Procoagulant Microparticles: Novel Determinants of Venous Thrombosis

静脉血栓栓塞（DVT）是一个主要的医疗保健问题，导致显着的发病率和死亡率。 根据AHA的数据，每年有多达200万美国人受到DVT的影响，每年有20万人死亡 其中一个并发症，肺栓塞，比乳腺癌和艾滋病加起来还要多。我们和 其他人已经证明静脉血栓栓塞会发生显著的炎症反应 这种炎症可能与慢性静脉壁变化有很大关系， 静脉血栓栓塞此外，炎症导致血栓放大和血栓形成。 促凝血微粒，其增加血栓形成。具体来说，P-选择素及其配体受体 PSGL-1，沿着E-选择素似乎与静脉血栓形成密切相关，因为具有高水平的 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-选择素基因缺失， 选择素产生小血栓。已经表明，当P-选择素与其受体PSGL-1结合时， 产生了促凝血微粒，其可被吸收到形成的血栓中。初步 研究中，我们已经表明，微粒在有记录的DVT患者中升高， 将微粒测量与d-二聚体和可溶性P-选择素测定相结合可预测DVT 灵敏度/特异性比单独的D-二聚体提高。然而，微粒的自然历史 其产生及其在静脉血栓形成中的作用目前尚不清楚。目前的提案涉及 微粒对静脉血栓形成的重要性。我们将确定 在静脉血栓形成的小鼠模型（1 - 3年）中的微粒形成，并确定其血栓形成 潜在的体外和体内（2-5年）。我们还将验证一种新的方法来确定是否存在 在我们的小鼠模型中使用发光的微粒（1-3年）。然后我们将确定 微颗粒，以增强DVT患者的DVT诊断（1-5年）。 微粒分析将结合可溶性P-选择素、可溶性E-选择素、d-二聚体、白细胞介素-10， TNF-α、C-反应蛋白和临床危险因素分析。我们还将确定 微粒表面的血栓前蛋白质（基本上是第一次）与蛋白质组学 方法（1-2年）。这些研究将更全面地描述微粒对 静脉血栓形成的过程。 概述：该提案将确定称为微粒的促凝血元素在血液中的作用。 静脉血栓形成的病因学及其作为诊断工具的用途。

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.