PDF herunterladen
Hamostaseologie 2011; 31(03): 185-195
DOI: 10.5482/ha-1166
Review
Schattauer GmbH

Multiple receptor-mediated functions of activated protein C

Rezeptor-vermittelte Funktionen von aktiviertem Protein C
H. Weiler
1   Blood Research Institute, BloodCenter of Wisconsin, Milwaukee
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received: 01. Juni 2011

accepted in revised form: 17. Juni 2011

Publikationsdatum:
28. Dezember 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The central effector protease of the protein C pathway, activated protein C (APC), interacts with the endothelial cell protein C receptor, with protease activated receptors (PAR), the apolipoprotein E2 receptor, and integrins to exert multiple effects on haemostasis and immune cell function. Such receptor interactions modify the activation of PC and determine the biological response to endogenous and therapeutically administered APC. This review summarizes the current knowledge about interactions of APC with cell surface-associated receptors, novel substrates such as histones and tissue factor pathway inhibitor, and their implications for the biologic function of APC in the control of coagulation and inflammation.

Zusammenfassung

Die im Zentrum des natürlichen Protein-C-Antikoagulans-Mechanismus stehende Protease, aktiviertes Protein C (APC), interagiert mit verschiedenen Rezeptoren, wie dem Endothelzell-Protein-C-Rezeptor, Proteaseaktivierten Rezeptoren (PAR), dem Apolipoprotein-E2-Rezeptor und Integrinen, was zu multiplen Wirkungen des Enzyms in der Hämostase und im Immunsystem führt. Solche unterschiedlichen Rezeptor-Wechselwirkungen können nicht nur die Aktivierung von Protein C beeinflussen, sondern determinieren auch die biologischen Funktionen von endogenem und therapeutisch eingesetztem APC.

Diese Übersicht fasst die aktuelle Datenlage zu Interaktionen des APC mit zellulären Rezeptoren, neuen Substraten (wie nuklearen Histonen) und Inhibitoren (z. B. Tissue Factor Pathway Inhibitor) zusammen und diskutiert Konsequenzen für die biologischen Funktionen von APC in der Kontrolle der Blutgerinnung und des Entzündungsgeschehens.

Keywords

Activated protein C - protein C - anticoagulation - cell signaling - protease activated receptors - apoER2 - integrin

Schlüsselwörter

Aktiviertes Protein C - Protein C - Gerinnungshemmung - Zellsignale - Protease-aktivierte Rezeptoren - apoER2 - Integrin
 

  • References

  • 1 Stenflo J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251: 355-363.
    PubMedGoogle Scholar
  • 2 Esmon CT, Stenflo J, Suttie JW. A new vitamin K-dependent protein. A phospholipid-binding zymogen of a serine esterase. J Biol Chem 1976; 251: 3052-3056.
    PubMedGoogle Scholar
  • 3 Kisiel W, Ericsson LH, Davie EW. Proteolytic activation of protein C from bovine plasma. Biochemistry 1976; 15: 4893-4900.
    CrossrefPubMedGoogle Scholar
  • 4 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-5831.
    CrossrefPubMedGoogle Scholar
  • 5 Comp PC, Jacocks RM, Ferrell GL, Esmon CT. Activation of protein C in vivo. J Clin Invest 1982; 70: 127-134.
    CrossrefPubMedGoogle Scholar
  • 6 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U S A 1981; 78: 2249-2252.
    CrossrefPubMedGoogle Scholar
  • 7 Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1982; 257: 859-864.
    PubMedGoogle Scholar
  • 8 Seegers WH, Heene DL, Marciniak E. Activation of purified prothrombin in ammonium sulfate solutions: purification of autoprothrombin C. Thromb Diath Haemorrh 1966; 15: 1-11.
    PubMedGoogle Scholar
  • 9 Marciniak E, Murano G, Seegers WH. Inhibitor of blood clotting derived from prothrombin. Thromb Diath Haemorrh 1967; 18: 161-166.
    PubMedGoogle Scholar
  • 10 Marciniak E. Coagulation inhibitor elicited by thrombin. Science 1970; 170: 452-453.
    CrossrefPubMedGoogle Scholar
  • 11 Dahlback B, Villoutreix BO. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 2005; 25: 1311-1320.
    CrossrefPubMedGoogle Scholar
  • 12 Esmon CT. Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 32 Suppl 2006; 01: 49-60.
    PubMedGoogle Scholar
  • 13 Griffin JH, Fernandez JA, Gale AJ, Mosnier LO. Activated protein C. J Thromb Haemost (Suppl. 05) 2007; 01: 73-80.
    PubMedGoogle Scholar
  • 14 Macias WL, Yan SB, Williams MD. et al. New insights into the protein C pathway: potential implications for the biological activities of drotrecogin alfa (activated). Crit Care 9 Suppl 2005; 04: S38-45.
    PubMedGoogle Scholar
  • 15 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109: 3161-3172.
    CrossrefPubMedGoogle Scholar
  • 16 Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004; 24: 1374-1383.
    CrossrefPubMedGoogle Scholar
  • 17 Vangerow B, Shorr AF, Wyncoll D. et al. The protein C pathway: implications for the design of the RESPOND study. Crit Care 11 Suppl. 2007 05. S4.
    PubMedGoogle Scholar
  • 18 Weiler H. Regulation of inflammation by the protein C system. Crit Care Med 2010; 38: S18-S25.
    CrossrefPubMedGoogle Scholar
  • 19 Weiler H, Ruf W. Activated protein C in sepsis: the promise of nonanticoagulant activated protein C. Curr Opin Hematol 2008; 15: 487-493.
    CrossrefPubMedGoogle Scholar
  • 20 Fletcher JR, McKee AE, Mills M. et al. Twenty-four hour membrane oxygenation in dogs without anticoagulation. Surgery 1976; 80: 214-223.
    PubMedGoogle Scholar
  • 21 Beller-Todd B, Archer LT, Hinshaw LB. Recovery from endotoxin shock after extracorporeal perfusion without anticoagulation. Circ Shock 1979; 06: 261-269.
    PubMedGoogle Scholar
  • 22 Taylor Jr FB, Chang A, Esmon CT. et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925.
    CrossrefPubMedGoogle Scholar
  • 23 Taylor Jr FB, Chang A, Hinshaw LB. et al. A model for thrombin protection against endotoxin. Thromb Res 1984; 36: 177-185.
    CrossrefPubMedGoogle Scholar
  • 24 Taylor FB, Kinasewitz G. Activated protein C in sepsis. J Thromb Haemost 2004; 02: 708-717.
    CrossrefPubMedGoogle Scholar
  • 25 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
    CrossrefPubMedGoogle Scholar
  • 26 Tang W, Basu S, Kong X. et al. Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study. Blood 2010; 116: 5032-5036.
    CrossrefPubMedGoogle Scholar
  • 27 Rezaie AR. Regulation of the protein C anticoagulant and anti-inflammatory pathways. Curr Med Chem 2010; 17: 2059-2069.
    CrossrefPubMedGoogle Scholar
  • 28 Yang L, Manithody C, Rezaie AR. Activation of protein C by the thrombin-thrombomodulin complex: cooperative roles of Arg-35 of thrombin and Arg-67 of protein C. Proc Natl Acad Sci USA 2006; 103: 879-884.
    CrossrefPubMedGoogle Scholar
  • 29 Preston RJ, Ajzner E, Razzari C. et al. Multifunctional specificity of the protein C/activated protein C Gla domain. J Biol Chem 2006; 281: 28850-28857.
    CrossrefPubMedGoogle Scholar
  • 30 Regan LM, Mollica JS, Rezaie AR, Esmon CT. The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C. J Biol Chem 1997; 272: 26279-26284.
    CrossrefPubMedGoogle Scholar
  • 31 Nishioka J, Ido M, Hayashi T, Suzuki K. The Gla26 residue of protein C is required for the binding of protein C to thrombomodulin and endothelial cell protein C receptor, but not to protein S and factor Va. Thromb Haemost 1996; 75: 275-282.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 32 Freyssinet JM, Beretz A, Klein-Soyer C. et al. Interference of blood-coagulation vitamin K-dependent proteins in the activation of human protein C. Involvement of the 4-carboxyglutamic acid domain in two distinct interactions with the thrombin-thrombomodulin complex and with phospholipids. Biochem J 1988; 256: 501-507.
    CrossrefPubMedGoogle Scholar
  • 33 Preston RJ, Villegas-Mendez A, Sun YH. et al. Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation. FEBS J 2005; 272: 97-108.
    PubMedGoogle Scholar
  • 34 Sun YH, Tran S, Norstrom EA, Dahlback B. Enhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C. J Biol Chem 2004; 279: 47528-47535.
    CrossrefPubMedGoogle Scholar
  • 35 Sun YH, Shen L, Dahlback B. Gla domain-mutated human protein C exhibiting enhanced anticoagulant activity and increased phospholipid binding. Blood 2003; 101: 2277-2284.
    CrossrefPubMedGoogle Scholar
  • 36 Pratt CW, Church FC. General features of the heparin-binding serpins antithrombin, heparin cofactor II and protein C inhibitor. Blood Coagul Fibrinolysis 1993; 04: 479-490.
    CrossrefPubMedGoogle Scholar
  • 37 Heeb MJ, Gruber A, Griffin JH. Identification of divalent metal ion-dependent inhibition of activated protein C by alpha 2-macroglobulin and alpha 2-antiplasmin in blood and comparisons to inhibition of factor Xa, thrombin, and plasmin. J Biol Chem 1991; 266: 17606-17612.
    PubMedGoogle Scholar
  • 38 Espana F, Gruber A, Heeb MJ. et al. In vivo and in vitro complexes of activated protein C with two inhibitors in baboons. Blood 1991; 77: 1754-1760.
    PubMedGoogle Scholar
  • 39 Heeb MJ, Griffin JH. Physiologic inhibition of human activated protein C by alpha 1-antitrypsin. J Biol Chem 1988; 263: 11613-11616.
    PubMedGoogle Scholar
  • 40 Geiger M, Heeb MJ, Binder BR, Griffin JH. Competition of activated protein C and urokinase for a heparin-dependent inhibitor. FASEB J 1988; 02: 2263-2267.
    CrossrefPubMedGoogle Scholar
  • 41 Sakata Y, Loskutoff DJ, Gladson C. et al. Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 68: 1218-1223.
    PubMedGoogle Scholar
  • 42 Rezaie AR. Vitronectin functions as a cofactor for rapid inhibition of activated protein C by plasminogen activator inhibitor-1. Implications for the mechanism of profibrinolytic action of activated protein C. J Biol Chem 2001; 276: 15567-15570.
    CrossrefPubMedGoogle Scholar
  • 43 Rezaie AR, Cooper ST, Church FC, Esmon CT. Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex. J Biol Chem 1995; 270: 25336-25339.
    CrossrefPubMedGoogle Scholar
  • 44 Mosnier LO, Bouma BN. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol 2006; 26: 2445-2453.
    CrossrefPubMedGoogle Scholar
  • 45 Han MH, Hwang SI, Roy DB. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451: 1076-1081.
    CrossrefPubMedGoogle Scholar
  • 46 Suzuki K. The multi-functional serpin, protein C inhibitor: beyond thrombosis and hemostasis. J Thromb Haemost 2008; 06: 2017-2026.
    CrossrefPubMedGoogle Scholar
  • 47 Slungaard A. Platelet factor 4: a chemokine enigma. Int J Biochem Cell Biol 2005; 37: 1162-1167.
    CrossrefPubMedGoogle Scholar
  • 48 Slungaard A, Key NS. Platelet factor 4 stimulates thrombomodulin protein C-activating cofactor activity. A structure-function analysis. J Biol Chem 1994; 269: 25549-25556.
    PubMedGoogle Scholar
  • 49 Kowalska MA, Mahmud SA, Lambert MP. et al. Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge. Blood 2007; 110: 1903-1905.
    CrossrefPubMedGoogle Scholar
  • 50 Slungaard A, Fernandez JA, Griffin JH. et al. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo. Blood 2003; 102: 146-151.
    CrossrefPubMedGoogle Scholar
  • 51 Dudek AZ, Pennell CA, Decker TD. et al. Platelet factor 4 binds to glycanated forms of thrombomodulin and to protein C. A potential mechanism for enhancing generation of activated protein C. J Biol Chem 1997; 272: 31785-31792.
    CrossrefPubMedGoogle Scholar
  • 52 Preston RJ, Tran S, Johnson JA. et al. Platelet factor 4 impairs the anticoagulant activity of activated protein C. J Biol Chem 2009; 284: 5869-5875.
    CrossrefPubMedGoogle Scholar
  • 53 Mosnier LO. Platelet factor 4 inhibits thrombomodulin-dependent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) by thrombin. J Biol Chem 2011; 286: 502-510.
    CrossrefPubMedGoogle Scholar
  • 54 Tran S, Dahlback B. Novel APC-cleavage sites in FVa provide insights into mechanisms of action of APC and its cofactor protein S. J Thromb Haemost 2010; 08: 129-136.
    CrossrefPubMedGoogle Scholar
  • 55 Norstrom E, Thorelli E, Dahlback B. Functional characterization of recombinant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524-530.
    CrossrefPubMedGoogle Scholar
  • 56 van der Neut MKolfschoten, Dirven RJ, Tans G. et al. The activated protein C (APC)-resistant phenotype of APC cleavage site mutants of recombinant factor V in a reconstituted plasma model. Blood Coagul Fibrinolysis 2002; 13: 207-215.
    CrossrefPubMedGoogle Scholar
  • 57 Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22: 530-538.
    CrossrefPubMedGoogle Scholar
  • 58 Kalafatis M, Mann KG. Factor V: Dr. Jeckyll and Mr. Hyde. Adv Exp Med Biol 2001; 489: 31-43.
    PubMedGoogle Scholar
  • 59 Castoldi E, Rosing J. Factor V Leiden: a disorder of factor V anticoagulant function. Curr Opin Hematol 2004; 11: 176-181.
    CrossrefPubMedGoogle Scholar
  • 60 Schuepbach RA, Velez K, Riewald M. Activated protein C upregulates procoagulant tissue factor activity on endothelial cells by shedding TFPI’s Kunitz 1 domain. Blood 2011; 117: 6338-6346.
    CrossrefPubMedGoogle Scholar
  • 61 Xu J, Lupu F, Esmon CT. Inflammation, innate immunity and blood coagulation. Hämostaseologie 2010; 30: 5-9.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 62 Xu J, Zhang X, Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15: 1318-1321.
    CrossrefPubMedGoogle Scholar
  • 63 Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 2008; 06: 415-420.
    CrossrefPubMedGoogle Scholar
  • 64 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
    CrossrefPubMedGoogle Scholar
  • 65 Fukudome K, Esmon CT. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-26491.
    PubMedGoogle Scholar
  • 66 Oganesyan V, Oganesyan N, Terzyan S. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 2002; 277: 24851-24854.
    CrossrefPubMedGoogle Scholar
  • 67 Esmon CT. Structure and functions of the endothelial cell protein C receptor. Crit Care Med 2004; 32: S298-301.
    CrossrefPubMedGoogle Scholar
  • 68 Ghosh S, Pendurthi UR, Steinoe A. et al. Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium. J Biol Chem 2007; 282: 11849-11857.
    CrossrefPubMedGoogle Scholar
  • 69 Zheng X, Li W, Song Y. et al. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost 2007; 05: 1394-1400.
    CrossrefPubMedGoogle Scholar
  • 70 Nayak RC, Sen P, Ghosh S. et al. Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. Blood 2009; 114: 1974-1986.
    CrossrefPubMedGoogle Scholar
  • 71 Rao LV, Pendurthi UR. Factor VIIa binding to endothelial cell protein C receptor. Thromb Res 2008; 122 (Suppl. 01) S3-S6.
    PubMedGoogle Scholar
  • 72 Pendurthi UR, Rao LV. Factor VIIa interaction with tissue factor and endothelial cell protein C receptor on cell surfaces. Semin Hematol 2008; 45: S21-S24.
    CrossrefPubMedGoogle Scholar
  • 73 Lopez-Sagaseta J, Montes R, Puy C. et al. Binding of factor VIIa to the endothelial cell protein C receptor reduces its coagulant activity. J Thromb Haemost 2007; 05: 1817-1824.
    CrossrefPubMedGoogle Scholar
  • 74 Schuepbach RA, Riewald M. Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. J Thromb Haemost 2010; 08: 379-388.
    CrossrefPubMedGoogle Scholar
  • 75 Puy C, Lopez-Sagaseta J, Hermida J, Montes R. The endothelial cells downregulate the generation of factor VIIa through EPCR binding. Br J Haematol 2010; 149: 111-117.
    CrossrefPubMedGoogle Scholar
  • 76 Gopalakrishnan R, Hedner U, Ghosh S. et al. Biodistribution of pharmacologically administered recombinant factor VIIa (rFVIIa). J Thromb Haemost 2010; 08: 301-310.
    CrossrefPubMedGoogle Scholar
  • 77 Kerschen E, Hernandez I, Zogg M. et al. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest 2010; 120: 3167-3178.
    CrossrefPubMedGoogle Scholar
  • 78 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-1882.
    CrossrefPubMedGoogle Scholar
  • 79 Guo H, Liu D, Gelbard H. et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004; 41: 563-572.
    CrossrefPubMedGoogle Scholar
  • 80 Guo H, Singh I, Wang Y. et al. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur J Neurosci 2009; 29: 1119-1130.
    CrossrefPubMedGoogle Scholar
  • 81 Zhong Z, Ilieva H, Hallagan L. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 2009; 119: 3437-3449.
    PubMedGoogle Scholar
  • 82 Swift S, Xu J, Trivedi V. et al. A novel protease-activated receptor-1 interactor, Bicaudal D1, regulates G protein signaling and internalization. J Biol Chem 2010; 285: 11402-11410.
    CrossrefPubMedGoogle Scholar
  • 83 Hammes SR, Coughlin SR. Protease-activated receptor-1 can mediate responses to SFLLRN in thrombin-desensitized cells. Biochemistry 1999; 38: 2486-2493.
    CrossrefPubMedGoogle Scholar
  • 84 Bae JS, Yang L, Rezaie AR. Factor X/Xa elicits protective signaling responses in endothelial cells directly via PAR-2 and indirectly via endothelial protein C receptor-dependent recruitment of PAR-1. J Biol Chem 2010; 285: 34803-34812.
    CrossrefPubMedGoogle Scholar
  • 85 Sen P, Gopalakrishnan R, Kothari H. et al. Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. Blood 2011; 117: 3199-3208.
    CrossrefPubMedGoogle Scholar
  • 86 Disse J, Petersen HH, Larsen KS. et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 2011; 286: 5756-5767.
    CrossrefPubMedGoogle Scholar
  • 87 Cao C, Gao Y, Li Y. et al. The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b. J Clin Invest 2010; 120: 1971-1980.
    CrossrefPubMedGoogle Scholar
  • 88 Elphick GF, Sarangi PP, Hyun YM. et al. Recombinant human activated protein C inhibits integrinmediated neutrophil migration. Blood 2009; 113: 4078-4085.
    CrossrefPubMedGoogle Scholar
  • 89 Pereira C, Schaer DJ, Bachli EB. et al. Wnt5A/CaMKII signaling contributes to the inflammatory response of macrophages and is a target for the anti-inflammatory action of activated protein C and interleukin-10. Arterioscler Thromb Vasc Biol 2008; 28: 504-510.
    CrossrefPubMedGoogle Scholar
  • 90 Pereira CP, Bachli EB, Schoedon G. The wnt pathway: a macrophage effector molecule that triggers inflammation. Curr Atheroscler Rep 2009; 11: 236-242.
    CrossrefPubMedGoogle Scholar
  • 91 Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol 2005; 77: 129-140.
    CrossrefPubMedGoogle Scholar
  • 92 Kurosawa S, Esmon CT, Stearns-Kurosawa DJ. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18. J Immunol 2000; 165: 4697-4703.
    CrossrefPubMedGoogle Scholar
  • 93 Gu JM, Katsuura Y, Ferrell GL. et al. Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Blood 2000; 95: 1687-1693.
    PubMedGoogle Scholar
  • 94 Xu J, Qu D, Esmon NL, Esmon CT. Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem 2000; 275: 6038-6044.
    CrossrefPubMedGoogle Scholar
  • 95 Saposnik B, Lesteven E, Lokajczyk A. et al. Alternative mRNA is favored by the A3 haplotype of the EPCR gene PROCR and generates a novel soluble form of EPCR in plasma. Blood 2008; 111: 3442-3451.
    CrossrefPubMedGoogle Scholar
  • 96 Harris KW, Esmon CT. Protein S is required for bovine platelets to support activated protein C binding and activity. J Biol Chem 1985; 260: 2007-2010.
    PubMedGoogle Scholar
  • 97 White TC, Berny MA, Tucker EI. et al. Protein C supports platelet binding and activation under flow: role of glycoprotein Ib and apolipoprotein E receptor 2. J Thromb Haemost 2008; 06: 995-1002.
    CrossrefPubMedGoogle Scholar
  • 98 Shi T, Giannakopoulos B, Yan X. et al. Antibeta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Arthritis Rheum 2006; 54: 2558-2567.
    CrossrefPubMedGoogle Scholar
  • 99 Pennings MT, Derksen RH, van Lummel M. et al. Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors. J Thromb Haemost 2007; 05: 369-377.
    CrossrefPubMedGoogle Scholar
  • 100 Pennings MT, Derksen RH, Urbanus RT. et al. Platelets express three different splice variants of ApoER2 that are all involved in signaling. J Thromb Haemost 2007; 05: 1538-1544.
    CrossrefPubMedGoogle Scholar
  • 101 Kassis J, Neville C, Rauch J. et al. Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis. Thromb Haemost 2004; 92: 1312-1319.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 102 Brouwer JL, Bijl M, Veeger NJ. et al. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004; 104: 143-148.
    CrossrefPubMedGoogle Scholar
  • 103 White-Adams TC, Berny MA, Tucker EI. et al. Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2). Arterioscler Thromb Vasc Biol 2009; 29: 1602-1607.
    CrossrefPubMedGoogle Scholar
  • 104 Muller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
    CrossrefPubMedGoogle Scholar
  • 105 Yang XV, Banerjee Y, Fernandez JA. et al. Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells. Proc Natl Acad Sci U S A 2009; 106: 274-279.
    CrossrefPubMedGoogle Scholar
  • 106 Shua F, Kobayashia H, Fukudomeb K. et al. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner. FEBS Lett 2000; 477: 208-212.
    CrossrefPubMedGoogle Scholar
  • 107 Grey ST, Tsuchida A, Hau H. et al. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. J Immunol 1994; 153: 3664-3672.
    PubMedGoogle Scholar
  • 108 Hancock WW, Grey ST, Hau L. et al. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 1995; 60: 1525-1532.
    CrossrefPubMedGoogle Scholar
  • 109 Sarangi PP, Lee HW, Kim M. Activated protein C action in inflammation. Br J Haematol 2010; 148: 817-833.
    CrossrefPubMedGoogle Scholar
  • 110 Shahzad K, Isermann B. The evolving plasticity of coagulation protease-dependent cytoprotective signalling. Hämostaseologie 2011; 31: 179-184.
    Artikel in Thieme ConnectPubMedGoogle Scholar