Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma
Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma
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DOI：
10.1073/pnas.1004741107
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发表时间：
2010-05-18
影响因子：
11.1
通讯作者：
Urbanus, Rolf T.
中科院分区：
文献类型：
--
作者：
Maas, Coen;Meijers, Joost C. M.;Urbanus, Rolf T.
内源性凝血途径促进生理性止血的机制尚不清楚。凝血酶激活因子XI，这是该途径中的关键酶原，导致凝血酶生成增加。由于体外凝血因子XI的凝血酶依赖性活化相对低效，我们假设生理辅因子支持血浆环境中的此反应。因此，我们研究了凝血的辅助因子，活化因子V，活化因子VIII，高分子量激肽原，或蛋白S，是否影响凝血酶对因子XI的活化。只有活化的因子V刺激因子XI的活化凝血酶在纯化的系统。结合研究表明，因子XI通过多个结合位点与因子V和因子Va特异性相互作用。我们进一步研究了血浆中活化因子V的辅因子功能。耗尽因子V，或添加活化蛋白C，降低了血浆中凝血酶对内源性途径的激活。然而，活化蛋白C没有发挥这种作用，在血浆中的血栓前因子V莱顿突变的纯合子载体。总之，我们提出了一个作用（激活）因子V作为辅因子在凝血酶激活因子XI。这些发现为健康和疾病中的凝血系统提供了见解。
The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.