Shear induced platelet procoagulant activity

当被激活时，来自初级止血装置的血小板在血管损伤部位堵塞。此外，激活的血小板为随后的凝血级联反应的激活提供了有效的促凝血剂表面。阴离子磷脂从血小板膜内到外的跨双层运动是促凝血活性的主要决定因素。伴随而来的是被称为微泡的促凝血膜颗粒的释放。血小板促凝血活性受损的个体具有终生出血素质(Scott综合征)我们的研究表明，切应力，例如发生在动脉粥样硬化性狭窄部位的切应力，是发展血小板促凝活性和微泡形成的有力刺激。此外，凝血酶加剧了切应力引起的阴离子磷脂暴露和微泡形成。微囊附着在基质成分上，为血小板黏附提供结合部位，并定位于体内血管损伤部位。微囊结合β2-糖蛋白I，一种阴离子磷脂结合的血浆蛋白，促进其被巨噬细胞清除。β2-糖蛋白I自身抗体的存在以及β2-糖蛋白I的遗传突变(这削弱了其哲学结合)与血栓发生率的增加有关。在这个方案中，我们将研究切应力诱导的血小板促凝活性在血栓形成中的作用。这项建议的具体目的是：(1)明确导致切应力诱导的血小板促凝血活性的信号转导途径。我们将验证这样一种假设，即信号转导通过含有ITAM的蛋白质和Syk导致阴离子磷脂暴露和微泡形成。(2)评价切应力作用下血小板促凝血活性的变化及其在血栓稳定性中的作用。需要检验的假设是：血小板在与von Willebrand因子和/或胶原表面黏附后产生促凝血活性，而这种黏附在血小板上的活性对血栓的稳定性起着重要作用。(3)明确β2-糖蛋白I在清除血小板源微泡中的作用。需要检验的假设是：β2-糖蛋白I与血小板衍生的微泡表面的阴离子磷脂结合，并介导巨噬细胞对其的清除。由此推论，β2-糖蛋白I功能缺陷将导致高凝状态。

Upon activation, platelets from the primary hemostatic plug at sites of vascular injury. In addition, activated platelets provide an efficient pro- coagulant surface for the subsequent activation of the coagulation cascade. The transbilayer movement of anionic phospholipids from the inner to the outer leaflet of the platelet membrane is a major determinant of pro-coagulant activity. This is accompanied by the release of procoagulant membrane particles called microvesicles. Individuals with impaired generation of platelet procoagulant activity have a life-long bleeding diathesis (Scott syndrome) Our studies show that shear stress, such as that which occurs at a site of atherosclerotic narrowing of arteries, is a potent stimulus for the development of platelet procoagulant activity and microvesiculation. Moreover, thrombin accentuates the shear stress- induced anionic phospholipid exposure and microvesiculation. The microvesicles adhere to matrix components, provide a binding site for platelet adhesion, and localize to the site of vascular injury in vivo. Microvesicles bind beta2-glycoprotein I, an anionic phospholipid-binding plasma protein, which promotes its clearance by macrophages. The presence of autoantibodies to beta2-glycoprotein I, as well as inherited mutations in beta2-glycoprotein I (which impair its philosophical- binding) are associated with increased incidence of thrombosis. In this proposal, we will investigate the role of shear stress-induced platelet procoagulant activity on thrombus formation. The specific aims of this proposal are: (1) To define the signal transduction pathways leading to shear stress-induced platelet pro-coagulant activity. We will test the hypothesis that signal transduction that signal transduction through ITAM-containing proteins and Syk leads to anionic phospholipid exposure and microvesiculation. (2) To assess, under shear stress, the development of platelet pro-coagulant activity and its role in the stability of thrombus. The hypothesis to be tested: Platelets develop procoagulant activity following adhesion on von Willebrand factor and/or a collagen surface and this activity on adherent platelets plays a significant role in thrombus stability. (3) To define the role of beta2-glycoprotein I in the clearance of platelet-derived microvesicles from the circulation. The hypothesis to be tested: beta2-glycoprotein I binds to anionic phospholipid on the surface of platelet-derived microvesicles and mediates their clearance by macrophages. The corollary of this is that deficiency of beta2-glycoprotein I function will lead to a hypercoagulable state.