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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/41143

Title: Platelet factor 4 impairs the anticoagulant activity of activated protein C.
Author: HARMON, SHONA
PRESTON, ROGER
JOHNSON, JENNIFER
O'DONNELL, JAMES
NI AINLE, FIONNUALA
Sponsor: Science Foundation Ireland
Health Research Board
Author's Homepage: http://people.tcd.ie/prestonr
http://people.tcd.ie/sharmon
http://people.tcd.ie/johnsoje
http://people.tcd.ie/jodonne
http://people.tcd.ie/niainlf
Keywords: Biochemistry and molecular biology
platelet activation
Issue Date: 2009
Publisher: American Society for Biochemistry and Molecular Biology
Citation: Preston, RJ, Tran, S, Johnson, JA, Ainle, FN, Harmon, S, White, B, Smith, OP, Jenkins, PV, Dahlbäck, B, O'Donnell, JS, Platelet factor 4 impairs the anticoagulant activity of activated protein C., The Journal of Biological Chemistry, 284, 9, 2009, 5869 - 5875
Series/Report no.: The Journal of Biological Chemistry;
284;
9;
Abstract: Platelet factor 4 (PF4) is an abundant platelet -granule chemokine released following platelet activation. PF4 interacts with thrombomodulin and the -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
Description: PUBLISHED
URI: http://hdl.handle.net/2262/41143
Related links: http://dx.doi.org/10.1074/jbc.M804703200
Appears in Collections:Haematology (Scholarly Publications)

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