Chapter 12 : Coagulation and Innate Immunity

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Coagulation and Innate Immunity, Page 1 of 2

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This chapter summarizes the current information on the linkage between the regulation of the coagulation and inflammatory responses to infection. Inflammation can affect coagulation status in less overt fashions. Inflammatory mediators such as interleukin-6 (IL-6) can not only increase platelet production, but the platelets that are generated are more thrombogenic, demonstrating an increased sensitivity to platelet agonists like thrombin. Among the major anticoagulant mechanisms, the protein C anticoagulant pathway is the most complex and appears to be the most impacted by acute inflammatory responses. Both antithrombin and protein C inhibitor play major roles in inactivating thrombomodulin (TM)-bound thrombin, resulting in a half-life for the bound thrombin of about 1 to 2 s. The difference in efficacy in modulating the host response to bacterial and endotoxin infusion between artificial anticoagulants and the natural anticoagulants suggests that the anti-inflammatory activities of the natural anticoagulants may be very important aspects of their physiological functions. The role of cleavage of the protease-activated receptors in activated protein C (APC) function remains to be fully elucidated. Most of the downstream events following activation of these receptors enhance inflammation. TM accelerates thrombin activation of a plasma procarboxypeptidase B, often named thrombin-activatable fibrinolysis inhibitor (TAFI). It is now recognized that even the statins thought originally to function by lowering cholesterol have important anti-inflammatory effects as well. Further identification of the links between inflammation and thrombosis should provide novel approaches to new diagnostics and therapeutics.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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A simplified view of the regulation of blood coagulation by the protein C pathway. Factor VIIa binds to tissue factor (TF) to activate factor X, generating factor Xa. Factor Xa then binds to factor Va. The complex of factors Xa and V converts prothrombin (Pro) to thrombin (T).Thrombin can then either bind to TM or carry out procoagulant reactions like fibrin formation or platelet activation. When bound to TM, thrombin can activate protein C (PC) to APC. This process is enhanced when protein C is bound to EPCR. APC bound to EPCR cleaves substrates other than factor Va. APC dissociates from EPCR and can then interact with protein S to inactivate factor Va. The middle row shows inactivation of the factor IXa (IXa)-factor VIIIa complex by APC. In this case, factor V participates with APC and protein S in the inactivation of factor VIIIa. In the bottom row, the plasma proteinase inhibitors that regulate the protein C activation complex and the anticoagulant complex of APC and protein S are illustrated. α-AT, α-antitrypsin; α-Mac, α-macroglobulin; PCI, protein C inhibitor; and AT, antithrombin. TAFI is activated (TAFIa) by the thrombin-TM complex. TAFIa then inactivates C5a. For simplicity, the activation of factors VII,V, and VIII is not shown. Figure modified with permission from Esmon, 1999, copyright F. K. Schattauer.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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Image of FIGURE 2

Thrombin is a multifunctional enzyme and generates the procoagulant, anticoagulant, inflammatory, and mitogenic responses. These responses serve to shift the hemostatic balance. EC, endothelial cell; PMNs, polymorphonucleocytes; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; CD40L, CD40 ligand; MCP-1, macrophage chemotactic protein-1. (From Esmon, 1993, with permission from the vol. 9, copyright by Annual Reviews.)

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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Image of FIGURE 3

Impact of inflammation on coagulation.

Citation: Esmon C. 2004. Coagulation and Innate Immunity, p 241-253. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch12
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1. Alberio, L.,, O. Safa,, K. J. Clemetson,, C. T. Esmon,, and G. L. Dale. 2000. Surface expression and functional characterization of α-granule factor V in human platelets: effects of ionophore A23187, thrombin, collagen, and convulxin. Blood 95:16941702.
2. André, P.,, K. S. Srinivasa Prasad,, C.V. Denis,, M. He,, J. M. Papalia,, R. O. Hynes,, D. R. Phillips,, and D. D. Wagner. 2002. CD40L stabilizes arterial thrombi by a β3 integrin-dependent mechanism. Nat. Med. 8:247252.
3. Bajzar, L.,, J. Morser,, and M. Nesheim. 1996. TAFI, or Plasma Procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J. Biol. Chem. 271:1660316608.
4. Bar-Shavit, R.,, A. J. Kahn,, K. G. Mann,, and G. D. Wilner. 1986. Identification of a thrombin sequence with growth factor activity on macrophages. Proc. Natl. Acad. Sci. USA 83:976980.
5. Bernard, G. R.,, J. L. Vincent,, P. F. Laterre,, S. P. LaRosa,, J. F. Dhainaut,, A. Lopez-Rodriguez,, J. S. Steingrub,, G. E. Garber,, J. D. Helterbrand,, E.W. Ely,, C. J. Fisher, Jr., and the Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. 2001. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344:699709.
6. Bevers, E. M.,, P. Comfurius,, and R. F. A. Zwaal. 1991. Platelet procoagulant activity: physiological significance and mechanisms of exposure. Blood Rev. 5:146154.
7. Broze, G. J., Jr.,, T. J. Girard,, and W. F. Novotny. 1990. Regulation of coagulation by a multivalent Kunitz-type inhibitor. Biochemistry 29:75397546.
8. Burstein, S. A. 1997. Cytokines, platelet production and hemostasis. Platelets 8:93104.
9. Campbell, W.,, N. Okada,, and H. Okada. 2001. Carboxypeptidase R is an inactivator of complementderived inflammatory peptides and an inhibitor of fibrinolysis. Immunol. Rev. 180:162167.
10. Campbell, W. D.,, E. Lazoura,, N. Okada,, and H. Okada. 2002. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol. Immunol. 46:131134.
11. Conway, E. M.,, and R. D. Rosenberg. 1988. Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells. Mol. Cell. Biol. 8:55885592.
12. Conway, E. M.,, M. Van de Wouwer,, S. Pollefeyt,, K. Jurk,, H. Van Aken,, A. De Vriese,, J. I. Weitz,, H. Weiler,, P.W. Hellings,, P. Schaeffer,, J.M. Herbert,, D. Collen,, and G. Theilmeier. 2002.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. 196:565577.
13. Coughlin, S. R. 1994. Thrombin receptor function and cardiovascular disease. Trends Cardiovasc. Med. 4:7783.
14. Coughlin, S. R. 2000.Thrombin signalling and protease- activated receptors. Nature 407:258264.
15. Dahlbäck, B. 1991. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system. Thromb. Haemost. 66:4961.
16. Dickneite, G. 1998. Antithrombin III in animal models of sepsis and organ failure. Sem. Thromb. Hemost. 24:6169.
17. Drake, T. A.,, J. H. Morrissey,, and T. S. Edgington. 1989. Selective cellular expression of tissue factor in human tissues: implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134:10871097.
18. Dreyfus, M.,, J. F. Magny,, F. Bridey,, H. P. Schwarz,, C. Planché,, M. Dehan,, and G. Tchernia. 1991.Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N. Engl. J. Med. 325: 15651568.
19. Edgington, T. S.,, N. Mackman,, K. Brand,, and W. Ruf. 1991. The structural biology of expression and function of tissue factor. Thromb. Haemost. 66:6779.
20. Enkhbaatar, P.,, K. Okajima,, K. Murakami,, M. Uchiba,, H. Okabe,, K. Okabe,, and Y. Yamaguchi. 2000. Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular injury by inhibiting leukocyte activation. Am. J. Respir. Crit. Care Med. 162:17521759.
21. Esmon, C.T. 1993. Cell mediated events that control blood coagulation and vascular injury. Annu. Rev. Cell Biol. 9:126.
22. Esmon, C.T. 2000. Introduction: are natural anticoagulants candidates for modulating the inflammatory response to endotoxin? Blood 95:11131116.
23. Esmon, C.T., 2001. Protein C, protein S, and thrombomodulin, p. 335353. In R. W. Colman,, J. Hirsh,, V. J. Marder,, A. W. Clowes,, and J. N. George (ed.), Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins, Philadelphia, Pa..
24. Esmon, C. T. 2002. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J. Exp. Med. 196:561564.
25. Esmon, C.T.,, J. Xu,, J. M. Gu,, D. Qu,, Z. Laszik,, G. Ferrell,, D. J. Stearns-Kurosawa,, S. Kurosawa,, F. B. Taylor, Jr.,, and N. L. Esmon. 1999. Endothelial protein C receptor. Thromb. Haemost. 82:251258.
26. Faust, S. N.,, M. Levin,, O. B. Harrison,, R. D. Goldin,, M. S. Lockhart,, S. Kondaveeti,, Z. Laszik,, C.T. Esmon,, and R. S. Heyderman. 2001. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl. J. Med. 345:408416.
27. Fukudome, K.,, and C. T. Esmon. 1994. Identification, cloning and regulation of a novel endothelial cell protein C/activated protein C receptor. J. Biol. Chem. 269:2648626491.
28. Giles, A. R.,, K. G. Mann,, and M. E. Nesheim. 1988. A combination of factor Xa and phosphatidylcholine- phosphatidylserine vesicles bypasses factor VIII in vivo. Br. J. Haematol. 69:491497.
29. Glaser, C. B.,, J. Morser,, J. H. Clarke,, E. Blasko,, K. McLean,, I. Kuhn,, R.-J. Chang,, J.-H. Lin,, L. Vilander,, W. H. Andrews,, and D. R. Light. 1992. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. J. Clin. Invest. 90:25652573.
30. Grey, S.,, H. Hau,, H. H. Salem,, and W. W. Hancock. 1993. Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-gamma, or PMA: modulation of effects on CD11b and CD14 but not CD25 or CD54 induction. Transplant. Proc. 25:29132914.
31. Gruber, A.,, and J. H. Griffin. 1992. Direct detection of activated protein C in blood from human subjects. Blood 79:23402348.
32. Gu, J.-M.,, J.T. B. Crawley,, G. Ferrell,, F. Zhang,, W. Li,, N. L. Esmon,, and C. T. Esmon. 2002. Disruption of the endothelial cell protein C receptor gene in mice causes placental thrombosis and early embryonic lethality. J. Biol. Chem. 277:4333543343.
33. Han, X.,, R. Fiehler,, and G. J. Broze, Jr. 2000. Characterization of the protein Z-dependent protease inhibitor. Blood 96:30493055.
34. Hancock, W.W.,, S.T. Grey,, L. Hau,, A. Akalin,, C. Orthner,, M. H. Sayegh,, and H. H. Salem. 1995. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation 60:15251532.
35. Heeb, M. J.,, A. Gruber,, and J. H. Griffin. 1991. Identification of divalent metal ion-dependent inhibition of activated protein C by alpha2-macroglobulin and alpha2-antiplasmin in blood and comparisons to inhibition of factor Xa, thrombin, and plasmin. J. Biol. Chem. 266:1760617612.
36. Henn, V.,, J. R. Slupsky,, M. Gräfe,, I. Anagnostopoulos,, R. Förster,, G. Müller- Berghaus,, and R. A. Kroczek. 1998. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591594.
37. Hong, S.,, D. C. Scherer,, N. Singh,, S. K. Mendiratta,, I. Serizawa,, Y. Koezuka,, and L. Van Kaer. 1999. Lipid antigen presentation in the immune system learned from CD1d knockout mice. Immunol. Rev. 169:3144.
38. Huang, Z.-F.,, D. Higuchi,, N. Lasky,, and G. J. Broze, Jr. 1997.Tissue factor pathway inhibitor gene disruption produces intrauterine lethality in mice. Blood 90:944951.
39. Jackman, R.W.,, D. L. Beeler,, L. Fritze,, G. Soff,, and R. D. Rosenberg. 1987. 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 84:64256429.
40. Joyce, D. E.,, L. Gelbert,, A. Ciaccia,, B. DeHoff,, and B.W. Grinnell. 2001. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J. Biol. Chem. 276:1119911203.
41. Klein, N. J.,, C. A. Ison,, M. Peakman,, M. Levin,, S. Hammerschmidt,, M. Frosch,, and R. S. Heyderman. 1996.The influence of capsulation and lipooligosaccharide structure on neutrophil adhesion molecule expression and endothelial injury by Neisseria meningitidis. J. Infect. Dis. 173:172179.
42. Kurosawa, S.,, C. T. Esmon,, and D. J. Stearns- Kurosawa. 2000. The soluble endothelial protein C receptor binds to activated neutrophils: involvement of proteinase-3 and CDIIb/CDI8. J. Immunol. 165:46974703.
43. Laszik, Z.,, A. Mitro,, F. B. Taylor, Jr.,, G. Ferrell,, and C.T. Esmon. 1997. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 96:36333640.
44. Levi, M.,, and H. ten Cate. 1999. Disseminated intravascular coagulation. N. Engl. J. Med. 341:586592.
45. Liaw, P. C. Y.,, P. F. Neuenschwander,, M. D. Smirnov,, and C. T. Esmon. 2000. Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J. Biol. Chem. 275:54475452.
46. Liaw, P. C. Y.,, G. L. Ferrell,, and C. T. Esmon. 2002.A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. J. Thromb. Haemost. 1:662670.
47. Lorant, D. E.,, K. D. Patel,, T. M. McIntyre,, R. P. McEver,, S. M. Prescott,, and G. A. Zimmerman. 1991. Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: a juxtacrine system for adhesion and activation of neutrophils. J. Cell Biol. 115:223234.
48. Lupu, C.,, F. Lupu,, U. Dennehy,, V.V. Kakkar,, and M. F. Scully. 1995.Thrombin induces the redistribution and acute release of tissue factor pathway inhibitor from specific granules within human endothelial cells in culture. Arterioscler. Thromb. Vasc. Biol. 15:20552062.
49. Miller, D. L.,, R. Yaron,, and M. J. Yellin. 1998. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J. Leukoc. Biol. 63:373379.
50. Moody, D. B.,, T. Ulrichs,, W. Mühlecker,, D. C. Young,, S. S. Gurcha,, E. Grant,, J.-P. Rosat,, M. B. Brenner,, C. E. Costello,, G. S. Besra,, and S. A. Porcelli. 2000. CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404:884888.
51. Morrissey, J. H.,, H. Fakhrai,, and T. S. Edgington. 1987. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell 50:129135.
52. Nesheim, M. E.,, W. M. Canfield,, W. Kisiel,, and K. G. Mann. 1982. Studies on the capacity of factor Xa to protect factor Va from inactivation by activated protein C. J. Biol. Chem. 257:14431447.
53. Oelschläger, C.,, J. Römisch,, A. Staubitz,, H. Stauss,, B. Leithäuser,, H. Tillmanns,, and H. Hölschermann. 2002. Antithrombin III inhibits nuclear factor κB activation in human monocytes and vascular endothelial cells. Blood 99:40154020.
54. Oganesyan, V.,, N. Oganesyan,, S. Terzyan,, D. Qu,, Z. Dauter,, N. L. Esmon,, and C.T. Esmon. 2002. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J. Biol. Chem. 277:2485124854.
55. Opal, S. M.,, and C. T. Esmon. 2002. Benchto- bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit. Care 7:2338.
56. Palabrica, T.,, R. Lobb,, B. C. Furie,, M. Aronovitz,, C. Benjamin,, Y. M. Hsu,, S.A. Sajer,, and B. Furie. 1992. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 359:848851.
57. Pendurthi, U. R.,, D. Alok,, and L.V. M. Rao. 1997. Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: upregulation of poly(A) polymerase. Proc. Natl. Acad. Sci. USA 94:1259812603.
58. Raczkowski, C. A.,, M. Reichlin,, C. T. Esmon,, and P. C. Comp. 1987. Protein Z is a negatively responding acute phase protein. Blood 70:393a. (Abstract 1427.)
59. Regan, L. M.,, B. J. Lamphear,, C. F. Huggins,, F. J. Walker,, and P. J. Fay. 1994. Factor IXa protects factor VIIIa from activated protein C. J. Biol. Chem. 269:94459452.
60. Rezaie, A. R. 2001.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. 276:1556715570.
61. Rezaie, A. R.,, S. T. Cooper,, F. C. Church,, and C. T. Esmon. 1995. Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex. J. Biol. Chem. 270:2533625339.
62. Riewald, M.,, R. J. Petrovan,, A. Donner,, B. M. Mueller,, and W. Ruf. 2002. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:18801882.
63. Sadler, J. E. 1997. Thrombomodulin structure and function. Thromb. Haemost. 78:392395.
64. Shu, F.,, H. Kobayashi,, K. Fukudome,, N. Tsuneyoshi,, M. Kimoto,, and T. Terao. 2000. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptordependent manner. FEBS Lett. 477:208212.
65. Simmonds, R. E.,, and D.A. Lane. 1999. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/activated protein C receptor (EPCR) gene: comparison with the structure of CD1/major histocompatibility complex α1 and α2 domains. Blood 94:632641.
66. Sims, P. J.,, F. M. Faioni,, T. Wiedmer,, and S. J. Shattil. 1988. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J. Biol. Chem. 263:1820518212.
67. Souter, P. J.,, S. Thomas,, A. R. Hubbard,, S. Poole,, J. Romisch,, and E. Gray. 2001. Antithrombin inhibits lipopolysaccharide-induced tissue factor and interleukin-6 production by mononuclear cells, human umbilical vein endothelial cells, and whole blood. Crit. Care Med. 29:134139.
68. Stearns-Kurosawa, D. J.,, S. Kurosawa,, J. S. Mollica,, G. L. Ferrell,, and C.T. Esmon. 1996.The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc. Natl. Acad. Sci. USA 93:1021210216.
69. Takano, S.,, S. Kimura,, S. Ohdama,, and N. Aoki. 1990. Plasma thrombomodulin in health and diseases. Blood 76:20242029.
70. Taoka, Y.,, K. Okajima,, M. Uchiba,, K. Murakami,, N. Harada,, M. Johno,, and M. Naruo. 1998. Activated protein C reduces the severity of compression- induced spinal cord injury in rats by inhibiting activation of leukocytes. J. Neurosci. 18:13931398.
71. Taylor, F. B., Jr.,, A. Chang,, C. T. Esmon,, A. D'Angelo,, S. Vigano-D'Angelo,, and K. E. Blick. 1987. Protein C prevents the coagulopathic and lethal effects of E. coli infusion in the baboon. J. Clin. Invest. 79:918925.
72. Taylor, F. B., Jr.,, A. C. K. Chang,, G. T. Peer,, T. Mather,, K. Blick,, R. Catlett,, M. S. Lockhart,, and C. T. Esmon. 1991.DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 78:364368.
73. Taylor, F. B., Jr.,, S. E. He,, A. C. K. Chang,, J. Box,, G. Ferrell,, D. Lee,, M. Lockhart,, G. Peer,, and C. T. Esmon. 1996. Infusion of phospholipid vesicles amplifies the local thrombotic response to TNF and anti-protein C into a consumptive response. Thromb. Haemost. 75:578584.
74. Taylor, F. B., Jr.,, D. J. Stearns-Kurosawa,, S. Kurosawa,, G. Ferrell,, A. C. K. Chang,, Z. Laszik,, S. Kosanke,, G. Peer,, and C. T. Esmon. 2000.The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95:16801686.
75. Uchiba, M.,, and K. Okajima. 1997. Antithrombin III (AT III) prevents LPS-induced vascular injury: novel biological activity of AT III. Thromb. Haemost. 23:583590.
76. Vasse, M.,, E. Guegan-Massardier,, J.-Y. Borg,, F. Woimant,, and C. Soria. 2001. Frequency of protein Z deficiency in patients with ischaemic stroke. Lancet 357:933934.
77. Wakefield, T.W.,, R.M. Strieter,, R. Schaub,, D. D. Myers,, M. R. Prince,, S. K. Wrobleski,, F. J. Londy,, A. M. Kadell,, S. L. Brown,, P. K. Henke,, and L. J. Greenfield. 2000.Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy. J.Vasc. Surg. 31:309324.
78. Walsh, P. N. 1987. Platelet-mediated trigger mechanisms in the contact phase of blood coagulation. Sem. Thromb. Hemost. 13:8694.
79. Waugh, J. M.,, E. Yuksel,, J. Li,, M. D. Kuo,, M. Kattash,, R. Saxena,, R. Geske,, S. N. Thung,, S. M. Shenaq,, and S. L. Woo. 1999. Local overexpression of thrombomodulin for in vivo prevention of arterial thrombosis in a rabbit model. Circ. Res. 84:8492.
80. Waugh, J. M.,, J. Li-Hawkins,, E. Yuksel,, M. D. Kuo,, P. N. Cifra,, P. R. Hilfiker,, R. Geske,, M. Chawla,, J. Thomas,, S. M. Shenaq,, M. D. Dake,, and S. L. Woo. 2000.Thrombomodulin overexpression to limit neointima formation. Circulation 102:332337.
81. Wen, D.,, W. A. Dittman,, R. D. Ye,, L. L. Deaven,, P. W. Majerus,, and J. E. Sadler. 1987. Human thrombomodulin: complete cDNA sequence and chromosome localization of the gene. Biochemistry 26:43504357.
82. White, B.,, M. Schmidt,, C. Murphy,, W. Livingstone,, D. O'Toole,, M. Lawler,, L. O'Neill,, D. Kelleher,, H. P. Schwarz,, and O. P. Smith. 2000.Activated protein C inhibits lipopolysaccharideinduced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br. J. Haematol. 110:130134.
83. Wolbink, G.-J.,, A. W. J. Bossink,, A. B. J. Groeneveld,, M. C. M. DeGroot,, L. G. Thijs,, and C. E. Hack. 1998. Complement activation in patients with sepsis is in part mediated by C-reactive protein. J. Infect. Dis. 177:8187.
84. Xu, J.,, D. Qu,, N. L. Esmon,, and C. T. Esmon. 1999. Metalloproteolytic release of endothelial cell protein C receptor. J. Biol. Chem. 275:60386044.
85. Yamauchi, T.,, F. Umeda,, T. Inoguchi,, and H. Nawata. 1989. Antithrombin III stimulates prostacyclin production by cultured aortic endothelial cells. Biochem. Biophys. Res. Commun. 163:14041411.
86. Yin, Z.-F.,, Z.-F. Huang,, J. Cui,, R. Fiehler,, N. Lasky,, and D. Ginsburg. 2000. Prothrombotic phenotype of protein Z deficiency. Proc. Natl. Acad. Sci. USA 97:67346738.
87. Yuksel, M.,, K. Okajima,, M. Uchiba,, S. Horiuchi,, and H. Okabe. 2002. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-α production by inhibiting activation of both nuclear factor-κB and activator protein-1 in human monocytes. Thromb. Haemost. 88:267273.

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