Platelet factor 4 impairs the anticoagulant activity of activated protein C.
AuthorsPreston, Roger J S
Johnson, Jennifer A
Ainle, Fionnuala Ní
Smith, Owen P
Jenkins, P Vince
O'Donnell, James S
AffiliationHaemostasis Research Group, Institute of Molecular Medicine, Trinity College Dublin, St James' Hospital, Dublin 8, Ireland. firstname.lastname@example.org
Platelet Factor 4
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CitationPlatelet factor 4 impairs the anticoagulant activity of activated protein C. 2009, 284 (9):5869-75 J. Biol. Chem.
JournalThe Journal of biological chemistry
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.
- Dissociation of activated protein C functions by elimination of protein S cofactor enhancement.
- Authors: Harmon S, Preston RJ, Ni Ainle F, Johnson JA, Cunningham MS, Smith OP, White B, O'Donnell JS
- Issue date: 2008 Nov 7
- Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis.
- Authors: Slungaard A, Key NS
- Issue date: 1994 Oct 14
- The roles of factor Va and protein S in formation of the activated protein C/protein S/factor Va inactivation complex.
- Authors: Gierula M, Salles-Crawley II, Santamaria S, Teraz-Orosz A, Crawley JTB, Lane DA, Ahnström J
- Issue date: 2019 Dec
- Platelet factor 4 enhances generation of activated protein C in vitro and in vivo.
- Authors: Slungaard A, Fernandez JA, Griffin JH, Key NS, Long JR, Piegors DJ, Lentz SR
- Issue date: 2003 Jul 1
- Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C.
- Authors: Sun YH, Tran S, Norstrøm EA, Dahlbäck B
- Issue date: 2004 Nov 12