Grant: Operating Grant

Most heart attacks and strokes are caused by blood clots that block arteries supplying blood to the heart or brain. These blood clots are comprised of small cells, known as platelets, together with fibrin, a strand-like substance that provides the clot with a net-like structure. Patients with heart attacks or strokes are often given aspirin and/or Plavix (platelet inhibiting drugs) and blood thinners (anticoagulants). Although this treatment helps, currently available anticoagulants still have problems. Thus, some patients will have ongoing clotting despite the use of anticoagulants, whereas others will respond to treatment, but have recurrent clotting when the anticoagulants are stopped. Ongoing and recurrent clotting are undesirable because the longer and more completely that heart or brain arteries are blocked, the more damage that occurs. This application focuses on (a) defining the reasons why blood clots in arteries are so resistant to inhibition by currently available anticoagulants, and (b) developing new blood thinners that can overcome the limitations of currently available agents. Already we have identified two new anticoagulants that appear to be better than existing drugs. We now plan to extend these findings using a combination of test tube-based experiments and rabbit studies that are aimed at comparing the efficacy and bleeding potential of our new blood thinners with those of currently available anticoagulants.