinic, an important treatment is "clot-busting" drugs of which the most prevalent are based on tissue plasminogen activator (tPA), a natural blood protein involved in dissolving clots. However, tPA is not a perfect drug, because it may cause life-threatening bleeding, some clots are resistant to its effect and it is useful only within a few hours after the onset of symptoms. To avoid some of the critical problems associated with tPA, this project focuses on a novel molecular strategy to trigger clot-busting. It is based on our lab's discovery that plasmin, a blood protein directly activated by tPA and ultimately responsible for dissolving the clot, modifies the function of the blood clotting factor Xa (FXa). We have discovered a new step in the clot-dissolving process where this altered FXa enhances the activity of tPA. Since this novel FXa function is only acquired in the vicinity of a clot, the risk of bleeding may be reduced compared to therapeutic tPA, which has systemic issues. However, this modified form of FXa is short-lived in blood. In order to stabilize this FXa intermediate for possible use as a medicine, we have produced a chemically modified form of FXa, called Xa-K. We have already demonstrated the exceptional clot-busting capabilities of Xa-K in blood plasma and thrombotic mice. The objectives of the current project are to understand the essential chemical components used to modify Xa-K, to optimize the modification efficacy, and to further understand the biochemistry of how Xa-K dissolves clots. Investigations spanning a variety of physical in vitro methods and in vivo mouse models will be used. The therapeutic potential of Xa-K offers an exciting direction in the treatment of blood clots and improving the care of Canadians and patients worldwide.