Tethered platelet capture provides a mechanism for restricting circulating platelet activation to the wound site.
Tethered platelet capture provides a mechanism for restricting circulating platelet activation to the wound site.
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DOI：
10.1016/j.rpth.2023.100058
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发表时间：
2023-02
影响因子：
4.6
通讯作者：
Storrie, Brian
中科院分区：
文献类型：
--
作者：
Pokrovskaya, Irina D.;Rhee, Sung W.;Ball, Kelly K.;Kamykowski, Jeffrey A.;Zhao, Oliver S.;Cruz, Denzel R. D.;Cohen, Joshua;Aronova, Maria A.;Leapman, Richard D.;Storrie, Brian
关键词：
穿刺伤是对人类健康的长期挑战，对此的理解有限，部分原因是缺乏关于循环血小板捕获到血管基质如何导致持续、自限性血小板积累的详细形态学数据。本研究的目的是建立小鼠颈静脉模型中自限性血栓生长的范例。先进电子显微镜图像的数据挖掘是在作者的实验室进行的。广域透射电子显微照片显示，暴露的外膜最初捕获血小板，导致局部出现脱颗粒、促凝血样血小板斑块。血小板激活至促凝血状态对达比加群（一种直接作用的 PAR 受体抑制剂）敏感，但对坎格瑞洛（一种 P2Y12 受体抑制剂）不敏感。随后的血栓生长对坎格雷洛和达比加群均敏感，并通过首先捕获胶原蛋白锚定的血小板，然后捕获松散粘附的外周血小板来维持盘状血小板串。空间检查表明，阶段性血小板激活导致盘状血小板束缚区，当血小板从一种激活状态转变为另一种激活状态时，该盘状血小板束缚区逐渐向外推。随着血栓生长减慢，盘状血小板募集变得罕见，松散粘附的血管内血小板未能转化为紧密粘附的血小板。总之，数据支持我们称之为“捕获和激活”的模型，其中最初的高血小板活化与暴露的外膜直接相关，所有随后的盘状血小板的束缚都是松散粘附的血小板，然后转化为紧密粘附的血小板，随着时间的推移，自限性血管内血小板活化是信号强度降低的结果。超微结构显示穿刺止血是通过封堵而不是堵塞孔来实现的。穿刺处的血小板募集必须在不危及循环血小板活化的情况下进行。高分辨率电子显微照片显示血小板在束缚到伤口后被激活。血小板束缚减少和信号减弱提供了一种自我限制血栓生长的方法。
Puncture wounding is a longstanding challenge to human health for which understanding is limited, in part, by a lack of detailed morphological data on how the circulating platelet capture to the vessel matrix leads to sustained, self-limiting platelet accumulation. The objective of this study was to produce a paradigm for self-limiting thrombus growth in a mouse jugular vein model. Data mining of advanced electron microscopy images was performed from authors’ laboratories. Wide-area transmission electron mcrographs revealed initial platelet capture to the exposed adventitia resulted in localized patches of degranulated, procoagulant-like platelets. Platelet activation to a procoagulant state was sensitive to dabigatran, a direct-acting PAR receptor inhibitor, but not to cangrelor, a P2Y12 receptor inhibitor. Subsequent thrombus growth was sensitive to both cangrelor and dabigatran and sustained by the capture of discoid platelet strings first to collagen-anchored platelets and later to loosely adherent peripheral platelets. Spatial examination indicated that staged platelet activation resulted in a discoid platelet tethering zone that was pushed progressively outward as platelets converted from one activation state to another. As thrombus growth slowed, discoid platelet recruitment became rare and loosely adherent intravascular platelets failed to convert to tightly adherent platelets. In summary, the data support a model that we term Capture and Activate, in which the initial high platelet activation is directly linked to the exposed adventitia, all subsequent tethering of discoid platelets is to loosely adherent platelets that convert to tightly adherent platelets, and self-limiting, intravascular platelet activation over time is the result of decreased signaling intensity. Ultrastructure shows that puncture bleeding cessation is by capping rather than plugging the hole. Platelet recruitment to a puncture must occur without endangering the circulating platelet activation. High-resolution electron micrographs reveal that platelets activate following tethering to wound. Decreased platelet tethering with weakened signaling provides a way to self-limit thrombus growth.
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