THROMBOSIS-SPECIFIC ANTICOAGULATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 血栓形成(血栓)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、外周动脉疾病或感染性弥漫性血管内凝血。因此，抗血栓治疗是治疗这些疾病的合理方法。然而，当给予有效剂量的全身抗凝剂时，组织中正常的血液凝结(止血)也会受到损害，出血发生率增加，因此往往抵消了好处。因此，迫切需要更安全的药物。为了寻找更具血栓特异性的抗凝剂，我们在灵长类动物血栓模型中发现，通过抑制凝血因子XI(FXI)来抗凝与公认的抗凝剂肝素一样有效，但不会增加出血倾向。我们还设计了一种名为W/E的新酶，它可以激活血管壁上的内源性抗凝剂蛋白C。W/E还可以阻止血栓形成，而不会对灵长类动物产生明显的全身性止血或其他副作用。用这些全新的治疗方法分离抗止血和抗血栓作用，可以用抗凝剂的分子机制来解释。因此，我们现在假设，药物抑制FXI，或依赖血栓调节蛋白激活蛋白C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.