ROLE OF MICROPARTICLES IN THE ANTI-PHOSPHOLIPID SYNDROME

微粒在抗磷脂综合征中的作用

• 批准号: 7226381
• 负责人: KEITH MCCRAE
• 金额: $ 31.98万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-24 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226381
• 关键词: annexins; antiantibody; antiphospholipid syndrome; aspirin; blood coagulation; flow cytometry; heparin; human subject; inflammation; monocyte; neutrophil; particle; patient oriented research; platelet activation; platelets; thrombosis

Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, as well as recurrent fetal loss, and are the most common cause of acquired thrombophilia. In vitro studies have suggested several mechanisms that might account for the pathogenic effects of these antibodies. APLA comprise a heterogeneous family of antibodies, and rather than binding anionic phospholipid as originally proposed, react preferentially with phospholipid binding proteins such as beta2 glycoprotein I (beta2GPI), prothrombin, or oxidized phospholipids; of these, beta2GPI is the most common. Several groups, including our own, have reported that APLA bind to endothelial cells, and we have recently demonstrated that "APLA"/anti-beta2GPI antibodies induce endothelial cell activation by cross-linking annexin II through binding of annexin ll-bound beta2GPI and initiation of an activation pathway involving TLR-4 and NF-KB. Despite these mechanistic observations, however, there are no specific markers of the prothrombotic state in patients with APLA. Two reports have suggested that increased levels of procoagulant microparticles circulate in the plasma of these patients; however, the origin of these microparticles, their association with "APLA" of defined specificity (i.e. anti-beta2GPI, anti-oxidized LDL), or their correlation with thrombotic events have not been well delineated. In Specific Aim 1 of this application, we propose to compare the levels of circulating microparticles in 200 patients with APLA with those in 50 normal individuals. We will also determine the cellular origin of the circulating microparticles, and whether the number of microparticles or their cell of origin correlates with the serologic specificity of the "APLA". In Specific Aim 2, we will assess the correlation between the level of circulating microparticles and a clinical history of thrombosis, compare the procoagulant activity of microparticles from patients and controls, determine whether therapy of patients with "APLA" with aspirin and heparin reduces the level of microparticles, and evaluate the relationship between circulating microparticles and the ability of APLA to activate cells in vitro. In Specific Aim 3, we will assess the thrombogenicity of "APLA" in a mice, and determine the role of annexin II in thrombus formation. These clinical/translational studies should provide new information concerning the role of circulating microparticles in APLA-associated thrombosis, as well as the in vivo mechanisms of APLA in patients.

抗磷脂抗体（APLA）与动脉和静脉血栓形成，以及复发性 胎儿丢失，并且是获得性血栓形成倾向的最常见原因。体外研究表明 可能解释这些抗体致病作用的几种机制。APLA包括 抗体的异质家族，而不是如最初提出的结合阴离子磷脂， 优先与磷脂结合蛋白如β 2糖蛋白I（β 2GPI）、凝血酶原或 氧化磷脂;其中，beta2 GPI是最常见的。包括我们自己在内的几个团体， 报道APLA与内皮细胞结合，我们最近证明“APLA”/抗β 2GPI 抗体通过与膜联蛋白II结合的结合来交联膜联蛋白II， β 2GPI和启动涉及TLR-4和NF-κ B的活化途径。尽管有这些机械的 然而，在APLA患者中没有特异性血栓前状态的标志物。两 有报道表明，促凝血微粒在这些患者的血浆中循环的水平增加， 患者;然而，这些微粒的来源，它们与确定特异性的“APLA”的关联（即， 抗β 2 GPI、抗氧化LDL），或它们与血栓形成事件的相关性尚未得到很好的描述。在 在本申请的具体目的1中，我们提出比较200名受试者中的循环微粒水平。 APLA患者与50例正常人的对照。我们还将确定细胞的起源， 循环微粒，以及微粒的数量或其来源细胞是否与 APLA的血清学特异性。在具体目标2中，我们将评估 循环微粒和血栓形成的临床病史，比较 从患者和对照组的微粒，确定是否用阿司匹林治疗患有“APLA”的患者 和肝素降低微粒水平，并评估循环之间的关系， APLA在体外活化细胞的能力。在具体目标3中，我们将评估 在小鼠中测定“APLA”的血栓形成性，并确定膜联蛋白II在血栓形成中的作用。这些 临床/转化研究应提供有关循环微粒作用的新信息 在APLA相关血栓形成中的作用，以及APLA在患者中的体内机制。