Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin
Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin
复制标题
DOI：
10.1182/blood-2011-03-339572
复制
发表时间：
2011-10-06
期刊：
影响因子：
20.3
通讯作者：
Ariens, Robert A. S.
中科院分区：
文献类型：
--
作者：
Konings, Joke;Govers-Riemslag, Jose W. P.;Ariens, Robert A. S.
最近的数据表明，凝血因子（F）XII在体内血栓形成的重要贡献。由于纤维蛋白结构在凝块稳定性和血栓形成中起关键作用，我们假设FXII（a）与纤维蛋白（原）相互作用，从而调节凝块结构和功能。在血浆和纯化系统中，我们观察到纤维蛋白纤维密度的剂量依赖性增加和浊度的降低，反映了更致密的结构，以及FXIIa的凝块硬度的非线性增加。在血浆中，这种增加部分独立于凝血酶的产生，如蛇毒酶引发的凝血酶原缺乏血浆中形成的凝块和FXII和凝血酶原缺乏血浆中形成的凝块所示。纯化的FXII和α-FXIIa，而不是β-FXIIa，以纳摩尔亲和力结合纯化的纤维蛋白原和纤维蛋白。人颈动脉血栓的免疫染色显示FXII与致密纤维蛋白沉积区域共定位，为FXIIa在体内调节纤维蛋白结构提供了证据。这些数据表明，FXIIa通过FXIIa的N-末端与纤维蛋白（原）的直接结合，独立于凝血酶的产生调节纤维蛋白凝块结构。FXIIa对纤维蛋白结构的修饰代表了接触途径的一种新的生理作用，可能有助于血栓形成的病理生理学。（血。2011;118（14）：3942-3951）
Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombin-deficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and alpha-FXIIa, but not beta-FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that FXIIa modulates fibrin clot structure independently of thrombin generation through direct binding of the N-terminus of FXIIa to fibrin(ogen). Modification of fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of thrombosis. (Blood. 2011;118(14):3942-3951)