Shear induced platelet procoagulant activity

激活后，血小板从血管损伤部位的初级止血栓中流出。此外，活化的血小板为随后的凝血级联活化提供了有效的促凝血表面。阴离子磷脂从血小板膜的内小叶到外小叶的跨双层运动是促凝血活性的主要决定因素。这伴随着称为微泡的促凝血膜颗粒的释放。血小板促凝活性生成受损的个体具有终身出血素质（Scott综合征）。我们的研究表明，剪切应力，例如发生在动脉粥样硬化狭窄部位的剪切应力，是血小板促凝活性和微泡形成发展的有力刺激。此外，凝血酶加重剪切应力诱导的阴离子磷脂暴露和微泡形成。微泡粘附于基质组分，为血小板粘附提供结合位点，并定位于体内血管损伤部位。微泡结合β 2-糖蛋白I，一种阴离子磷脂结合血浆蛋白，可促进其被巨噬细胞清除。β 2-糖蛋白I自身抗体的存在，以及β 2-糖蛋白I的遗传突变（削弱其哲学结合）与血栓形成的发生率增加有关。在这个提议中，我们将研究剪切应力诱导的血小板促凝活性对血栓形成的作用。本研究的具体目的是：（1）明确切应力诱导血小板促凝活性的信号转导途径。我们将测试信号转导的假设，即通过含ITAM蛋白和Syk的信号转导导致阴离子磷脂暴露和微泡形成。(2)评估在剪切应力下血小板促凝活性的发展及其在血栓稳定性中的作用。待检验的假设：血小板在粘附于血管性血友病因子和/或胶原表面后产生促凝血活性，并且粘附血小板上的这种活性在血栓稳定性中起重要作用。(3)确定β 2-糖蛋白I在血小板衍生微泡从循环中清除中的作用。待检验的假设：β 2-糖蛋白I与血小板衍生的微泡表面上的阴离子磷脂结合，并介导它们被巨噬细胞清除。其必然结果是β 2-糖蛋白I功能的缺乏将导致高凝状态。

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.