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MECHANISMS OF ACTIVATION OF COAGULATION FACTOR XI

凝血因子 XI 的激活机制

基本信息

批准号：
2459849
负责人：
David Gailani
金额：
$ 8.63万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-08-01 至 1998-07-31
项目状态：
已结题

项目摘要

The purpose of this research project is to investigate the mechanisms by which coagulation factor XI becomes an active serine protease. Factor XI is a plasma glycoprotein which is clearly required for normal hemostasis, as persons deficient in this protein have abnormal bleeding, particularly after surgical procedures. In vitro, factor XI is activated by factor XII in conjunction with high molecular weight kininogen and prekallikrein, however, congenital deficiencies of these "contact activation" proteins do not cause clinical hemostatic problems. This observation suggests that an alternative mechanism for factor XI activation exists. The recent findings that the serine protease thrombin is able to activate factor XI in vitro and that factor XI undergoes autoactivation in the presence of certain negatively charged surfaces suggests that factor XI may play a role in sustaining the hemostatic process after some thrombin has been generated at the site of a wound. The activation of factor XI by thrombin and by autoactivation will be studied in physiologic systems containing plasma and in the presence of various cells which may function in normal hemostasis. A search will be conducted for additional, previously undescribed, mechanisms of factor XI activation. Finally, factor XI mutants will be produced to study the interaction of thrombin with factor XI and the autoactivation process. The data obtained will provide far a better understanding of normal hemostasis and will provide a firmer knowledge base from which to study thromboembolic diseases.

本研究项目的目的是通过以下方法研究其机制：该凝血因子XI变成活性丝氨酸蛋白酶。因子XI 是一种血浆糖蛋白，它显然是正常止血所需的，由于缺乏这种蛋白质的人会出现异常出血，特别是在外科手术之后。在体外，因子XI被因子XII激活与高分子量激肽原和前激肽释放酶结合，然而，这些“接触激活”蛋白的先天性缺陷，不会引起临床止血问题。这一观察表明，存在因子XI激活的替代机制。近期发现丝氨酸蛋白酶凝血酶能够激活因子XI 并且因子XI在存在下经历自活化某些带负电荷的表面表明，因子XI可能发挥作用，在维持止血过程中的作用后，一些凝血酶已经在伤口处产生。凝血酶对凝血因子XI的激活作用并通过自激活将在生理系统中进行研究，血浆和在各种细胞的存在下，这些细胞可以在正常情况下发挥功能，止血。将进行一次搜索，未描述的因子XI激活机制。最后，因子XI 将产生突变体以研究凝血酶与因子第十一章和自动激活过程获得的数据将提供远更好地了解正常止血，并将提供更可靠的研究血栓栓塞性疾病的知识基础。