PLATELET BINDING SITES FOR BOVINE FACTOR VIII

因子VIII是高分子量血浆糖蛋白复合物， 是血液凝固的重要调节剂，也是 血小板对受损内皮表面的识别。 一 凝血因子VIII在血小板介导的 通过牛因子VIII与人因子VIII的结合来提供止血， 血小板 我们建议鉴定和分离蛋白质（S）上的 凝血因子VIII结合的血小板表面。 纯化的结合 蛋白质将通过生物化学技术表征， 确定与因子VIII相关的机制。 化学和 分离的结合蛋白的酶促修饰将用于 确定负责职能活动的区域。 的影响 药物，如ADP，可改变血小板对凝血因子的反应性 第八，将审查其对具有约束力的可用性的影响 在血小板表面的位置。 我们还将研究因素的影响 VIII结合血小板的代谢和功能反应， 将研究这种结合如何改变血小板对其他细胞的反应性， 激动剂 人类先天性凝血因子VIII蛋白缺乏症 (von Willebrand氏病）可导致严重出血综合征，因为 导致血小板介导的止血缺陷。 替代疗法 用第八因子浓缩物可以纠正这种缺陷。 另 一方面，缺乏因子VIII（猪）已被证明是 与形成动脉粥样硬化斑块的倾向降低相关- 可能是因为血小板对血小板的反应性降低， 血管内膜损伤的早期阶段 这些观察结果表明 凝血因子VIII与血小板的相互作用起着关键作用， 不仅在保护性止血机制中， 血栓性疾病。 更好地理解这种相互作用是 因此，对于治疗管理的合理方法至关重要， 了以下条件

Factor VIII is a high molecular weight plasma glycoprotein complex which is an important regulator of blood coagulation and is also required for the recognition of damaged endothelial surfaces by blood platelets. A convenient model for the function of Factor VIII in platelet-mediated hemostasis is provided by the binding of bovine Factor VIII to human platelets. We propose to identify and to isolate the protein(s) on the platelet surface to which Factor VIII binds. The purified binding protein(s) will be characterized by biochemical techniques and the mechanism of association with Factor VIII determined. Chemical and enzymatic modification of the isolated binding protein(s) will be used to identify the regions responsible for functional activity. The effects of agents, such as ADP, which alter the responsiveness of platelets to Factor VIII, will be examined for their effects on the availability of binding sites on the platelet surface. We will also examine the effects of Factor VIII binding on the metabolic and functional responses of platelets and will study how this binding alters the responsiveness of platelets to other agonists. A congenital deficiency of the Factor VIII protein in humans (von Willebrand's disease) can cause a severe bleeding syndrome, because of the resulting defect in platelet-mediated hemostasis. Replacement therapy with concentrates of Factor VIII can correct this defect. On the other hand, a deficiency of Factor VIII (in swine) has been shown to be associated with a decreased tendency to form atherosclerotic plaques - probably because of a decreased responsiveness of the platelets to the early stages of damage to the vascular intima. These observations suggest that the interaction of Factor VIII with platelets plays a key role not only in protective hemostatic mechanisms but also in those which could lead to thrombotic conditions. A better understanding of this interaction is thus essential for a rational approach to the therapeutic management of these conditions.