Dual role of collagen in factor XII-dependent thrombus formation
Dual role of collagen in factor XII-dependent thrombus formation
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DOI：
10.1182/blood-2008-07-171066
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发表时间：
2009-07-23
期刊：
影响因子：
20.3
通讯作者：
Heemskerk, Johan W. M.
中科院分区：
文献类型：
--
作者：
van der Meijden, Paola E. J.;Munnix, Imke C. A.;Heemskerk, Johan W. M.
体内小鼠模型已经表明，由因子XII启动的内源性凝血途径有助于响应于主要血管损伤的血栓形成。在这里，我们表明，纤维I型胶原蛋白引起剂量依赖性缩短凝血时间的人血浆通过激活因子XII。这种激活是由因子XII与胶原蛋白结合介导的。因子XII活化也有助于胶原对血浆中凝血酶生成的刺激作用，并通过糖蛋白VI活化增加血小板的作用。此外，在凝血条件下的流动依赖性血栓形成中，胶原蛋白促进磷脂酰丝氨酸暴露血小板的出现和纤维蛋白的形成。糖蛋白VI信号传导缺陷（血小板LAT或磷脂酶C γ 2缺陷）延迟和抑制磷脂酰丝氨酸暴露和血栓形成。明显地，这些过程也被抑制因子XII或XI的情况下，而组织因子/因子-VIIa的阻断几乎没有效果。总之，这些结果指出胶原蛋白在血栓形成中的双重作用：通过LAT和PLC γ 2刺激糖蛋白VI信号传导以形成促凝血血小板;以及激活因子XII以刺激凝血酶产生并增强血小板-纤维蛋白血栓的形成。（血。2009; 114：881-890）
In vivo mouse models have indicated that the intrinsic coagulation pathway, initiated by factor XII, contributes to thrombus formation in response to major vascular damage. Here, we show that fibrillar type I collagen provoked a dose-dependent shortening of the clotting time of human plasma via activation of factor XII. This activation was mediated by factor XII binding to collagen. Factor XII activation also contributed to the stimulating effect of collagen on thrombin generation in plasma, and increased the effect of platelets via glycoprotein VI activation. Furthermore, in flow-dependent thrombus formation under coagulant conditions, collagen promoted the appearance of phosphatidylserine-exposing platelets and the formation of fibrin. Defective glycoprotein VI signaling (with platelets deficient in LAT or phospholipase C gamma 2) delayed and suppressed phosphatidylserine exposure and thrombus formation. Markedly, these processes were also suppressed by absence of factor XII or XI, whereas blocking of tissue factor/factor-VIIa was of little effect. Together, these results point to a dual role of collagen in thrombus formation: stimulation of glycoprotein VI signaling via LAT and PLC gamma 2 to form procoagulant platelets; and activation of factor XII to stimulate thrombin generation and potentiate the formation of platelet-fibrin thrombi. (Blood. 2009; 114: 881-890)