Key role of integrin alpha(IIb)beta(3) signaling to Syk kinase in tissue factor-induced thrombin generation

Paola E. J. van der Meijden*, Marion A. H. Feijge, Frauke Swieringa, Karen Gilio, Reyhan Nergiz-Unal, Karly Hamulyak, Johan W. M. Heemskerk

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Web of Science)

Abstract

The fibrin(ogen) receptor, integrin alpha(IIb)beta(3), has a well-established role in platelet spreading, aggregation and clot retraction. How alpha(IIb)beta(3) contributes to platelet-dependent coagulation is less well resolved. Here, we demonstrate that the potent suppressing effect of clinically used alpha(IIb)beta(3) blockers on tissue factor-induced thrombin generation is linked to diminished platelet Ca2+ responses and phosphatidylserine (PS) exposure. The same blockers suppress these responses in platelets stimulated with collagen and thrombin receptor agonists, whereas added fibrinogen potentiates these responses. In platelets spreading on fibrinogen, outside-in alpha(IIb)beta(3) signaling similarly enhances thrombin-induced Ca2+ rises and PS exposure. These responses are reduced in alpha(IIb)beta(3)-deficient platelets from patients with Glanzmann's thrombasthenia. Furthermore, the contribution of alpha(IIb)beta(3) to tissue factor-induced platelet Ca2+ rises, PS exposure and thrombin generation in plasma are fully dependent on Syk kinase activity. Tyrosine phosphorylation analysis confirms a key role of Syk activation, which is largely but not exclusively dependent on alpha(IIb)beta(3) activation. It is concluded that the majority of tissue factor-induced procoagulant activity of platelets relies on Syk activation and ensuing Ca2+ signal generation, and furthermore that a considerable part of Syk activation relies on alpha(IIb)beta(3) signaling. These results hence point to a novel role of Syk in integrin-dependent thrombin generation.
Original languageEnglish
Pages (from-to)3481-3492
JournalCellular and Molecular Life Sciences
Volume69
Issue number20
DOIs
Publication statusPublished - Oct 2012

Keywords

  • Platelets
  • Integrin alpha(IIb)beta(3)
  • Thrombin generation
  • Syk kinase
  • PS exposure

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