Procoagulant Microparticles: Novel Determinants of Venous Thrombosis

静脉血栓栓塞症(DVT)是一个主要的医疗保健问题，导致显著的发病率和死亡率。 根据美国心脏协会的数据，每年有多达200万美国人受到深静脉血栓的影响，20万人死亡 它的并发症之一是肺栓塞，超过了乳腺癌和艾滋病的总和。我们和 其他研究表明，静脉血栓栓塞症会引起显著的炎症反应。 这种炎症可能与慢性静脉壁改变有很大关系 静脉血栓栓塞症。此外，炎症会导致血栓放大，并产生 促凝血剂微粒，可促进血栓形成。具体而言，P-选择素及其配体受体 PSGL-1和E-选择素似乎与静脉血栓形成密切相关，因为高水平的 循环水平的P-选择素产生大的静脉血栓，而动物的P-选择素/E基因缺失- 选择素会产生细小的血栓。研究表明，当P-选择素与其受体PSGL-1结合时， 会产生促凝剂微粒，这些微粒可以被带入血栓的形成。在预赛中 研究表明，有记录的深静脉血栓患者的微粒水平升高，而且 结合微粒测量、D-二聚体和可溶性P-选择素检测可以预测DVT 与单独使用d-二聚体相比，灵敏度/特异度均有所提高。然而，微粒子的自然历史 其产生及其在静脉血栓形成中的作用目前尚不清楚。目前的提案针对的是 微粒在静脉血栓形成中的重要性。我们将确定地球的自然历史 静脉血栓形成(1-3年)小鼠模型中微粒的形成及其血栓形成的研究 体外和体内的潜力(2-5岁)。我们还将验证一种新的方法来确定 在我们的小鼠模型中使用发光的微粒(1-3岁)。然后我们将确定是否有能力 微粒可增加已发展为深静脉血栓(1-5岁)患者的深静脉血栓的诊断。 微粒分析将与可溶性P-选择素、可溶性E-选择素、D-二聚体、白细胞介素10、 肿瘤坏死因子-α、C-反应蛋白和临床危险因素分析。我们还将确定是否存在 微粒子表面血栓前蛋白的蛋白质组学研究(本质上是首次) 方法(1-2年级)。这些研究将更全面地表征微粒对 静脉血栓形成的过程。 这项提议将决定被称为微粒的促凝血元素在 静脉血栓形成的病因及其作为诊断工具的应用。

Venous thromboembolism (DVT) is a major healthcare problem causing significant morbidity and mortality. According to the AHA, up to two million Americans are affected annually by DVT and 200,000 die annually from one of its complications, pulmonary embolism, more than breast cancer and AIDs combined. We and others have demonstrated that a significant inflammatory response occurs with venous thromboembolism and that this inflammation likely has a great deal to do with the chronic vein wall changes associated with venous thromboembolism. Additionally, inflammation leads to thrombus amplification and the production of procoagulant microparticles, which augment thrombogenesis. Specifically, P-selectin and its ligand receptor PSGL-1, along with E-selectin appear to be strongly related to venous thrombogenesis, as animals with high circulating level of P-selectin produce large venous thrombi, while animals gene deleted for P-selectin/E- selectin produce small thrombi. It has been shown that when P-selectin binds to its receptor PSGL-1, procoagulant microparticles are produced, which can be taken up into developing thrombi. In preliminary studies, we have shown that microparticles are elevated in patients with documented DVT and that combining microparticle measurements with d-dimer and soluble P-selectin assays allows prediction of DVT with sensitivity/specificity improved over d-dimer alone. However, the natural history of microparticle production and their role in venous thrombogenesis is currently not known. The current proposal addresses the importance of microparticles to venous thrombogenesis. We will determine the natural history of microparticle formation in a mouse model of venousthrombosis (years 1 -3) and define their thrombogenic potential in-vitro and in-vivo (years 2-5). We will also validate a new means to determine the presence of microparticles using luminescence in our mouse model (years 1-3). We will then determine the ability of microparticles to augment the diagnosis of DVT in patients who have developed DVT (years 1-5). Microparticle analysis will be combined with soluble P-selectin, soluble E-selectin, d-dimer, interleukin-10, TNF-alpha, C-reactive protein, and clinical risk factor analysis. We will also determine the presence of prothrombotic proteins on the surface of microparticles (essentially for the first time) with a proteomics approach (years 1-2). These studies will more completely characterize the importance of microparticles to the process of venous thrombogenesis. Lay Summary: This proposal will determine the role of procoagulant elements termed microparticles in the etiology of venous thrombosis and their use as a diagnostic tool.