Platelet Microvesicles

摘要 在血小板中，磷脂酰丝氨酸(PS)仅存在于膜双层的内叶中。vt.在.的基础上 在某些激动剂的作用下，血小板使PS外化，并提供促凝剂表面。PS的曝光是 伴随着富含PS的促凝血膜片段的释放，称为血小板源 微泡。缺乏PS暴露和微泡形成会导致遗传性出血障碍，Scott 综合症。在与动脉或静脉相关的情况下，检测到微泡增加 血栓形成。这些关联表明，虽然它们可能是正常止血所必需的，但 微泡容易形成血栓。我们已经鉴定出乳胶粘附素和Del-1(发育表达 位点-1)作为微泡清除的介体。乳胶粘附素和Del-1存在于循环中 并在体外以浓度依赖的方式促进其被巨噬细胞吞噬。 乳胶粘附素缺陷小鼠循环中的微泡增加，凝血酶增强 在他们的血浆中产生。此外，在光染料诱导的内皮细胞损伤/血栓形成模型中， 与野生型对照相比，乳黏附素缺乏的小鼠血栓形成倾向增加。我们的 目前提案中的目标是定义微泡清除的机制(S)及其与 血栓形成。我们还将检验这一假设，即每个S的微泡清除受损会导致 抗磷脂抗体综合征的高凝状态。这项提议的具体目的是进一步 表征乳黏附素和Del-1在体内清除微泡中的作用，并测试 抗磷脂综合征患者微泡导致血栓形成的假说。

Abstract In platelets, phosphatidylserine (PS) is present exclusively in the inner leaflet of the membrane bilayer. Upon activation with some agonists, platelets externalize PS and provide a procoagulant surface. Exposure of PS is accompanied by the release of PS-rich procoagulant membrane fragments called platelet-derived microvesicles. Deficiency of PS exposure and microvesiculation leads to an inherited bleeding disorder, Scott syndrome. Increased microvesicles have been detected in conditions associated with either arterial or venous thrombosis. These associations suggest that, while they may be necessary for normal hemostasis, elevated microvesicles predispose to thrombosis. We have identified lactadherin and Del-1 (developmentally expressed locus-1) as mediators of microvesicles clearance. Lactadherin and Del-1 are present in circulating microvesicles and promotes their phagocytosis by macrophages in a concentration-dependent manner in vitro. Lactadherin-deficient mice have increased microvesicles in the circulation and an enhanced thrombin generation in their plasma. Furthermore, in a light-dye-induced endothelial cell injury/thrombosis model, lactadherin-deficient mice have increased thrombotic tendency compared to wild type littermate controls. Our goals in the current proposal are to define the mechanism(s) of microvesicles clearance and its relation to thrombosis. We will also test the hypothesis that impaired clearance of the microvesicles per s¿ leads to a hypercoagulable state in antiphospholipid antibody syndrome. The specific aims of this proposal are to further characterize the role of lactadherin and Del-1 in the clearance of microvesicles in vivo and to test the hypothesis that microvesicles causes thrombosis in antiphospholipid syndrome.