This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Thrombosis (blood clots) is integral to the pathomechanism of several prevalent catastrophic disorders, including stroke, heart attack, pulmonary embolism, peripheral arterial disease, or septic disseminated intravascular coagulation. Accordingly, antithrombotic therapy is a rational approach to the treatment of these diseases. However, when systemic anticoagulants are given at efficacious doses, the normal blood clotting in tissues (hemostasis) is also impaired, and there is an increase in the incidence of hemorrhage, thereby often offsetting the benefits. Thus, safer drugs are urgently needed. In search for more thrombosis-specific anticoagulants, we discovered in primate thrombosis models that anticoagulation by inhibition of the blood coagulation factor XI (FXI) was as effective as the accepted anticoagulant, heparin, but did not produce an increased bleeding tendency. We also engineered a new enzyme, designated W/E, which activates the endogenous anticoagulant, protein C, on the blood vessel wall. W/E also blocks thrombosis without significant systemic antihemostatic or other side effects in primates. The separation of antihemostatic and antithrombotic effects with these fundamentally new treatments can be explained by the molecular mechanisms of the anticoagulants. Accordingly, we now hypothesize that pharmacological inhibition of FXI, or thrombomodulin-dependent activation of protein C will improve the outcome of thrombotic diseases.
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