MECHANISMS OF ACTIVATION OF COAGULATION FACTOR XI

本研究项目的目的是通过以下方法研究其机制： 所述凝血因子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， 因为缺乏这种蛋白质的人会有异常出血， 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活化的替代机制。 近期 发现丝氨酸蛋白酶凝血酶能够激活因子Xi 且因子Xi在存在 某些带负电荷的表面表明，因子Xi可能起作用， 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， 血浆和存在可能正常发挥功能的各种细胞的情况下 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 Xi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。

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.