Grant: Travel Awards - Institute Community Support

The persistence of an abnormal clot blocking the flow of blood is a major cause of stroke and heart attack. To dissolve these clots therapeutically, a genetically engineered form of the naturally occurring clot-busting protein, tissue plasminogen activator (tPA) is used. It converts the plasma protein, plasminogen, into its active form, plasmin, which directly dissolves the clot. The use of tPA, however, is limited by the risk of increased bleeding and its need to be given shortly after the onset of a stroke or heart attack. Thus, safer and more effective clot-busters are needed. Our laboratory has reported that clotting protein factor Xa enhances clot dissolution when it is cut by plasmin at specific locations. These cleavages expose areas where plasminogen and small amounts of tPA bind to generate more plasmin at the site of the clot. Working towards a clot-buster based on factor Xa, we have found that changing its functional region conferred clot-dissolving activity in plasma. Rivaroxaban is a new generation drug used to prevent clot formation by binding to the same functional region of factor Xa. Here we address the hypothesis that rivaroxaban will enhance the function of factor Xa by investigating, in the presence of rivaroxaban: 1) the cleavage of factor Xa, 2) its ability to help tPA, and 3) its clot-busting function in clot dissolution tests. We found that rivaroxaban enhanced plasma clot dissolution even when its ability to prevent clot formation was negated. Interestingly, this effect was lost in experiments using purified proteins instead of plasma suggesting the involvement of a different form of factor Xa or other as yet unidentified plasma components. The same observations were made for apixaban, a drug with a similar function as rivaroxaban. These results suggest a new role for rivaroxaban and apixaban in clot dissolution. By understanding how the function of factor Xa is regulated, better treatments for stroke and heart attack may be developed.