Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network

Timothy J. Stalker, Elizabeth A. Traxler, Jie Wu, Kenneth M. Wannemacher, Samantha L. Cermignano, Roman Voronov, Scott L. Diamond, Lawrence F. Brass

Research output: Contribution to journalArticlepeer-review

271 Scopus citations

Abstract

Achieving hemostasis following vascular injury requires the rapid accumulation of platelets and fibrin. Here we used a combination of confocal intravital imaging, genetically engineered mice, and antiplatelet agents to determine how variations in the extent of platelet activation following vascular injury arise from the integration of different elements of the platelet-signaling network. Two forms of penetrating injury were used to evoke the hemostatic response. Both produced a hierarchically organized structure in which a core of fully activated platelets was overlaid with an unstable shell of less-activated platelets. This structure emerged as hemostasis was achieved and persisted for at least 60 minutes following injury, its organization at least partly reflecting agonist concentration gradients. Thrombin activity and fibrin formation were found primarily in the innermost core. As proposed previously, greater packing density in the core facilitated contact-dependent signaling and limited entry of plasmaborne molecules visualized with fluorophores coupled to dextran and albumin. Blocking contact-dependent signaling or inhibiting thrombin reduced the size of the core, while the shell was heavily influenced by adenosine 5'-diphosphate and regulators of Gi2-mediated signaling. Thus, the hemostatic response is shown to produce a hierarchical structure arising, in part, from distinct elements of the platelet-signaling network.

Original languageEnglish (US)
Pages (from-to)1875-1885
Number of pages11
JournalBlood
Volume121
Issue number10
DOIs
StatePublished - Mar 7 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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