HUMAN TISSUE FACTOR AND ITS PLASMA INHIBITOR

凝血因子VII-组织因子启动凝血的研究 通路不仅对正常止血很重要，而且还参与了 还有病理性血栓形成。组织的细胞表达 因子与感染性、炎症性和肿瘤性相关 疾病，并可能是血栓栓塞症的部分原因 不仅是这些疾病的并发症，还有静脉血栓形成 而肺栓塞发生在其他正常的人身上。 血浆中含有内源性因子VIIa/组织因子抑制物 复杂的，称为组织因子途径抑制物(TFPI)。一种形式的TFPI 与血浆中的脂蛋白结合，而另一种形式被释放 在体内移植到血浆中(可能是从内皮细胞) 注射肝素。在生理浓度下，TFPI需要 因子Xa的存在表示对该因子的反馈抑制 VIIa/组织因子复合体。 我们计划广泛研究脂蛋白相关物质和肝素-- TFPI的可发布形式和研究结构/功能关系 在TFPI分子中，相对于其脂蛋白结合，其 抑制因子Xa，抑制因子VIIa/组织 Xa因子的存在与缺失及其抑制作用的增强 肝素和其他氨基葡聚糖的活性。其他研究 将研究TFPI的内源性蛋白分解机制和 TFPI与血管内皮细胞的联系方式。最后，为了 测试TFPI在修正的凝血假说中的作用，我们将 确定内源性抑制TFPI是否能减少出血 在患有血友病的狗身上。 这些实验旨在提供目前缺乏的信息， 关于TFPI的生理及其对组织的调节 因子诱导的凝血。结果应该会增进我们的理解 包括正常止血和病理性血栓栓塞症。

The initiation of blood coagulation through the factor VII-tissue factor pathway is not only important for normal hemostasis, but is involved in pathological thrombosis as well. The cellular expression of tissue factor has been correlated with infectious, inflammatory, and neoplastic disease, and may be responsible in part for the thromboembolic complications of not only these illnesses, but also the venous thrombosis and pulmonary embolism occurring in otherwise normal individuals. Plasma contains an endogenous inhibitor of the factor VIIa/tissue factor complex, termed Tissue Factor Pathway Inhibitor (TFPI). One form of TFPI is bound to the lipoproteins in plasma, whereas another form is released into plasma (presumably from the endothelium) following the in vivo infusion of heparin. At physiologic concentrations, TFPI requires the presence of factor Xa to express feedback inhibition of the factor VIIa/tissue factor complex. We plan to extensively characterize lipoprotein-associated and heparin-- releasable forms of TFPI and investigate structure/function relationships in the TFPI molecule vis a vis its lipoprotein association, its inhibition of factor Xa, its inhibition of factor VIIa/tissue in the presence and absence of factor Xa, and the enhancement of its inhibitory activity by heparin and other glucosaminoglycans. Additional studies will investigate the mechanism of endogenous proteolysis of TFPI and the manner by which TFPI is associated with endothelial cells. Finally, to test the role of TFPI in a revised hypothesis of coagulation, we will determine whether the endogenous inhibition of TFPI ameliorates bleeding in dogs with hemophilia. The experiments are designed to provide information, now lacking, concerning the physiology of TFPI and its regulation of tissue factor-induced coagulation. The results should enhance our understanding of both normal hemostasis and pathological thromboembolism.