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Platelet Factor 4 Impairs the Anticoagulant Activity of Activated Protein C

Preston, Roger J. S. ; Tran, Sinh LU ; Johnson, Jennifer A. ; Ainle, Fionnuala Ni ; Harmon, Shona ; White, Barry ; Smith, Owen P. ; Jenkins, P. Vince ; Dahlbäck, Björn LU and O'Donnell, James S. (2009) In Journal of Biological Chemistry 284(9). p.5869-5875
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... (More)
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. (Less)
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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
284
issue
9
pages
5869 - 5875
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • wos:000263560600050
  • scopus:65549096799
ISSN
1083-351X
DOI
10.1074/jbc.M804703200
language
English
LU publication?
yes
id
d38932d1-dd90-477d-99aa-362d4d43f181 (old id 1372166)
date added to LUP
2016-04-01 12:26:29
date last changed
2025-04-04 14:11:16
@article{d38932d1-dd90-477d-99aa-362d4d43f181,
  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.}},
  author       = {{Preston, Roger J. S. and Tran, Sinh and Johnson, Jennifer A. and Ainle, Fionnuala Ni and Harmon, Shona and White, Barry and Smith, Owen P. and Jenkins, P. Vince and Dahlbäck, Björn and O'Donnell, James S.}},
  issn         = {{1083-351X}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{5869--5875}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Platelet Factor 4 Impairs the Anticoagulant Activity of Activated Protein C}},
  url          = {{http://dx.doi.org/10.1074/jbc.M804703200}},
  doi          = {{10.1074/jbc.M804703200}},
  volume       = {{284}},
  year         = {{2009}},
}