Dubois Christophe, Panicot-Dubois Laurence, Merrill-Skoloff Glenn, Furie Bruce, Furie Barbara C
Division of Hemostasis and Thrombosis, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, 840 Memorial Drive, Cambridge, MA 02139, USA.
Blood. 2006 May 15;107(10):3902-6. doi: 10.1182/blood-2005-09-3687. Epub 2006 Feb 2.
The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRgamma-null mice (FcRgamma(-/-)) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl(3) injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl(3) injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRgamma(-/-) compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRgamma(-/-). These data indicate a significant role for GPVI in FeCl(3)-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl(3)-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRgamma(-/-) was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl(3)-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.
在缺乏血小板表面糖蛋白VI（GPVI）的FcRγ基因敲除小鼠（FcRγ(-/-)）中，研究了胶原受体糖蛋白VI（GPVI）在小动脉血栓形成中的作用。采用重度或轻度FeCl₃损伤诱导血栓形成。与重度FeCl₃损伤相比，轻度损伤时胶原暴露显著延迟且减少。重度损伤后，与野生型小鼠相比，FcRγ(-/-)小鼠初次形成血栓和血管闭塞的时间延迟。与重度损伤相比，轻度损伤后野生型小鼠的血小板聚集减少。然而，FcRγ(-/-)小鼠在重度或轻度损伤后的血小板聚集差异不大。这些数据表明GPVI在FeCl₃诱导的血栓形成中起重要作用。用重组水蛭素预处理野生型小鼠进一步损害了轻度FeCl₃诱导的血栓形成，证明了凝血酶的作用。野生型和FcRγ(-/-)小鼠激光诱导的血栓形成情况相当。激光损伤后未检测到循环血液中有胶原暴露。以血栓大小进行标准化后，激光诱导血栓中的血栓相关组织因子比重度FeCl₃诱导血栓中的高5倍。因此，激光损伤后凝血酶介导的血小板激活似乎比GPVI - 胶原介导的血小板激活更重要。因此，在考虑抗血栓治疗靶点时，使用多种具有不同血栓形成途径的动物模型可能很重要。
