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Platelet factor 4 impairs the anticoagulant activity of activated protein C. |
HARMON, SHONA; PRESTON, ROGER; JOHNSON, JENNIFER; O'DONNELL, JAMES; NI AINLE, FIONNUALA
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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
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Keyword(s):
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Biochemistry and molecular biology; platelet activation |
Publication Date:
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2009 |
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Type:
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Journal article |
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Peer-Reviewed:
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Yes |
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Language(s):
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English |
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Institution:
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Trinity College Dublin |
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Funder(s):
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Science Foundation Ireland; Health Research Board |
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Citation(s):
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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 |
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Publisher(s):
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American Society for Biochemistry and Molecular Biology |
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Related Link(s):
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http://dx.doi.org/10.1074/jbc.M804703200 |
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First Indexed:
2010-11-12 05:17:20 Last Updated:
2012-05-21 05:30:44 |
