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

Hdl Handle:
http://hdl.handle.net/10147/82459
Title:
Platelet factor 4 impairs the anticoagulant activity of activated protein C.
Authors:
Preston, Roger J S; Tran, Sinh; Johnson, Jennifer A; Ainle, Fionnuala Ní; Harmon, Shona; White, Barry; Smith, Owen P; Jenkins, P Vince; Dahlbäck, Björn; 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:
Platelet factor 4 impairs the anticoagulant activity of activated protein C. 2009, 284 (9):5869-75 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
27-Feb-2009
URI:
http://hdl.handle.net/10147/82459
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:
en
MeSH:
Anticoagulants; Apoptosis; Cells, Cultured; Endothelium, Vascular; Factor Va; Hexadimethrine; Humans; Platelet Factor 4; Protamines; Protein C; Protein S; Thrombin
ISSN:
0021-9258

Full metadata record

DC FieldValue Language
dc.contributor.authorPreston, Roger J S-
dc.contributor.authorTran, Sinh-
dc.contributor.authorJohnson, Jennifer A-
dc.contributor.authorAinle, Fionnuala Ní-
dc.contributor.authorHarmon, Shona-
dc.contributor.authorWhite, Barry-
dc.contributor.authorSmith, Owen P-
dc.contributor.authorJenkins, P Vince-
dc.contributor.authorDahlbäck, Björn-
dc.contributor.authorO'Donnell, James S-
dc.date.accessioned2009-09-24T09:59:38Z-
dc.date.available2009-09-24T09:59:38Z-
dc.date.issued2009-02-27-
dc.identifier.citationPlatelet factor 4 impairs the anticoagulant activity of activated protein C. 2009, 284 (9):5869-75 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid19129181-
dc.identifier.doi10.1074/jbc.M804703200-
dc.identifier.urihttp://hdl.handle.net/10147/82459-
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.-
dc.language.isoenen
dc.subject.meshAnticoagulants-
dc.subject.meshApoptosis-
dc.subject.meshCells, Cultured-
dc.subject.meshEndothelium, Vascular-
dc.subject.meshFactor Va-
dc.subject.meshHexadimethrine-
dc.subject.meshHumans-
dc.subject.meshPlatelet Factor 4-
dc.subject.meshProtamines-
dc.subject.meshProtein C-
dc.subject.meshProtein S-
dc.subject.meshThrombin-
dc.titlePlatelet factor 4 impairs the anticoagulant activity of activated protein C.en
dc.contributor.departmentHaemostasis Research Group, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin 8, Ireland. prestonr@tcd.ieen
dc.identifier.journalThe Journal of biological chemistryen
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