Platelet factor 4 impairs the anticoagulant activity of activated protein C.

Hdl Handle:
http://hdl.handle.net/10147/207829
Title:
Platelet factor 4 impairs the anticoagulant activity of activated protein C.
Authors:
Preston, Roger J S; Tran, 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.ie
Citation:
J Biol Chem. 2009 Feb 27;284(9):5869-75. Epub 2009 Jan 6.
Journal:
The Journal of biological chemistry
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207829
DOI:
10.1074/jbc.M804703200
PubMed ID:
19129181
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 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:
eng
MeSH:
Anticoagulants/*pharmacology; Apoptosis/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
ISSN:
0021-9258 (Print); 0021-9258 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorPreston, Roger J Sen_GB
dc.contributor.authorTran, Sinhen_GB
dc.contributor.authorJohnson, Jennifer Aen_GB
dc.contributor.authorNi Ainle, Fionnualaen_GB
dc.contributor.authorHarmon, Shonaen_GB
dc.contributor.authorWhite, Barryen_GB
dc.contributor.authorSmith, Owen Pen_GB
dc.contributor.authorJenkins, P Vinceen_GB
dc.contributor.authorDahlback, Bjornen_GB
dc.contributor.authorO'Donnell, James Sen_GB
dc.date.accessioned2012-02-01T10:45:53Z-
dc.date.available2012-02-01T10:45:53Z-
dc.date.issued2012-02-01T10:45:53Z-
dc.identifier.citationJ Biol Chem. 2009 Feb 27;284(9):5869-75. Epub 2009 Jan 6.en_GB
dc.identifier.issn0021-9258 (Print)en_GB
dc.identifier.issn0021-9258 (Linking)en_GB
dc.identifier.pmid19129181en_GB
dc.identifier.doi10.1074/jbc.M804703200en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207829-
dc.description.abstractPlatelet 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.en_GB
dc.language.isoengen_GB
dc.subject.meshAnticoagulants/*pharmacologyen_GB
dc.subject.meshApoptosis/physiologyen_GB
dc.subject.meshCells, Cultureden_GB
dc.subject.meshEndothelium, Vascular/cytology/metabolismen_GB
dc.subject.meshFactor Va/metabolismen_GB
dc.subject.meshHexadimethrine/pharmacologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshPlatelet Factor 4/genetics/*metabolismen_GB
dc.subject.meshProtamines/pharmacologyen_GB
dc.subject.meshProtein C/antagonists & inhibitors/*metabolismen_GB
dc.subject.meshProtein S/metabolismen_GB
dc.subject.meshThrombin/metabolismen_GB
dc.titlePlatelet factor 4 impairs the anticoagulant activity of activated protein C.en_GB
dc.contributor.departmentHaemostasis Research Group, Institute of Molecular Medicine, Trinity College, Dublin, St James' Hospital, Dublin 8, Ireland. prestonr@tcd.ieen_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
dc.description.provinceLeinster-
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