Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.
Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.
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DOI：
10.1084/jem.20052458
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发表时间：
2006-03-20
期刊：
影响因子：
--
通讯作者：
Renné T
中科院分区：
文献类型：
--
作者：
Kleinschnitz C;Stoll G;Bendszus M;Schuh K;Pauer HU;Burfeind P;Renné C;Gailani D;Nieswandt B;Renné T
纤维蛋白的形成对于限制血管损伤部位的失血（止血）至关重要，但也可能导致血管血栓形成。触发体外凝血内在途径的蛋白酶——因子XII （FXII）的遗传性缺乏与自发性或过度损伤性出血无关，表明FXII不需要用于止血。我们证明，缺乏或抑制FXII保护小鼠缺血性脑损伤。短暂性大脑中动脉闭塞后，FXII缺乏和FXII抑制剂处理的小鼠梗死脑容量明显小于野生型对照组，但梗死相关出血未增加。靶向FXII可减少缺血血管中纤维蛋白的形成，用人FXII重建FXII缺陷小鼠可恢复纤维蛋白沉积。缺乏FXII底物因子XI的小鼠同样受到血管闭塞纤维蛋白形成的保护，这表明FXII通过内在途径参与病理性凝血。这些数据表明，病理性血栓形成的某些过程不同于正常止血所需的过程。由于FXII似乎在病理性纤维蛋白形成中起作用，但在止血中是必不可少的，因此抑制FXII可能为预防中风和其他血栓栓塞性疾病提供了一种选择性和安全的策略。
Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.
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DOI：
10.1084/jem.190.1.91
发表时间：
1999-07-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Choudhri TF;Hoh BL;Prestigiacomo CJ;Huang J;Kim LJ;Schmidt AM;Kisiel W;Connolly ES Jr;Pinsky DJ
通讯作者：
Pinsky DJ
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
影响因子：
56.9
作者：
GAILANI, D;BROZE, GJ
通讯作者：
BROZE, GJ
DOI：
10.1111/j.1432-1033.1987.tb11174.x
发表时间：
1987-05-04
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
TANS, G;JANSSENCLAESSEN, T;GRIFFIN, JH
通讯作者：
GRIFFIN, JH
影响因子：
15.9
作者：
GHEBREHIWET, B;RANDAZZO, BP;KAPLAN, AP
通讯作者：
KAPLAN, AP