ANTIPHOSPHOLIPID SYNDROME AND THE PROTEIN C PATHWAY

具有明显特异性的自身抗体之间的关联 阴离子磷脂伴静脉和动脉血栓形成，复发性 胎儿丢失，血小板减少被认为是抗磷脂 抗体(APL)综合征。据推测，自身抗体 与APL综合征相关直接导致血栓形成 通过干扰患者的止血反应提高身体素质 血细胞和血管内皮细胞表面。重要新闻 对APL综合征的病理生理学的见解已经被 由最近的证据提供，这些自身抗体不识别 只针对阴离子磷脂，但针对许多 磷脂结合血浆蛋白和表达于 血管内皮细胞表面。某些自杀性疾病的目标 属于蛋白C的组成部分或可能与蛋白C相互作用的蛋白质 途径，一种生理上重要的天然抗凝机制。 拟议的研究将检验假设1) 大部分急性早幼粒细胞白血病患者的高凝状态 综合征是由于自身抗体介导的对蛋白C的抑制 通过特定的自身抗体和2)自身抗体能够 对蛋白C途径的抑制与 遗传性通路缺陷的临床特征， 即静脉血栓形成和复发性胎儿丧失。世界银行的目标是 目前的建议是确定哪些自身抗体与 随着APL综合征抑制蛋白C途径，临床 与这种自身抗体相关的表现，要点是 自身抗体作用的蛋白C途径 影响其抑制活性的性质，以及是否 抗体介导的蛋白C途径抑制与 具有体内血栓形成能力。这项提议的具体目的是 1)鉴定、表征和提纯 针对蛋白C蛋白S、凝血酶、 血栓调节蛋白、因子V和β2GPI及其相关性 自身抗体与a-APL综合征的临床表现 人源性单抗的制备及鉴定 从患者的外周B细胞中提取的这些特异性 使用CD40系统的APL综合征，3)疗效的测定 在前两个目标中描述的抗体的反应 蛋白C途径，以及4)抗体凝血性的评价 在静脉血栓形成的活体动物模型中。

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.