RELATIONSHIPS BETWEEN COAGULATION AND THROMBOSIS

凝血与血栓形成之间的关系

• 批准号: 3485909
• 负责人: SAMUEL I RAPAPORT
• 金额: $ 59.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3485909
• 关键词: activation product; anticoagulants; antithrombin III; clotting factor; coagulation factor IX; coagulation factor V; coagulation factor VII; coagulation factor X; goats; human subject; laboratory mouse; laboratory rabbit; phospholipids; plasma; protein C; protein S; systemic lupus erythematosus; thromboplastin; thrombosis

The goal of this integrated biochemical, physiological and clinical program is to study mechanisms initiating and regulating the tissue factor-dependent pathway of blood coagulation during hemostasis and in pathologic states. Biochmical reactions will be studied in purified and plasma systems, utilizing activation peptide release assays to measure activation of factors IX and X and the ratio of factor VII clotting to amidolytic activity coupled with radioactivity profiles of labeled factor VII measure activation of factor VII. A major effort will be made to purify a previously undescribed plasma material that, with factor Xa, inhibits factor VIIa-tissue factor enzymatic activity and to delineate the mechanism of the inhibition. A second biochemical project will focus upon activation of factor VII. The extent of activation will be related to rates of tissue factor-dependent activation of factor IX and X to determine whether generation of minimal amounts of factor VIIa can yield maximum rates of activation of factors IX and X. The ability will be evaluated of phospholipid on activated platelets and of phospholipid on unperturbed human endothelial cells to support factor Xa and factor IXa-induced activation of factor VII. A third biochemical project will focus upon the ability of zymogen factor VII to interact with tissue factor formed on cultured human endothelial cells with resultant activation of factors IX and X. Antithrombin III and the above described plasma inhibitory material will be included in some reaction mixtures. In additional experiments, increasing amounts of preformed factor VIIa will be added to the incubation mixtures with factor VII. Physiologic experiments will be carried out in rabbits to determine if infusion of tissue factor or injection of endotoxin can deplete plasma of the inhibitory material required for neutralization of factor VIIa-tissue factor. Plasma inhibitory factor levels will also be measured in patients. A quantitative assay for plasma inhibitory factor has been designed for these purposes. Other clinical projects will include studies of (1) the importance of platelet factor V for hemostasis in patients with factor V anticoagulants, (2) the relation between antiprothrombin antibodies and the lupus anticoagulant, and (3) diagnostic techniques and manifestations of thrombosis in hereditary protein C and protein S deficiency.

这个综合的生化，生理和临床计划的目标 是研究启动和调节组织的机制 凝血因子依赖性途径 病理状态 生物化学反应将在纯化和 血浆系统，利用活化肽释放测定来测量 因子IX和X的活化以及因子VII凝血与 标记因子的酰胺分解活性与放射性特征 VII测量因子VII的激活。 将作出重大努力， 纯化先前未描述的血浆材料，用因子Xa， 抑制因子VIIa-组织因子酶活性，并描绘 抑制机制。 第二个生化项目将集中在 激活因子VII。 激活的程度将与 因子IX和X的组织因子依赖性活化率，以确定 产生最少量的因子VIIa是否能产生最大的 因子IX和X的激活率。 能力将被评估为 活化血小板上的磷脂和未扰动血小板上的磷脂 人内皮细胞支持因子Xa和因子IXa诱导的 激活因子VII。 第三个生化项目将集中在 酶原因子VII与组织因子相互作用的能力 培养的人内皮细胞，其结果是因子IX的活化 和X. 抗凝血酶III和上述血浆抑制物质 将被包含在一些反应混合物中。 在另外的实验中， 将增加量的预制因子VIIa加入到培养物中 与因子VII混合。 生理学实验将在 家兔，以确定是否输注组织因子或注射内毒素 可以耗尽血浆中的抑制物质 第七因子组织因子。 血浆抑制因子水平也将 在患者中测量。 血浆抑制因子的定量测定 都是为这些目的而设计的。 其他临床项目包括 研究（1）血小板因子V对止血的重要性， 患者与凝血因子V抗凝剂，（2）之间的关系 抗凝血酶原抗体和狼疮抗凝剂，和（3）诊断 遗传性蛋白C血栓形成的技术和表现， 蛋白S缺乏症