Segregation of platelet aggregatory and procoagulant Microdomains in thrombus formation - Regulation by transient integrin activation
Segregation of platelet aggregatory and procoagulant Microdomains in thrombus formation - Regulation by transient integrin activation
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DOI：
10.1161/atvbaha.107.151100
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发表时间：
2007-11-01
影响因子：
8.7
通讯作者：
Heemskerk, Johan W. M.
中科院分区：
文献类型：
--
作者：
Munnix, Imke C. A.;Kuijpers, Marijke J. E.;Heemskerk, Johan W. M.
目的：血小板在血栓形成中起双重作用：形成聚集体和促进凝血。我们在体外和体内研究了血小板在胶原诱导血栓形成过程中承担的这些独立功能。方法和结果：高分辨率双光子荧光显微镜显示，在血流形成血栓时，纤维蛋白（原）结合的血小板聚集成单独的聚集体，而不同斑块的非聚集血小板暴露于磷脂酰丝氨酸。后一组血小板中α IIb β 3整合素失活，凝血因子结合增加。表达5 -羟色胺结合位点的包被血小板未被确定为单独的人群。凝血酶的产生和凝血有利于向暴露磷脂酰丝氨酸的血小板转化，使整合素失活并降低粘连。体外酪氨酸磷酸化的延长导致活性α IIb β 3的继发性下调。结论：这些结果导致血栓形成的一个新的空间模型，其中聚集的血小板确保血栓的稳定性，而不同斑块的非聚集血小板发挥促凝活性并产生凝血酶和纤维蛋白。在这里，血栓形成的止血活性是由促凝血小板和促凝血小板形成的平衡决定的。这种平衡受到抗血小板和抗凝药物的影响。
Objective-Platelets play a dual role in thrombosis by forming aggregates and stimulating coagulation. We investigated the commitment of platelets to these separate functions during collagen-induced thrombus formation in vitro and in vivo.Methods and Results-High-resolution 2-photon fluorescence microscopy revealed that in thrombus formation under flow, fibrin(ogen)-binding platelets assembled into separate aggregates, whereas distinct patches of nonaggregated platelets exposed phosphatidylserine. The latter platelet population had inactivated alpha IIb beta 3 integrins and displayed increased binding of coagulation factors. Coated platelets, expressing serotonin binding sites, were not identified as a separate population. Thrombin generation and coagulation favored the transformation to phosphatidylserine-exposing platelets with inactivated integrins and reduced adhesion. Prolonged tyrosine phosphorylation in vitro resulted in secondary downregulation of active alpha IIb beta 3.Conclusions-These results lead to a new spatial model of thrombus formation, in which aggregated platelets ensure thrombus stability, whereas distinct patches of nonaggregated platelets effectuate procoagulant activity and generate thrombin and fibrin. Herein, the hemostatic activity of a developing thrombus is determined by the balance in formation of proaggregatory and procoagulant platelets. This balance is influenced by antiplatelet and anticoagulant medication.