Tethered platelet capture provides a mechanism for restricting circulating platelet activation to the wound site

Irina D Pokrovskaya; Sung W Rhee; Kelly K Ball; Jeffrey A Kamykowski; Oliver S Zhao; Denzel R D Cruz; Joshua Cohen; Maria A Aronova; Richard D Leapman; Brian Storrie

doi:10.1016/j.rpth.2023.100058

Tethered platelet capture provides a mechanism for restricting circulating platelet activation to the wound site

Res Pract Thromb Haemost. 2023 Jan 23;7(2):100058. doi: 10.1016/j.rpth.2023.100058. eCollection 2023 Feb.

Authors

Affiliations

¹ Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
² Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
³ Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.

Abstract

Background: 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.

Objectives: The objective of this study was to produce a paradigm for self-limiting thrombus growth in a mouse jugular vein model.

Methods: Data mining of advanced electron microscopy images was performed from authors' laboratories.

Results: 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.

Conclusions: 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.

Keywords: image analysis; platelets; puncture wound hemostasis; serial block face electron microscopy; thrombus formation; wide-area transmission electron microscopy.

Abstract

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