Semin Thromb Hemost 2006; 32: 049-060
DOI: 10.1055/s-2006-939554
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Inflammation and the Activated Protein C Anticoagulant Pathway

Charles T. Esmon1
  • 1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation; Departments of Pathology, and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center; and Howard Hughes Medical Institute, Oklahoma City, Oklahoma
Further Information

Publication History

Publication Date:
02 May 2006 (online)

ABSTRACT

After a coagulation stimulus, the blood clotting cascade amplifies largely unchecked until very high levels of thrombin are generated. Natural anticoagulant mechanisms (for example, the protein C anticoagulant pathway) are amplified to prevent excessive thrombin generation. Thrombin binds to thrombomodulin (TM) and this complex and then activates protein C ~1000 times faster than free thrombin. Protein C activation is enhanced ~20-fold further by the endothelial cell protein C receptor (EPCR). Activated protein C proteolytically inactivates factor Va (FVa) and FVIIIa, thereby blocking the amplification of the coagulation system, a process that is accelerated by protein S. TM not only accelerates protein C activation, but also decreases endothelial cell activation by blocking high-mobility group protein-B1 inflammatory functions and suppressing both nuclear factor-kappa B nuclear translocation and the mitogen-activated protein kinase pathways. The thrombin-TM complex also activates thrombin-activatable fibrinolysis inhibitor, a procarboxypeptidase that renders fibrin resistant to clot lysis and neutralizes vasoactive molecules such as complement C5a. Activated protein C has a variety of antiinflammatory activities. It suppresses inflammatory cytokine elevation in animal models of severe sepsis, inhibits leukocyte adhesion, decreases leukocyte chemotaxis, reduces endothelial cell apoptosis, helps maintain endothelial cell barrier function through activation of the sphingosine-1 phosphate receptor, and minimizes the decrease in blood pressure associated with severe sepsis. Most of these functions are dependent on binding to EPCR. Overall this pathway is critical to both regulation of the blood coagulation process, and control of the innate inflammatory response and some of its associated downstream pathologies.

REFERENCES

  • 1 Kisiel W. Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin.  J Clin Invest. 1979;  64 761-769
  • 2 Salem H H, Broze G J, Miletich J P, Majerus P W. Human coagulation factor Va is a cofactor for the activation of protein C.  Proc Natl Acad Sci USA. 1983;  80 1584-1588
  • 3 Esmon C T. The roles of protein C and thrombomodulin in the regulation of blood coagulation.  J Biol Chem. 1989;  264 4743-4746
  • 4 Esmon C T, Owen W G. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C.  Proc Natl Acad Sci USA. 1981;  78 2249-2252
  • 5 Busch C, Cancilla P A, DeBault L E, Goldsmith J C, Owen W G. Use of endothelium cultured on microcarriers as a model for the microcirculation.  Lab Invest. 1982;  47 498-504
  • 6 Esmon N L, Owen W G, Esmon C T. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C.  J Biol Chem. 1982;  257 859-864
  • 7 Jackman R W, Beeler D L, Fritze L, Soff G, Rosenberg R D. Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control.  Proc Natl Acad Sci USA. 1987;  84 6425-6429
  • 8 Shirai T, Shiojiri S, Ito H et al.. Gene structure of human thrombomodulin, a cofactor for thrombin-catalyzed activation of protein C.  J Biochem (Tokyo). 1988;  103 281-285
  • 9 Wen D Z, Dittman W A, Ye R D et al.. Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene.  Biochemistry. 1987;  26 4350-4357
  • 10 Kurosawa S, Stearns D J, Jackson K W, Esmon C T. A 10-kDa cyanogen bromide fragment from the epidermal growth factor homology domain of rabbit thrombomodulin contains the primary thrombin binding site.  J Biol Chem. 1988;  263 5993-5996
  • 11 Kurosawa S, Galvin J B, Esmon N L, Esmon C T. Proteolytic formation and properties of functional domains of thrombomodulin.  J Biol Chem. 1987;  262 2206-2212
  • 12 He X, Ye J, Esmon C T, Rezaie A R. Influence of Arginines 93, 97, and 101 of thrombin to its functional specificity.  Biochemistry. 1997;  36 8969-8976
  • 13 Rezaie A R, Cooper S T, Church F C, Esmon C T. Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex.  J Biol Chem. 1995;  270 25336-25339
  • 14 Fuentes-Prior P, Iwanaga Y, Huber R et al.. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex.  Nature. 2000;  404 518-525
  • 15 van de Locht A, Bode W, Huber R et al.. The thrombin E192Q-BPTI complex reveals gross structural rearrangements: implications for the interaction with antithrombin and thrombomodulin.  EMBO J. 1997;  16 2977-2984
  • 16 Rezaie A R, Yang L. Mutagenesis studies toward understanding the mechanism of the cofactor function of thrombomodulin.  Biophys Chem. 2005;  117 255-261
  • 17 Ye J, Liu L W, Esmon C T, Johnson A E. The fifth and sixth growth factor-like domains of thrombomodulin bind to the anion-binding exosite of thrombin and alter its specificity.  J Biol Chem. 1992;  267 11023-11028
  • 18 Fukudome K, Esmon C T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor.  J Biol Chem. 1994;  269 26486-26491
  • 19 Fukudome K, Ye X, Tsuneyoshi N et al.. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor.  J Exp Med. 1998;  187 1029-1035
  • 20 Stearns-Kurosawa D J, Kurosawa S, Mollica J S, Ferrell G L, Esmon C T. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex.  Proc Natl Acad Sci USA. 1996;  93 10212-10216
  • 21 Taylor Jr F B, Peer G T, Lockhart M S, Ferrell G, Esmon C T. Endothelial cell protein C receptor plays an important role in protein C activation in vivo.  Blood. 2001;  97 1685-1688
  • 22 Preston R J, Villegas-Mendez A, Sun Y H et al.. Selective modulation of protein C affinity for EPCR and phospholipids by Gla domain mutation.  FEBS J. 2005;  272 97-108
  • 23 Xu J, Esmon N L, Esmon C T. Reconstitution of the human endothelial cell protein C receptor with thrombomodulin in phosphatidylcholine vesicles enhances protein C activation.  J Biol Chem. 1999;  274 6704-6710
  • 24 Laszik Z, Mitro A, Taylor Jr F B, Ferrell G, Esmon C T. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway.  Circulation. 1997;  96 3633-3640
  • 25 Kisiel W, Canfield W M, Ericsson L H, Davie E W. Anticoagulant properties of bovine plasma protein C following activation by thrombin.  Biochemistry. 1977;  16 5824-5831
  • 26 Walker F J, Sexton P W, Esmon C T. The inhibition of blood coagulation by activated protein C through the selective inactivation of activated factor V.  Biochim Biophys Acta. 1979;  571 333-342
  • 27 Eaton D, Rodriguez H, Vehar G A. Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity.  Biochemistry. 1986;  25 505-512
  • 28 Heeb M J, Rehemtulla A, Moussalli M, Kojima Y, Kaufman R J. Importance of individual activated protein C cleavage site regions in coagulation factor V for factor Va inactivation and for factor Xa activation.  Eur J Biochem. 1999;  260 64-75
  • 29 Kalafatis M, Rand M D, Mann K G. The mechanism of inactivation of human factor V and human factor Va by activated protein C.  J Biol Chem. 1994;  269 31869-31880
  • 30 Walker F J. Regulation of activated protein C by a new protein. A possible function for bovine protein S.  J Biol Chem. 1980;  255 5521-5524
  • 31 Shen L, Dahlbäck B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa.  J Biol Chem. 1994;  269 18735-18738
  • 32 Varadi K, Rosing J, Tans G et al.. Factor V enhances the cofactor function of protein S in the APC-mediated inactivation of factor VIII: influence of the factor VR506Q mutation.  Thromb Haemost. 1996;  76 208-214
  • 33 Heeb M J, Mesters R M, Tans G, Rosing J, Griffin J H. Binding of protein S to factor Va associated with inhibition of prothrombinase that is independent of activated protein C.  J Biol Chem. 1993;  268 2872-2877
  • 34 Dahlbäck B, Frohm B, Nelsestuen G. High affinity interaction between C4b-binding protein and vitamin K-dependent protein S in the presence of calcium. Suggestion of a third component in blood regulating the interaction.  J Biol Chem. 1990;  265 16082-16087
  • 35 Dahlbäck B. Interaction between vitamin K-dependent protein S and the complement protein, C4b-binding protein. A link between coagulation and the complement system.  Semin Thromb Hemost. 1984;  10 139-148
  • 36 Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein.  Proc Natl Acad Sci USA. 1981;  78 2512-2516
  • 37 Dahlbäck B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system.  Thromb Haemost. 1991;  66 49-61
  • 38 Smirnov M D, Safa O, Esmon N L, Esmon C T. Inhibition of activated protein C anticoagulant activity by prothrombin.  Blood. 1999;  94 3839-3846
  • 39 Nesheim M E, Canfield W M, Kisiel W, Mann K G. Studies of the capacity of factor Xa to protect factor Va from inactivation by activated protein C.  J Biol Chem. 1982;  257 1443-1447
  • 40 Oliver J A, Monroe D M, Church F C, Roberts H R, Hoffman M. Activated protein C cleaves factor Va more efficiently on endothelium than on platelet surfaces.  Blood. 2002;  100 539-546
  • 41 Solymoss S, Tucker M M, Tracy P B. Kinetics of inactivation of membrane-bound factor Va by activated protein C. Protein S modulates factor Xa protection.  J Biol Chem. 1988;  263 14884-14890
  • 42 Solymoss S, Nguyen K T. Plasma factor V activation is prevented by activated protein C in the presence of phospholipid vesicles, not platelets.  Thromb Haemost. 1993;  69 124-129
  • 43 Bernard G R, Macias W L, Joyce D E et al.. Safety assessment of drotrecogin alfa (activated) in the treatment of adult patients with severe sepsis.  Crit Care. 2003;  7 155-163
  • 44 Smirnov M D, Ford D A, Esmon C T, Esmon N L. The effect of membrane composition on the hemostatic balance.  Biochemistry. 1999;  38 3591-3598
  • 45 Safa O, Hensley K, Smirnov M D, Esmon C T, Esmon N L. Lipid oxidation enhances the function of activated protein C.  J Biol Chem. 2001;  276 1829-1836
  • 46 Safa O, Esmon C T, Esmon N L. Inhibition of APC anticoagulant activity on oxidized phospholipid by anti-β2-glycoprotein I monoclonal antibodies.  Blood. 2005;  106 1629-1635
  • 47 Sanmarco M, Alessi M C, Harle J R et al.. Antibodies to phosphatidylethanolamine as the only antiphospholipid antibodies found in patients with unexplained thromboses.  Thromb Haemost. 2001;  85 800-805
  • 48 Suzuki K. Activated protein C inhibitor.  Semin Thromb Hemost. 1984;  10 154-161
  • 49 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization.  J Biol Chem. 1983;  258 163-168
  • 50 de Fouw N J, van Hinsbergh V, de Jong Y F, Haverkate F, Bertina R M. The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells.  Thromb Haemost. 1987;  57 176-182
  • 51 Heeb M J, Gruber A, Griffin J H. 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
  • 52 Rezaie A R. 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
  • 53 Han K H, Hong K H, Park J H et al.. C-reactive protein promotes monocyte chemoattractant protein-1-mediated chemotaxis through upregulating CC chemokine receptor 2 expression in human monocytes.  Circulation. 2004;  109 2566-2571
  • 54 Devaraj S, Xu D Y, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis.  Circulation. 2003;  107 398-404
  • 55 Cermak J, Key N S, Bach R R et al.. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor.  Blood. 1993;  82 513-520
  • 56 Ballantyne C M, Hoogeveen R C, Bang H et al.. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study.  Circulation. 2004;  109 837-842
  • 57 Paul A, Ko K W, Li L et al.. C-reactive protein accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.  Circulation. 2004;  109 647-655
  • 58 Danenberg H D, Szalai A J, Swaminathan R V et al.. Increased thrombosis after arterial injury in human C-reactive protein-transgenic mice.  Circulation. 2003;  108 512-515
  • 59 Conway E M, Rosenberg R D. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells.  Mol Cell Biol. 1988;  8 5588-5592
  • 60 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases.  Blood. 1990;  76 2024-2029
  • 61 Glaser C B, Morser J, Clarke J H et al.. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.  J Clin Invest. 1992;  90 2565-2573
  • 62 Faust S N, Levin M, Harrison O B et al.. Dysfunction of endothelial protein C activation in severe meningococcal sepsis.  N Engl J Med. 2001;  345 408-416
  • 63 Liaw P C, Esmon C T, Kahnamoui K et al.. Patients with severe sepsis vary markedly in their ability to generate activated protein C.  Blood. 2004;  104 3958-3964
  • 64 Fisher Jr C J, Yan S B. Protein C levels as a prognostic indicator of outcome in sepsis and related diseases.  Crit Care Med. 2000;  28 S49-S56
  • 65 Rivard G E, David M, Farrell C, Schwarz H P. Treatment of purpura fulminans in meningococcemia with protein C concentrate.  J Pediatr. 1995;  126 646-652
  • 66 White B, Livingstone W, Murphy C et al.. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia.  Blood. 2000;  96 3719-3724
  • 67 Dreyfus M, Magny J F, Bridey F et al.. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate.  N Engl J Med. 1991;  325 1565-1568
  • 68 Esmon C T. Coagulation and inflammation.  J Endotoxin Res. 2003;  9 192-198
  • 69 Dhainaut J F, Laterre P F, LaRosa S P et al.. The clinical evaluation committee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results.  Crit Care Med. 2003;  31 2291-2301
  • 70 Ely E W, Laterre P F, Angus D C et al.. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis.  Crit Care Med. 2003;  31 12-19
  • 71 Vincent J L, Bernard G R, Beale R et al.. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment.  Crit Care Med. 2005;  33 2266-2277
  • 72 Kim A Y, Walinsky P L, Kolodgie F D et al.. Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure.  Circ Res. 2002;  90 205-212
  • 73 Waugh J M, Yuksel E, Li J et al.. Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model.  Circ Res. 1999;  84 84-92
  • 74 Waugh J M, Li-Hawkins J, Yuksel E et al.. Thrombomodulin overexpression to limit neointima formation.  Circulation. 2000;  102 332-337
  • 75 Conway E M, Van de Wouwer M, Pollefeyt S et al.. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways.  J Exp Med. 2002;  196 565-577
  • 76 Abeyama K, Stern D M, Ito Y et al.. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism.  J Clin Invest. 2005;  115 1267-1274
  • 77 Tracey K J. The inflammatory reflex.  Nature. 2002;  420 853-859
  • 78 Laszik Z G, Zhou X J, Ferrell G L, Silva F G, Esmon C T. Down-regulation of endothelial expression of endothelial cell protein C receptor and thrombomodulin in coronary atherosclerosis.  Am J Pathol. 2001;  159 797-802
  • 79 Masamura K, Oida K, Kanehara H et al.. Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family.  Arterioscler Thromb Vasc Biol. 2003;  23 512-517
  • 80 Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation.  Blood. 2005;  105 3178-3184
  • 81 Finigan J H, Dudek S M, Singleton P A et al.. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation.  J Biol Chem. 2005;  280 17286-17293
  • 82 Esmon C T. Is APC activation of endothelial cell PAR1 important in severe sepsis?: No.  J Thromb Haemost. 2005;  3 1910-1911
  • 83 Ruf W. Is APC activation of endothelial cell PAR1 important in severe sepsis?: Yes.  J Thromb Haemost. 2005;  3 1912-1914
  • 84 Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression.  Arterioscler Thromb Vasc Biol. 2000;  20 2322-2328
  • 85 Miller D L, Yaron R, Yellin M J. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression.  J Leukoc Biol. 1998;  63 373-379
  • 86 Andre P, Prasad K S, Denis C V et al.. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism.  Nat Med. 2002;  8 247-252
  • 87 Henn V, Slupsky J R, Grafe M et al.. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.  Nature. 1998;  391 591-594
  • 88 Ruf W, Dorfleutner A, Riewald M. Specificity of coagulation factor signaling.  J Thromb Haemost. 2003;  1 1495-1503
  • 89 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem. 1995;  270 4650-4660
  • 90 Cunningham M A, Romas P, Hutchinson P, Holdsworth S R, Tipping P G. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages.  Blood. 1999;  94 3413-3420
  • 91 Loike J D, El K J, Cao L et al.. Fibrin regulates neutrophil migration in response to interleukin 8, leukotriene B4, tumor necrosis factor, and formyl-methionyl-leucyl-phenylalanine.  J Exp Med. 1995;  181 1763-1772
  • 92 Okajima K. Regulation of inflammatory responses by natural anticoagulants.  Immunol Rev. 2001;  184 258-274
  • 93 Altieri D C, Etingin O R, Fair D S et al.. Structurally homologous ligand binding of integrin Mac-1 and viral glycoprotein C receptors.  Science. 1991;  254 1200-1202
  • 94 Altieri D C, Morrissey J H, Edgington T S. Adhesive receptor Mac-1 coordinates the activation of factor X on stimulated cells of monocytic and myeloid differentiation: an alternative initiation of the coagulation protease cascade.  Proc Natl Acad Sci USA. 1988;  85 7462-7466
  • 95 Liu L W, Vu T K, Esmon C T, Coughlin S R. The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity.  J Biol Chem. 1991;  266 16977-16980
  • 96 Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex.  J Biol Chem. 1996;  271 16603-16608
  • 97 Wang W, Nagashima M, Schneider M, Morser J, Nesheim M. Elements of the primary structure of thrombomodulin required for efficient thrombin-activable fibrinolysis inhibitor activation.  J Biol Chem. 2000;  275 22942-22947
  • 98 Campbell W D, Lazoura E, Okada N, Okada H. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N.  Microbiol Immunol. 2002;  46 131-134
  • 99 Myles T, Nishimura T, Yun T H et al.. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation.  J Biol Chem. 2003;  278 51059-51067
  • 100 Hancock W W, Grey S T, 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
  • 101 Yuksel M, Okajima K, Uchiba M, Horiuchi S, Okabe H. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes.  Thromb Haemost. 2002;  88 267-273
  • 102 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
  • 103 Sturn D H, Kaneider N C, Feistritzer C et al.. Expression and function of the endothelial protein C receptor in human neutrophils.  Blood. 2003;  102 1499-1505
  • 104 Joyce D E, Gelbert L, Ciaccia A, DeHoff B, Grinnell B W. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis.  J Biol Chem. 2001;  276 11199-11203
  • 105 Riewald M, Petrovan R J, Donner A, Mueller B M, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway.  Science. 2002;  296 1880-1882
  • 106 Cheng T, Liu D, Griffin J H et al.. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective.  Nat Med. 2003;  9 338-342
  • 107 Pawlinski R, Pedersen B, Schabbauer G et al.. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia.  Blood. 2004;  103 1342-1347
  • 108 Liu D, Cheng T, Guo H et al.. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C.  Nat Med. 2004;  10 1379-1383
  • 109 Iwanaga S. The molecular basis of innate immunity in the horseshoe crab.  Curr Opin Immunol. 2002;  14 87-95
  • 110 Dahlbäck B. Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein.  J Biol Chem. 1986;  261 12022-12027
  • 111 He X, Dahlbäck B. Rabbit plasma, unlike its human counterpart, contains no complex between protein S and C4b-binding protein.  Thromb Haemost. 1994;  71 446-451
  • 112 Oganesyan V, Oganesyan N, Terzyan S et al.. The crystal structure of the endothelial protein C receptor and a bound phospholipid.  J Biol Chem. 2002;  277 24851-24854
  • 113 Moody D B, Ulrichs T, Muhlecker W et al.. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection.  Nature. 2000;  404 884-888
  • 114 Hong S, Scherer D C, Singh N et al.. Lipid antigen presentation in the immune system: lessons learned from CD1d knockout mice.  Immunol Rev. 1999;  169 31-44
  • 115 Taylor Jr F B, Stearns-Kurosawa D J, Kurosawa S et al.. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis.  Blood. 2000;  95 1680-1686
  • 116 Hurtado V, Montes R, Gris J C et al.. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death.  Blood. 2004;  104 1369-1374
  • 117 Conway E M, Pollefeyt S, Collen D, Steiner-Mosonyi M. The amino terminal lectin-like domain of thrombomodulin is required for constitutive endocytosis.  Blood. 1997;  89 652-661
  • 118 Huang H C, Shi G Y, Jiang S J et al.. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain.  J Biol Chem. 2003;  278 46750-46759
  • 119 Kirchhofer D, Banner D W. Molecular and structural advances in tissue factor-dependent coagulation.  Trends Cardiovasc Med. 1997;  7 316-324
  • 120 Kurosawa S, Esmon C T, Stearns-Kurosawa D J. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CD11b/CD18.  J Immunol. 2000;  165 4697-4703
  • 121 Creasey A A, Chang A C, Feigen L et al.. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest. 1993;  91 2850-2860
  • 122 Emerson Jr T E, Fournel M A, Redens T B, Taylor Jr F B. Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia.  Am J Med. 1989;  87 27S-33S
  • 123 Taylor Jr F B, Chang A, Esmon C T et al.. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.  J Clin Invest. 1987;  79 918-925
  • 124 Bernard G R, Vincent J L, Laterre P F et al.. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
  • 125 Warren B L, Eid A, Singer P et al.. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial.  JAMA. 2001;  286 1869-1878
  • 126 Abraham E, Reinhart K, Opal S et al.. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.  JAMA. 2003;  290 238-247
  • 127 Esmon C T. Why do animal models (sometimes) fail to mimic human sepsis?.  Crit Care Med. 2004;  32 S219-S222
  • 128 Faioni E M, Ferrero S, Fontana G et al.. Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease.  Crit Care Med. 2004;  32 S266-S270
  • 129 Maradit-Kremers H, Crowson C S, Nicola P J et al.. Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study.  Arthritis Rheum. 2005;  52 402-411
  • 130 Ye X, Fukudome K, Tsuneyoshi N et al.. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries.  Biochem Biophys Res Commun. 1999;  259 671-677
  • 131 Undas A, Celinska-Lowenhoff M, Kaczor M, Musial J. New nonlipid effects of statins and their clinical relevance in cardiovascular disease.  Thromb Haemost. 2004;  91 1065-1077
  • 132 Klerk C P, Smorenburg S M, Otten H M et al.. The effect of low molecular weight heparin on survival in patients with advanced malignancy.  J Clin Oncol. 2005;  23 2130-2135

Charles T EsmonPh.D. 

Oklahoma Medical Research Foundation

Cardiovascular Biology Research Program, 825 NE 13th Street, Oklahoma City, OK 73104

Email: Charles-Esmon@omrf.ouhsc.edu

    >