From the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (M.J.E.K., P.E.J.v.d.M., M.A.H.F., N.J.A.M., J.G.-R., J.W.M.H., J.M.E.M.C.); CSL Behring GmbH, Marburg, Germany (F.M.); Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (J.C.M.M.); Department of Plasma Proteins, Sanquin, Amsterdam, The Netherlands (J.C.M.M.); Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden (T.R.); and Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (T.R.).
Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1674-80. doi: 10.1161/ATVBAHA.114.303315. Epub 2014 May 22.
Atherothrombosis is the main cause of myocardial infarction and ischemic stroke. Although the extrinsic (tissue factor-factor VIIa [FVIIa]) pathway is considered as a major trigger of coagulation in atherothrombosis, the role of the intrinsic coagulation pathway via coagulation FXII herein is unknown. Here, we studied the roles of the extrinsic and intrinsic coagulation pathways in thrombus formation on atherosclerotic plaques both in vivo and ex vivo.
Plaque rupture after ultrasound treatment evoked immediate formation of subocclusive thrombi in the carotid arteries of Apoe(-/-) mice, which became unstable in the presence of structurally different FXIIa inhibitors. In contrast, inhibition of FVIIa reduced thrombus size at a more initial stage without affecting embolization. Genetic deficiency in FXII (human and mouse) or FXI (mouse) reduced ex vivo whole-blood thrombus and fibrin formation on immobilized plaque homogenates. Localization studies by confocal microscopy indicated that FXIIa bound to thrombi and fibrin particularly in luminal-exposed thrombus areas.
The FVIIa- and FXIIa-triggered coagulation pathways have distinct but complementary roles in atherothrombus formation. The tissue factor-FVIIa pathway contributes to initial thrombus buildup, whereas FXIIa bound to thrombi ensures thrombus stability.
动脉粥样硬化血栓形成是心肌梗死和缺血性脑卒中的主要病因。尽管外源性（组织因子-因子 VIIa[FVIIa]）途径被认为是动脉粥样硬化血栓形成中凝血的主要触发因素，但在此情况下凝血 FXII 介导的内源性凝血途径的作用尚不清楚。在此，我们研究了外源性和内源性凝血途径在体内和体外动脉粥样硬化斑块血栓形成中的作用。
超声处理后的斑块破裂会立即在载脂蛋白 E 基因敲除（Apoe(-/-)）小鼠的颈动脉中引发亚闭塞性血栓形成，而结构不同的 FXIIa 抑制剂会使其变得不稳定。相比之下，FVIIa 的抑制作用在更早的阶段减小了血栓的大小，而不影响栓塞。FXII（人源和鼠源）或 FXI（鼠源）的基因缺失减少了在固定化斑块匀浆上的全血血栓和纤维蛋白形成。共聚焦显微镜定位研究表明，FXIIa 特别在暴露于管腔的血栓区域与血栓和纤维蛋白结合。
FVIIa 和 FXIIa 触发的凝血途径在动脉粥样硬化血栓形成中具有不同但互补的作用。组织因子-FVIIa 途径有助于初始血栓形成，而结合于血栓的 FXIIa 则确保血栓的稳定性。
