Laboratory for Clinical Thrombosis and Haemostasis, Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
Blood. 2011 Oct 6;118(14):3942-51. doi: 10.1182/blood-2011-03-339572. Epub 2011 Aug 9.
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 α-FXIIa, but not β-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.
最近的数据表明凝血因子（F）XII 对体内血栓形成有重要贡献。由于纤维蛋白结构在血栓稳定性和血栓形成中起着关键作用，我们假设 FXII(a)与纤维蛋白（原）相互作用，从而调节血栓结构和功能。在血浆和纯化系统中，我们观察到纤维蛋白纤维密度呈剂量依赖性增加，浊度降低，反映出结构更加致密，FXIIa 使血栓的硬度呈非线性增加。在血浆中，这种增加部分独立于凝血酶生成，如在缺乏凝血酶原的血浆中用蛇毒酶启动制成的血栓和缺乏 FXII 和凝血酶原的血浆制成的血栓中所示。纯化的 FXII 和 α-FXIIa，但不是 β-FXIIa，与纯化的纤维蛋白原和纤维蛋白以纳摩尔亲和力结合。对人颈动脉血栓的免疫染色显示，FXII 与纤维蛋白沉积密集区共定位，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 端与纤维蛋白（原）的直接结合，独立于凝血酶生成来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个新的生理作用，可能有助于血栓形成的病理生理学。
