The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion
The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion
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DOI：
10.1182/blood-2003-03-0717
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发表时间：
2003-09-01
期刊：
影响因子：
20.3
通讯作者：
Ware, J
中科院分区：
文献类型：
--
作者：
Kato, K;Kanaji, T;Ware, J
血小板与血管损伤部位暴露的粘附配体相互作用是启动正常止血反应所必需的，并且可能成为导致血栓形成的动脉疾病的致病因素。我们报道了胶原诱导血小板活化的关键受体糖蛋白（GP） VI的靶向破坏。具有杂合子GP VI等位基因的小鼠的繁殖产生了野生型，杂合子和纯合子基因型的预期频率，表明这些动物没有生殖问题和正常的生存能力。在I型纤维胶原蛋白或惊厥素（一种蛇毒蛋白和已知的GP VI的血小板激动剂）作用下，GP VI全血小板不能聚集。然而，尾出血时间测量显示GP VI缺乏没有导致严重出血倾向。使用GP VInull或FcR-gamma（null）动物的血液可以消除I型胶原原纤维上的体外血小板血栓形成。反射干涉对比显微镜显示，GP VInull血小板缺乏血栓形成可能与血小板激活缺陷有关，在正常的初始粘附表面后，表现为缺乏扩散和不稳定的粘附。这些结果说明了GP VI在导致胶原原纤维上血小板血栓形成的粘附后事件中的作用。
Platelet interaction with exposed adhesive ligands at sites of vascular injury is required to initiate a normal hemostatic response and may become a pathogenic factor in arterial diseases leading to thrombosis. We report a targeted disruption in a key receptor for collagen-induced platelet activation, glycoprotein (GP) VI. The breeding of mice with heterozygous GP VI alleles produced the expected frequency of wild-type, heterozygous, and homozygous genotypes, indicating that these animals had no reproductive problems and normal viability. GP VInull platelets failed to aggregate in response to type I fibrillar collagen or convulxin, a snake venom protein and known platelet agonist of GP VI. Nevertheless, tail bleeding time measurements revealed no severe bleeding tendency as a consequence of GP VI deficiency. Ex vivo platelet thrombus formation on type I collagen fibrils was abolished using blood from either GP VInull or FcR-gamma(null) animals. Reflection interference contrast microscopy revealed that the lack of thrombus formation by GP VInull platelets could be linked to a defective platelet activation following normal initial tethering to the surface, visualized as lack of spreading and less stable adhesion. These results illustrate the role of GP VI in postadhesion events leading to the development of platelet thrombi on collagen fibrils.