THROMBOSIS-SPECIFIC ANTICOAGULATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。血栓形成（血凝块）是几种流行的灾难性疾病的病理机制的组成部分，包括中风、心脏病发作、肺栓塞、外周动脉疾病或脓毒性弥散性血管内凝血。因此，抗血栓治疗是治疗这些疾病的合理方法。然而，当以有效剂量给予全身抗凝剂时，组织中的正常血液凝固（止血）也会受损，出血发生率增加，从而通常抵消了获益。因此，迫切需要更安全的药物。为了寻找更多的血栓特异性抗凝剂，我们在灵长类动物血栓形成模型中发现，通过抑制凝血因子Xi（FXi）进行的抗凝与公认的抗凝剂肝素一样有效，但不产生出血倾向增加。我们还设计了一种新的酶，命名为W/E，它可以激活血管壁上的内源性抗凝剂蛋白C。在灵长类动物中，W/E还可阻断血栓形成，而无显著的全身抗止血或其他副作用。抗凝血剂的分子机制可以解释这些全新治疗方法的抗止血和抗血栓作用的分离。因此，我们现在假设FXI的药理学抑制或蛋白C的血栓调节蛋白依赖性活化将改善血栓性疾病的结局。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.