Progress in the Understanding of the Protein C Anticoagulant Pathway

International Journal of Hematology

Volumn 79, Issue 2, 2004, Pages 109-116

  Dahlbäck, Björn ^a  

^a LUND UNIVERSITY   (Sweden)

Author keywords

Factor V; Protein C; Protein S; Thrombomodulin

Indexed keywords

ACTIVATED PROTEIN C; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 5; BLOOD CLOTTING FACTOR 5A; BLOOD CLOTTING FACTOR 8A; PROTEIN C; PROTEIN S; PROTHROMBIN; RECEPTOR PROTEIN; SERINE PROTEINASE; THROMBIN; THROMBOMODULIN; VITAMIN K GROUP;

ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; BLOOD CLOTTING; CHEMICAL BOND; COMPLEX FORMATION; DRUG ACTIVITY; DRUG EFFECT; DRUG MECHANISM; ENDOTHELIUM CELL; GENETIC DISORDER; INFLAMMATION; MEMBRANE BINDING; MOLECULAR MECHANICS; NONHUMAN; PROTEIN BINDING; PROTEIN DEFECT; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; REVIEW; RISK FACTOR; SEPTIC SHOCK; THROMBOPHILIA; VEIN THROMBOSIS;

EID: 18144440602     PISSN: 09255710     EISSN: None     Source Type: Journal    
DOI: 10.1532/IJH97.03149     Document Type: Review

References (78)

1. Dahlbäck B. Blood coagulation. Lancet. 2000;355:1627-1632.
2. Dahlbäck B, Stenflo J. The protein C anticoagulant system. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H, eds. The Molecular Basis of Blood Disease. 3rd ed. Philadelphia, Pa: W. B. Saunders; 2001:614-656.
3. Mann KG, Kalafatis M. Factor V: Dr. Jeckyll and Mr. Hyde. Adv Exp Med Biol. 2001;489:31-43.
4. Nicolaes GA, Dahlbäck B. Factor V and thrombotic disease: description of a Janus-faced protein. Arterioscler Thromb Vasc Biol. 2002;22:530-538.
5. Esmon CT. The protein C pathway. Chest. 2003;124:26S-32S.
6. Butenas S, Mann KG. Blood coagulation. Biochemistry (Mosc). 2002;67:3-12.
7. Stenflo J, Dahlbäck B. Vitamin K-dependent proteins in blood coagulation. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H, eds. The Molecular Basis of Blood Disease. 3rd ed. Philadelphia, Pa: W. B. Saunders; 2001:579-613.
8. 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.
9. Knobe KE, Berntsdotter A, Shen L, Morser J, Dahlbäck B, Villoutreix BO. Probing the activation of protein C by the thrombin-thrombomodulin complex using structural analysis, site-directed mutagenesis, and computer modeling. Proteins. 1999;35:218-234.
10. Gerlitz B, Grinnell BW. Mutation of protease domain residues Lys37-39 in human protein C inhibits activation by the thrombomodulin-thrombin complex without affecting activation by free thrombin. J Biol Chem. 1996; 271:22285-22288.
11. Yang L, Rezaie AR. The fourth epidermal growth factor-like domain of thrombomodulin interacts with the basic exosite of protein C. J Biol Chem. 2003;278:10484-10490.
12. Esmon CT. The endothelial cell protein C receptor. Thromb Haemost. 2000;83:639-643.
13. 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.
14. Villoutreix BO, Dahlbäck B. Structural investigation of the A domains of human blood coagulation factor V by molecular modeling. Protein Sci. 1998;7:1317-1325.
15. Villoutreix B, Bucher P, Hofmann K, Baumgartner S, Dahlbäck B. Molecular models for the C1 and C2 domains of factor V: new structure-function insights. J Mol Model. 1998;4:268-275.
16. Pemberton S, Lindley P, Zaitsev V, Card G, Tuddenham EG, Kemball-Cook G. A molecular model for the triplicated A domains of human factor VIII based on the crystal structure of human ceruloplasmin. Blood. 1997;89:2413-2421.
17. Kemball-Cook G, Tuddenham EG, Wacey AI. The factor VIII Structure and Mutation Resource Site: HAMSTeRS version 4. Nucleic Acids Res. 1998;26:216-219.
18. Pellequer JL, Gale AJ, Griffin JH, Getzoff ED. Homology models of the C domains of blood coagulation factors V and VIII: a proposed membrane binding mode for FV and FVIII C2 domains. Blood Cells Mol Dis. 1998;24:448-461.
19. Pellequer JL, Gale AJ, Getzoff ED, Griffin JH. Three-dimensional model of coagulation factor Va bound to activated protein C. Thromb Haemost. 2000;84:849-857.
20. Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. 2002;99:1215-1223.
21. Macedo-Ribeiro S, Bode W, Huber R, et al. Crystal structures of the membrane-binding C2 domain of human coagulation factor V. Nature. 1999;402:434-439.
22. Pratt KP, Shen BW, Takeshima K, Davie EW, Fujikawa K, Stoddard BL. Structure of the C2 domain of human factor VIII at 1.5 Å resolution. Nature. 1999;402:439-442.
23. Nicolaes GA, Villoutreix BO, Dahlbäck B. Mutations in a potential phospholipid binding loop in the C2 domain of factor V affecting the assembly of the prothrombinase complex. Blood Coagul Fibrinolysis. 2000;11:89-100.
24. Kim SW, Quinn-Allen MA, Camp JT, et al. Identification of functionally important amino acid residues within the C2-domain of human factor V using alanine-scanning mutagenesis. Biochemistry. 2000;39:1951-1958.
25. Gilbert GE, Kaufman RJ, Arena AA, Miao H, Pipe SW. Four hydrophobic amino acids of the factor VIII C2 domain are constituents of both the membrane-binding and von Willebrand factor-binding motifs. J Biol Chem. 2002;277:6374-6381.
26. Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP. Structure of a factor VIII C2 domain-immunoglobulin G4κ Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood. 2001;98:13-19.
27. Hockin MF, Cawthern KM, Kalafatis M, Mann KG. A model describing the inactivation of factor Va by APC: bond cleavage, fragment dissociation, and product inhibition. Biochemistry. 1999;38:6918-6934.
28. Kalafatis M, Egan JO, van't Veer C, Cawthern KM, Mann KG. The regulation of clotting factors. Crit Rev Eukaryot Gene Expr. 1997;7:241-280.
29. Fay PJ, Smudzin TM, Walker FJ. Activated protein C-catalyzed inactivation of human factor VIII and factor VIIIa: identification of cleavage sites and correlation of protcolysis with cofactor activity. J Biol Chem. 1991;266:20139-20145.
30. Fay PJ. Regulation of factor VIIIa in the intrinsic factor Xase. Thromb Haemost. 1999;82:193-200.
31. Nicolaes GA, Tans G, Thomassen MC, et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem. 1995;270:21158-21166.
32. Rosing J, Hoekema L, Nicolaes GA, et al. Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C. J Biol Chem. 1995;270:27852-27858.
33. Gale AJ, Heeb MJ, Griffin JH. The autolysis loop of activated protein C interacts with factor Va and differentiates between the Arg506 and Arg306 cleavage sites. Blood. 2000;96:585-593.
34. Gale AJ, Xu X, Pellequer JL, Getzoff ED, Griffin JH. Interdomain engineered disulfide bond permitting elucidation of mechanisms of inactivation of coagulation factor Va by activated protein C. Protein Sci. 2002;11:2091-2101.
35. Friedrich U, Nicolaes GA, Villoutreix BO, Dahlbäck B. Secondary substrate-binding exosite in the serine protease domain of activated protein C important for cleavage at Arg-506 but not at Arg-306 in factor Va. J Biol Chem. 2001;276:23105-23108.
36. Fay PJ, Mastri M, Koszelak ME, Wakabayashi H. Cleavage of factor VIII heavy chain is required for the functional interaction of A2 subunit with factor IXa. J Biol Chem. 2001;276:12434-12439.
37. 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.
38. Shen L, He X, Dahlbäck B. Synergistic cofactor function of factor V and protein S to activated protein C in the inactivation of the factor VIIIa-factor IXa complex: species specific interactions of components of the protein C anticoagulant system. Thromb Haemost. 1997;78:1030-1036.
39. Varadi K, Rosing J, Tans G, Pabinger I, Keil B, Schwarz HP. 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.
40. Thorelli E, Kaufman RJ, Dahlbäck B. Cleavage of factor V at Arg 506 by activated protein C and the expression of anticoagulant activity of factor V. Blood. 1999;93:2552-2558.
41. Thorelli E, Kaufman RJ, Dahlbäck B. The C-terminal region of the factor V B-domain is crucial for the anticoagulant activity of factor V. J Biol Chem. 1998;273:16140-16145.
42. Dahlbäck B, Smith CA, Muller-Eberhard HJ. Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proc Natl Acad Sci U S A. 1983;80:3461-3465.
43. Villoutreix BO, Blom AM, Webb J, Dahlbäck B. The complement regulator C4b-binding protein analyzed by molecular modeling, bioinformatics and computer-aided experimental design. Immunopharmacology. 1999;42:121-134.
44. Webb JH, Villoutreix BO, Dahlbäck B, Blom AM. Localization of a hydrophobic binding site for anticoagulant protein S on the β-chain of complement regulator C4b-binding protein. J Biol Chem. 2001;276:4330-4337.
45. Hardig Y, Dahlbäck B. The amino-terminal module of the C4b-binding protein β-chain contains the protein S-binding site. J Biol Chem. 1996;271:20861-20867.
46. Webb JH, Villoutreix BO, Dahlbäck B, Blom AM. Role of CCP2 of the C4b-binding protein β-chain in protein S binding evaluated by mutagenesis and monoclonal antibodies. Eur J Biochem. 2003;270:93-100.
47. van de Poel RHL, Meijers JCM, Dahlbäck B, Bouma BN. C4b-binding protein (C4BP) β-chain short consensus repeat-2 specifically contributes to the interaction of C4BP with protein S. Blood Cells Mol Dis. 1999;25:279-286.
48. Walker FJ. Protein S and thrombotic disease. Proc Soc Exp Biol Med. 1992;200:285-295.
49. Webb JH, Blom AM, Dahlbäck B. The binding of protein S and the protein S-C4BP complex to neutrophils is apoptosis dependent. Blood Coagul Fibrinolysis. 2003;14:355-359.
50. Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat Immunol. 2003;4:87-91.
51. Saxena SP, Israels ED, Israels LG. Novel vitamin K-dependent pathways regulating cell survival. Apoptosis. 2001;6:57-68.
52. Dahlbäck B. Activated protein C resistance and thrombosis: molecular mechanisms of hypercoagulable state due to FVR506Q mutation. Semin Thromb Hemost. 1999;25:273-289.
53. Dahlbäck B. The discovery of activated protein C resistance. J Thromb Haemost. 2003;1:3-9.
54. Rosendaal FR. Risk factors for venous thrombosis: prevalence, risk, and interaction. Semin Hematol. 1997;34:171-187.
55. Lindqvist PG, Svensson PJ, Dahlbäck B, Marsal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood loss: a possible evolutionary selection mechanism. Thromb Haemost. 1998;79:69-73.
56. Riedemann NC, Guo RF, Ward PA. The enigma of sepsis. J Clin Invest. 2003;112:460-467.
57. Esmon CT. Protein C pathway in sepsis. Ann Med. 2002;34:598-605.
58. Taylor FB Jr, Stearns-Kurosawa DJ, Kurosawa S, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000;95:1680-1686.
59. Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood. 2001;97:1685-1688.
60. Taylor FB Jr, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest. 1987;79:918-925.
61. Taylor F, Chang A, Ferrell G, et al. C4b-binding protein exacerbates the host response to Escherichia coli. Blood. 1991;78:357-363.
62. Taylor FB Jr, Dahlbäck B, Chang AC, et al. Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli. Blood. 1995;86:2642-2652.
63. 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.
64. Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW. 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.
65. Brueckmann M, Marx A, Martin Weiler H, et al. Stabilization of monocyte chemoattractant protein-1-mRNA by activated protein C. Thromb Haemost. 2003;89:149-160.
66. Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-κB. Crit Care Med. 2002;30:S288-S293.
67. Grinnell BW, Joyce D. Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med. 2001;29:S53-S60; discussion, S60-1.
68. Cheng T, Liu D, Griffin JH, et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003;9:338-342.
69. Liu D, Guo H, Griffin JH, Fernandez JA, Zlokovic BV. Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation. 2003;107:1791-1796.
70. Mosnier LO, Griffin JH. Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor. Biochem J. 2003;373:65-70.
71. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001;276:11199-11203.
72. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296:1880-1882.
73. Riewald M, Ruf W. Science review: role of coagulation protease cascades in sepsis. Crit Care. 2003;7:123-129.
74. Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature. 2001;413:74-78.
75. Grinnell BW, Hermann RB, Yan SB. Human protein C inhibits selectin-mediated cell adhesion: role of unique fucosylated oligosaccharide. Glycobiology. 1994;4:221-225.
76. Sturn DH, Kaneider NC, Feistritzer C, Djanani A, Fukudome K, Wiedermann CJ. Expression and function of the endothelial protein C receptor in human neutrophils. Blood, 2003;102:1499-1505.
77. Conway EM, 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 κB and mitogen-activated protein kinase pathways. J Exp Med. 2002;196:565-577.
78. Gu JM, Crawley JT, Ferrell G, et al. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J Biol Chem. 2002;277:43335-43343.