FACTOR VIIA IN COAGULATION/THROMBOSIS

组织因子，一种完整的膜蛋白，是主要的触发因素 凝血级联剂。它的配体因子VII/VIIa是丝氨酸 可以以惰性酶原(第VII因子)或活性形式存在的蛋白水解酶 酶(因子VIIa)。两种形式的凝血因子VII在血浆中循环， 平均约99%的因子VII和1%的因子VIIa，范围广泛 个体差异(后者从0.1%到1.8%)。一位批评者 在两种正常情况下控制凝血级联的调节步骤 止血和血栓性疾病是组织的集合 细胞表面的因子/因子VIIa复合体。正因为如此，也因为 血浆凝血因子VII活性升高可能是高血压的危险因素 缺血性心脏病，这个实验室的长期目标是 了解组织因子/因子VIIa系统是如何调节的，以及如何 这一过程在血栓性疾病中会改变。 本项目将研究血浆因子VIIa在 高凝状态，并将研究磷脂的变化 含量和抗磷脂抗体改变组织的功能 因子/因子VIIa复合体。具体而言，该项目将解决 以下问题：(1)磷脂成分如何调节 组织因子/因子VIIa的性质？(2)抗磷脂 抗体改变组织因子/因子VIIa的功能？(3)蛋白质是如何 辅因子和磷脂调节因子VII的蛋白水解性激活 ？(4)血浆因子VIIa水平与 因子VII的Arg353和Gln353等位基因存在吗？什么是 Gln353凝血因子VII？以及(5)血浆因子如何 VIIa水平在正常人中有差异吗？此外，协作式 与项目1(项目负责人：G.Raskob)一起研究将直接测试 假设血浆因子VIIa水平(尤其是血浆中的反弹 华法林停药后因子VIIa)预测再发风险 既往报道的深静脉血栓形成患者中的血栓形成。 实现本项目的目标将提供以下方面的基本知识 如何调节组织因子和因子VIIa的活性。它 还将提供有关因子VIIa参与 高凝状态。

Tissue factor, an integral membrane protein, is the primary triggering agent of the clotting cascade. Its ligand, factor VII/VIIa, is a serine proteinase that can exist as an inert zymogen (factor VII) or active enzyme (factor VIIa). Both forms of factor VII circulate in plasma, averaging about 99% factor VII and 1% factor VIIa, with a wide range of individual variation (the latter from 0.1 % to 1.8%). A critical regulatory step in controlling the clotting cascade in both normal hemostasis and thrombotic disease is the assembly of the tissue factor/factor VIIa complex on cell surfaces. Because of this, and because elevated plasma factor VII activity is implicated as a risk factor for ischemic heart disease, a long-term goal of this laboratory is to understand how the tissue factor/factor VIIa system is regulated and how this process is altered in thrombotic disease. This project will investigate the role of plasma factor VIIa in hypercoagulable states, and will examine how changes in phospholipid content and antiphospholipid antibodies alter the function of the tissue factor/factor VIIa complex. Specifically the project will address the following questions: (1) How does phospholipid composition regulate the properties of tissue factor/factor VIIa? (2) How do anti-phospholipid antibodies alter tissue factor/factor VIIa function? (3) How do protein cofactors and phospholipid modulate proteolytic activation of factor VII ? (4) What is the relationship between plasma factor VIIa levels and the presence of Arg353 versus Gln353 alleles of factor VII? What are the activation properties of Gln353 factor VII? and (5) How do plasma factor VIIa levels vary in normal individuals? In addition, a collaborative study with Project 1 (Project leader: G. Raskob) will directly test hypotheses that plasma factor VIIa levels (especially rebound in plasma factor VIIa following cessation of warfarin therapy) predict risk of re- thrombosis in patients with previously documented deep vein thrombosis. Achieving the goals of this project will provide basic knowledge about how the activity of tissue factor and factor VIIa can be modulated. It will also provide knowledge about the participation of factor VIIa in hypercoagulable states.