Platelet factor 4 impairs the anticoagulant activity of activated protein C.
Authors
Preston, Roger J STran, Sinh
Johnson, Jennifer A
Ni Ainle, Fionnuala
Harmon, Shona
White, Barry
Smith, Owen P
Jenkins, P Vince
Dahlback, Bjorn
O'Donnell, James S
Affiliation
Haemostasis Research Group, Institute of Molecular Medicine, Trinity College, Dublin, St James' Hospital, Dublin 8, Ireland. prestonr@tcd.ieIssue Date
2012-02-01T10:45:53ZMeSH
Anticoagulants/*pharmacologyApoptosis/physiology
Cells, Cultured
Endothelium, Vascular/cytology/metabolism
Factor Va/metabolism
Hexadimethrine/pharmacology
Humans
Platelet Factor 4/genetics/*metabolism
Protamines/pharmacology
Protein C/antagonists & inhibitors/*metabolism
Protein S/metabolism
Thrombin/metabolism
Metadata
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J Biol Chem. 2009 Feb 27;284(9):5869-75. Epub 2009 Jan 6.Journal
The Journal of biological chemistryDOI
10.1074/jbc.M804703200PubMed ID
19129181Abstract
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 anti-coagulant activity. PF4 inhibited both protein S-dependent APC 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 Arg(306) 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.Language
engISSN
0021-9258 (Print)0021-9258 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M804703200
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