ANTIPHOSPHOLIPID SYNDROME AND THE PROTEIN C PATHWAY

具有明显特异性的自身抗体的结合 阴离子磷脂与静脉和动脉血栓形成，复发性 胎儿丢失和血小板减少被认为是抗磷脂 抗体（aPL）综合征。 假设自身抗体 与aPL综合征相关的直接导致血栓形成 通过干扰发生在血管上的止血反应， 血细胞表面和血管内皮。 重要的新 对aPL综合征的病理生理学的了解已经 最近的证据表明这些自身抗体不能识别 阴离子磷脂单独，但针对许多 磷脂结合血浆蛋白质和蛋白质表达的 血管内皮细胞表面。 某些自身抗体靶向 作为蛋白C的组分或可能与蛋白C相互作用的蛋白质 这是一种生理上重要的天然抗凝机制。 拟议的研究将检验以下假设：1） 大部分aPL患者存在高凝状态 综合征是由于自身抗体介导的蛋白C抑制 2）特异性自身抗体的途径和2）自身抗体能够 抑制蛋白C通路的作用与 该途径的遗传缺陷的临床特征， 也就是说，静脉血栓和反复流产 的目标 目前的建议是确定哪些自身抗体与 与aPL综合征抑制蛋白C途径，临床 与这种自身抗体相关的临床表现， 自身抗体作用的蛋白C途径，自身抗体 影响其抑制活性的性质，以及 抗体介导的蛋白C途径抑制与 体内血栓形成。 该提案的具体目标是 1)鉴定、表征和纯化 针对蛋白C蛋白S的自身抗体，凝血酶， 血栓调节蛋白、因子V和β 2GPI，以及它们之间的相关性 具有aPL综合征临床表现的自身抗体; 2） 人源单克隆抗体制备及鉴定 这些特异性来自于患有这种疾病的患者的外周B细胞， 利用CD 40系统的aPL综合征，3）确定效果 在前两个目标中表征的抗体的反应， 蛋白C途径，和4）抗体促凝性的评价 在静脉血栓形成的体内动物模型中。

The association of autoantibodies having an apparent specificity for anionic phospholipids with venous and arterial thrombosis, recurrent fetal loss, and thrombocytopenia is recognized as the antiphospholipid antibody (aPL) syndrome. It is hypothesized that autoantibodies associated with the aPL syndrome directly contribute to a thrombotic diathesis by interfering with hemostatic reactions that occur on the surface of blood cells and vascular endothelium. Important new insights into the pathophysiology of the aPL syndrome have been provided by recent evidence these autoantibodies do not recognize anionic phospholipids alone, but are directed against a number of phospholipid-binding plasma proteins and proteins expressed on the surface of vascular endothelial cells. Certain autoantidies target proteins that are components of, or may interact with, the protein C pathway, a physiologically important natural anticoagulant mechanism. The proposed studies will test the hypotheses 1) that hypercoagulability in a large proportion of patients with the aPL syndrome is due to autoantibody-mediated inhibition of the protein C pathway by specific autoantibodies and 2) that autoantibodies capable of inhibiting the protein C pathway are strongly associated with the clinical features characteristic of inherited defects of the pathway, i.e., venous thrombosis and recurrent fetal loss. The goals of the current proposal are to determine which autoantibodies associated with the aPL syndrome inhibit the protein C pathway, the clinical manifestations associated with such autoantibodies, the point in the protein C pathway at which the autoantibodies act, autoantibody properties that influence their inhibitory activity, and whether antibody-mediated inhibition of the protein C pathway is associated with in vivo thrombogenicity. The specific aims of the proposal are 1) the identification, characterization, and purification of autoantibodies directed against protein C protein S, thrombin, thrombomodulin, factor V, and beta2GPI, and correlation of these autoantibodies with clinical manifestations of the a aPL syndrome; 2) the production and characterization of human monoclonal antibodies with these specificities from peripheral B cells of patients with the aPL syndrome utilizing a CD40 system, 3) determination of the effects of the antibodies characterized in the first two aims on reactions of the protein C pathway, and 4) evaluation of antibody thrombogenicity in an in vivo animal model of venous thrombosis.