Scott C F, Colman R W
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140.
Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11189-93. doi: 10.1073/pnas.89.23.11189.
The intrinsic pathway of blood coagulation is activated when factor XIa, one of the three contact-system enzymes, is generated and then activates factor IX. Factor XI has been shown to be efficiently activated in vitro by surface-bound factor XIIa after factor XI is transported to the surface by its cofactor, high molecular weight kininogen (HK). However, individuals lacking any of the three contact-system proteins--namely, factor XII, prekallikrein, and HK--do not suffer from bleeding abnormalities. This mystery has led several investigators to search for an "alternate" activation pathway for factor XI. Recently, factor XI has been reported to be autoactivated on the soluble "surface" dextran sulfate, and thrombin was shown to accelerate the autoactivation. However, it was also reported that HK, the cofactor for factor XIIa-mediated activation of factor XI, actually diminishes the thrombin-catalyzed activation rate of factor XI. Nonetheless, it was suggested that thrombin was a more efficient activator than factor XIIa. In this report we investigated the effect of fibrinogen, the major coagulation protein in plasma, on the activation rate of factor XI. Fibrinogen, the preferred substrate for thrombin in plasma, virtually prevented autoactivation of factor XI as well as the thrombin-mediated activation of factor XI, while having no effect on factor XIIa-catalyzed activation. HK dramatically curtailed the autoactivation of factor XI in addition to the thrombin-mediated activation. These data indicate that factor XI would not be autoactivated in a plasma environment, and thrombin would, therefore, be unlikely to potentiate the activation. We believe that the "missing pathway" for factor XI activation remains an enigma that warrants further investigation.
当三种接触系统酶之一的因子 XIa 产生并激活因子 IX 时，血液凝固的内源性途径被激活。因子 XI 已被证明在通过其辅因子高分子量激肽原（HK）转运到表面后，可被表面结合的因子 XIIa 在体外有效激活。然而，缺乏三种接触系统蛋白（即因子 XII、前激肽释放酶和 HK）中任何一种的个体并不会出现出血异常。这一谜团促使一些研究人员寻找因子 XI 的“替代”激活途径。最近，有报道称因子 XI 在可溶性“表面”硫酸葡聚糖上自动激活，并且凝血酶可加速这种自动激活。然而，也有报道称，作为因子 XIIa 介导的因子 XI 激活的辅因子，HK 实际上会降低凝血酶催化的因子 XI 激活速率。尽管如此，有人认为凝血酶是比因子 XIIa 更有效的激活剂。在本报告中，我们研究了血浆中主要凝血蛋白纤维蛋白原对因子 XI 激活速率的影响。纤维蛋白原是血浆中凝血酶的首选底物，实际上可阻止因子 XI 的自动激活以及凝血酶介导的因子 XI 激活，而对因子 XIIa 催化的激活没有影响。除了凝血酶介导的激活外，HK 还显著抑制因子 XI 的自动激活。这些数据表明，因子 XI 在血浆环境中不会自动激活，因此凝血酶不太可能增强这种激活。我们认为，因子 XI 激活的“缺失途径”仍然是一个谜，值得进一步研究。
