Platelet Factor 4 Impairs the Anticoagulant Activity of Activated Protein C

Research output: Contribution to journalArticle

Abstract

Platelet factor 4 (PF4) is an abundant platelet alpha-granule chemokine released following platelet activation. PF4 interacts with thrombomodulin and the gamma-carboxyglutamic acid (Gla) domain of protein C, thereby enhancing activated protein C (APC) generation by the thrombin-thrombomodulin complex. However, the protein C Gla domain not only mediates protein C activation in vivo, but also plays a critical role in modulating the diverse functional properties of APC once generated. In this study we demonstrate that PF4 significantly inhibits APC anticoagulant activity. PF4 inhibited both protein S-dependentAPC anticoagulant function in plasma and protein S-dependent factor Va (FVa) proteolysis 3- to 5-fold, demonstrating that PF4 impairs protein S cofactor enhancement of APC anticoagulant function. Using recombinant factor Va variants FVa-R506Q/R679Q and FVa-R306Q/R679Q, PF4 was shown to impair APC proteolysis of FVa at position Arg306 by 3-fold both in the presence and absence of protein S. These data suggest that PF4 contributes to the poorly understood APC resistance phenotype associated with activated platelets. Finally, despite PF4 binding to the APC Gla domain, we show that APC in the presence of PF4 retains its ability to initiate PAR-1-mediated cytoprotective signaling. In summary, we propose that PF4 acts as a critical regulator of APC generation, but also differentially targets APC toward cytoprotective, rather than anticoagulant function at sites of vascular injury with concurrent platelet activation.

Details

Authors
  • Roger J. S. Preston
  • Sinh Tran
  • Jennifer A. Johnson
  • Fionnuala Ni Ainle
  • Shona Harmon
  • Barry White
  • Owen P. Smith
  • P. Vince Jenkins
  • Björn Dahlbäck
  • James S. O'Donnell
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)5869-5875
JournalJournal of Biological Chemistry
Volume284
Issue number9
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes