Semin Thromb Hemost 2001; 27(6): 639-652
DOI: 10.1055/s-2001-18868
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Regulatory Role of Cytokines in Disseminated Intravascular Coagulation

Tom van der Poll1,2 , Evert de Jonge3 , Marcel Levi4
  • 1Laboratory of Experimental Internal Medicine, , Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • 2Department of Infectious Diseases, Tropical Medicine and AIDS, , Academic Medical Center, University of Amsterdam, Amsterdam, The Netherland
  • 3Department of Intensive Care Medicine, , Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and the
  • 4Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Further Information

Publication History

Publication Date:
06 December 2001 (online)

ABSTRACT

Disseminated intravascular coagulation (DIC) can complicate a number of diseases. DIC in the setting of sepsis is considered to result from strong activation of the coagulation system and concurrent inhibition of fibrinolysis and other anticoagulant pathways. Cytokines have been implicated as important mediators in these hemostatic alterations. This article summarizes recent insights into which cytokines are likely to be involved in the procoagulant response to systemic infection.

REFERENCES

  • 1 Hack C E, Aarden L A, Thijs L G. Role of cytokines in sepsis.  Adv Immunol . 1997;  66 101-195
  • 2 van der Poll T, van Deventer J H S. Cytokines and anti-cytokines in the pathogenesis of sepsis.  Infect Dis Clin North Am . 1999;  13 413-426
  • 3 Lowry S F, Calvano S E, van der Poll T. Measurement of inflammatory mediators in clinical sepsis. In: Sibbald WJ, Vincent JL, eds. Clinical Trials for the Treatment of Sepsis New York: Springer 1995: 86-105
  • 4 Dehoux M S, Boutten A, Ostinelli J. Compartimentalized cytokine production within the human lung in unilateral pneumonia.  Am J Respir Crit Care Med . 1994;  150 710-716
  • 5 Fröhlich D, Eiber R M, Jochum M, Billing A. Perioperative pattern of peritoneal interleukin 8, tumour necrosis factor-α, and granulocyte elastase release in human secondary peritonitis.  Cytokine . 1997;  9 288-292
  • 6 Olszyna D P, Prins J M, Buis B. Levels of inhibitors of tumor necrosis factor-α and interleukin 1 in urine and sera of patients with urosepsis.  Infect Immun . 1998;  66 3527-3534
  • 7 Marchant A, Deviere J, Byl B. Interleukin-10 production during septicaemia.  Lancet . 1994;  343 707-710
  • 8 van der Poll T, de Waal Malefyt R, Coyle S M, Lowry S F. Antiinflammatory cytokine responses during clinical sepsis and experimental endotoxemia: Sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10 and IL-13 concentrations.  J Infect Dis . 1997;  175 118-122
  • 9 van Zee J K, Kohno T, Fischer E. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor α in vitro and in vivo.  Proc Natl Acad Sci USA . 1992;  89 4845-4849
  • 10 Fong Y, Tracey K J, Moldawer L L. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia.  J Exp Med . 1989;  170 1627-1633
  • 11 van der Poll T, van Deventer J H S. Endotoxemia in healthy subjects as a human model of inflammation. In: Cohen J, Marshall J, eds. The Immune Response in the Critically Ill New York: Springer 1999: 335-357
  • 12 van der Poll T, Levi M, van Deventer J H S. Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees.  Blood . 1994;  83 446-451
  • 13 van der Poll T, Coyle S M, Levi M. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans.  Blood . 1997;  89 3727-3734
  • 14 van der Poll T, Jansen J, Levi M. Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees.  J Exp Med . 1994;  180 1985-1988
  • 15 Jansen P M, van der Pouw Kraan T C T M, de Jong W I. Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: Relation to plasma levels of interleukin-10 and interferon-γ.  Blood . 1996;  87 5144-5151
  • 16 Jansen J, van der Poll T, Levi M. Inhibition of the release of soluble tumour necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-α antibody.  J Clin Immunol . 1995;  15 45-50
  • 17 Tracey K J, Beutler B, Lowry S F. Shock and tissue injury induced by recombinant human cachectin.  Science . 1986;  234 470-474
  • 18 Okusawa S, Gelfland J A, Ikejima T, Connolly R J, Dinarello C A. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.  J Clin Invest . 1988;  81 1162-1172
  • 19 Leonard J P, Sherman M L, Fisher G L. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production.  Blood . 1997;  90 2541-2548
  • 20 Van Gameren M M, Willemse P HB, Mulder N H. Effects of recombinant human interleukin-6 in cancer patients: A phase I/II study.  Blood . 1994;  84 1434-1441
  • 21 Stouthard J ML, Romijn J A, van der Poll T. Endocrine and metabolic effects of interleukin-6 in humans.  Am J Physiol . 1995;  268 E813-E819
  • 22 Preiser J C, Schmartz D, van der Linden P. Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog.  Cytokine . 1991;  3 1-4
  • 23 Tracey K J, Fong Y, Hesse D G. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.  Nature . 1987;  330 662-664
  • 24 Hinshaw L B, Tekamp-Olson P, Chang A CK. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF).  Circ Shock . 1990;  30 279-292
  • 25 Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson R C. Interleukin 1 receptor antagonist reduces mortality from endotoxin shock.  Nature . 1990;  348 550-552
  • 26 Fischer E, Marano M A, Van Zee J K. Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia.  J Clin Invest . 1992;  89 1551-1557
  • 27 Fattori E, Cappelletti M, Costa P. Defective inflammatory response in interleukin-6-deficient mice.  J Exp Med . 1994;  180 1243-1250
  • 28 Silva A T, Cohen J. Role of interferon-γ in experimental gram-negative sepsis.  J Infect Dis . 1992;  166 331-335
  • 29 Wysocka M, Kubin M, Vieira L Q. Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice.  Eur J Immunol . 1995;  25 672-676
  • 30 Car B D, Eng V M, Schnyder B. Interferon-γ receptor deficient mice are resistant to endotoxic shock.  J Exp Med . 1994;  179 1437-1444
  • 31 Berg D J, Kühn R, Rajewsky K. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance.  J Clin Invest . 1995;  96 2339-2347
  • 32 Marchant A, Bruyns C, Vandenabeele P. IL-10 controls IFN-γ and TNF production during experimental endotoxemia.  Eur J Immunol . 1994;  24 1167-1171
  • 33 Muchamuel T, Menon S, Pisacane P, Howard M C, Cockayne D A. IL-13 protects mice from lipopolysaccharide-induced lethal endotoxemia: correlation with down-modulation of TNF-α, IFN-γ, and IL-12 production.  J Immunol . 1997;  158 2898-2903
  • 34 Levi M, ten Cate H. Disseminated intravascular coagulation.  N Engl J Med . 1999;  341 586-592
  • 35 Østerud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infections related to unfavourable prognosis.  Thromb Haemost . 1983;  49 5-7
  • 36 Li A, Chang A C, Peer G T, Hinshaw L B, Taylor Jr B F. Comparison of the capacity of rhTNF-alpha and Escherichia coli to induce procoagulant activity by baboon mononuclear cells in vivo and in vitro.  Shock . 1996;  5 274-279
  • 37 Taylor Jr B F, Chang A, Ruf W. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody.  Circ Shock . 1991;  33 127-134
  • 38 Levi M, ten Cate H, Bauer K A. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.  J Clin Invest . 1994;  93 114-120
  • 39 Biemond B J, ten Cate H, Levi M. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa.  Thromb Haemost . 1995;  73 223-230
  • 40 Taylor Jr B F, Chang A CK, Peer G, Ezban M, Hedner U. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli Blood .  1998;  91 1609-1615
  • 41 Creasey A A, Chang A CK, Feigen L. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock.  J Clin Invest . 1993;  91 2850-2860
  • 42 Carr C, Bild G S, Chang A CK. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock.  Circ Shock . 1995;  44 126-137
  • 43 De Jonge E, Dekkers P EP, Creasey A A. Tissue factor pathway inhibitor (TFPI) dose-dependently inhibits coagulation activation without influencing the fibrinolytic and the cytokine response during human endotoxemia.  Blood . 2000;  95 1124-1129
  • 44 Nawroth P P, Stern D M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor.  J Exp Med . 1986;  163 740-745
  • 45 Nawroth P P, Handley D A, Esmon C T, Stern D M. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity.  Proc Natl Acad Sci USA . 1986;  83 3460-3464
  • 46 Scarpati E M, Sadler J E. Regulation of endothelial cell coagulant properties. Modulation of tissue factor, plasminogen activator inhibitors and thrombomodulin by phorbol 12-myristate 13-acetate and tumor necrosis factor.  J Biol Chem . 1989;  264 20705-20713
  • 47 Conckling P R, Greenberg C S, Weinberg J B. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes.  Blood . 1988;  72 128-133
  • 48 Herbert J M, Savi P, Laplace M C, Lale A. IL-4 inhibits LPS-, IL-1β- and TNFα-induced expression of tissue factor in endothelial cells and monocytes.  FEBS Lett . 1992;  310 31-33
  • 49 Herbert J M, Savi P, Laplace M C. IL-4 and IL-13 exhibit comparable abilities to reduce pyrogen-induced expression of procoagulant activity in endothelial cells and monocytes.  FEBS Lett . 1993;  328 268-270
  • 50 Martin N B, Jamieson A, Tuffin D P. The effect of interleukin-4 on tumour necrosis factor-alpha induced expression of tissue factor and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells.  Thromb Haemost . 1993;  70 1037-1042
  • 51 Schwager I, Jungi T W. Effect of human recombinant cytokines on the induction of macrophage procoagulant activity.  Blood . 1994;  83 152-160
  • 52 Kirchhofer D, Tschopp T B, Hadvary P, Baumgartner H R. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogeneous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors.  J Clin Invest . 1994;  93 2073-2083
  • 53 Paleolog E M, Delasalle S AJ, Buurman W A, Feldmann M. Functional activities of receptors for tumor necrosis factor-a on human vascular endothelial cells.  Blood . 1994;  84 2578-2590
  • 54 Schmid E F, Binder K, Grell M, Scheurich P, Pfizenmaier K. Both tumor necrosis factor receptors, TNFR60 and TNFR80, are involved in signaling endothelial tissue factor expression by juxtracrine tumor necrosis factor alpha.  Blood . 1995;  86 1836-1841
  • 55 Del Prete G, de Carli M, Lammel R M. Th1 and Th2 T-helper cells exert opposite effects on procoagulant activity and tissue factor production by human monocytes.  Blood . 1995;  86 250-257
  • 56 Osnes L T, Westvik A B, Joo G B, Okkenhaug C, Kierulf P. Inhibition of IL-1 induced tissue factor (TF) synthesis and procoagulant activity (PCA) in purified human monocytes by IL-4, IL-10 and IL-13.  Cytokine . 1996;  8 822-827
  • 57 Ernofsson M, Tenno T, Siegbahn A. Inhibition of tissue factor surface expression in human peripheral blood monocytes exposed to cytokines.  Br J Haematol . 1996;  95 249-257
  • 58 Schecter A D, Rollins B J, Zhang Y J. Tissue factor induced by monocyte chemoattractant protein-1 in human aortic smooth muscle and THP-1 cells.  J Biol Chem . 1997;  272 28568-28573
  • 59 Neumann F J, Ott I, Marx N. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity.  Arterioscler Thromb Vasc Biol . 1997;  17 3399-3405
  • 60 Meisel S R, Shimon I, Edgington T S. Leukemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: A gp130-mediated mechanism.  Br J Haematol . 1999;  107 747-755
  • 61 Veltrop M H, Beekhuizen H, Thompson J. Bacterial species- and strain-dependent induction of tissue factor in human vascular endothelial cells.  Infect Immun . 1999;  67 6130-6138
  • 62 Pradier O, Gérard C, Delvaux A. Interleukin-10 inhibits the induction of monocyte procoagulant activity by bacterial lipopolysaccharide.  Eur J Immunol . 1993;  23 2700-2703
  • 63 Ramani M, Khechai F, Ollivier V. Interleukin-10 and pentoxifylline inhibit C-reactive protein-induced tissue factor gene expression in peripheral human blood monocytes.  FEBS Lett . 1994;  356 86-88
  • 64 Wharram B L, Fitting K, Kunkel S L. Tissue factor expression in endothelial cell/monocyte cocultures stimulated by lipopolysaccharide and/or aggregated IgG. Mechanisms of cell:cell communication.  J Immunol . 1991;  146 1437-1445
  • 65 Lo S K, Cheung A, Zheng Q, Silverstein R L. Induction of tissue factor on monocytes by adhesion to endothelial cells.  J Immunol . 1995;  154 4768-4777
  • 66 van der Poll T, Büller H R, ten Cate H. Activation of coagulation after administration of tumor necrosis factor to normal subjects.  N Engl J Med . 1990;  322 1622-1627
  • 67 Bauer K A, ten Cate H, Barzegar S. Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans.  Blood . 1989;  74 165-172
  • 68 van der Poll T, Jansen P M, van Zee J K. Tumor necrosis factor induces activation of coagulation and fibrinolysis in baboons through an exclusive effect on the p55 receptor.  Blood . 1996;  88 922-927
  • 69 DeLa Cadena A R, Majluf-Cruz A, Stadnicki A. Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans.  Thromb Haemost . 1998;  80 114-118
  • 70 Jansen P M, Boermeester M A, Fischer E. Contribution of interleukin-1 to activation of coagulation and fibrinolysis, to neutrophil degranulation and the release of sPLA2 in sepsis. Studies in non-human primates following interleukin-1 administration and during lethal bacteremia.  Blood . 1995;  86 1027-1034
  • 71 Stouthard J ML, Levi M, Hack C E. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans.  Thromb Haemost . 1996;  76 738-742
  • 72 van der Poll T, Levi M, Hack C E. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees.  J Exp Med . 1994;  179 1253-1259
  • 73 Lauw F N, Dekkers P EP, te Velde A A. Interleukin 12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees.  J Infect Dis . 1999;  179 646-652
  • 74 Baars J W, de Boer P J, Wagstaff J. Interleukin-2 induces activation of coagulation and fibrinolysis: Resemblance to the changes seen during endotoxaemia.  Br J Haematol . 1992;  82 295-301
  • 75 Pajkrt D, van der Poll T, Levi M. Interleukin 10 inhibits activation of coagulation and fibrinolysis during human endotoxemia.  Blood . 1997;  89 2701-2705
  • 76 van der Poll T, Jansen P M, Montegut W J. Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia.  J Immunol . 1997;  158 1971-1975
  • 77 Esmon C T. New potential therapeutic modalities: APC.  Sepsis . 1999;  3 161-172
  • 78 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
  • 79 Regan L M, Stearns-Kurosawa D J, Kurosawa S. The endothelial cell protein C receptor: Inhibition of activated protein C anticoagulant function without modulation of reaction with proteinase inhibitors.  J Biol Chem . 1996;  271 17499-17503
  • 80 Taylor Jr B F, Chang A, Esmon T. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.  J Clin Invest . 1987;  79 918-925
  • 81 Taylor Jr B F, Stearns-Kurosawa J, Kurosawa S. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis.  Blood . 2000;  95 1680-1686
  • 82 Taylor Jr B F, Chang A, Ferrell G. C4b-binding protein exacerbates the host response to Escherichia coli Blood .  1991;  78 357-363
  • 83 Lentz S R, Tsiang M, Sadler J E. Regulation of thrombomodulin by tumor necrosis factor-α: comparison of transcriptional and posttranscriptional mechanism.  Blood . 1991;  77 542-550
  • 84 Grey S T, Csizmadia V, Hancock W W. Differential effect of tumor necrosis factor-α on thrombomodulin gene expression by human monocytoid (THP-1) cells versus endothelial cells.  Int J Hematol . 1998;  67 53-62
  • 85 Raife T J, Demetroulis E M, Lentz S R. Regulation of thrombomodulin expression by all-trans retinoic acid and tumor necrosis factor-α: differential responses in keratinocytes and endothelial cells.  Blood . 1996;  88 2043-2049
  • 86 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
  • 87 Xu J, Qu D, Esmon N L, Esmon C T. Metalloproteolytic release of endothelial cell protein C receptor.  J Biol Chem . 2000;  275 6038-6044
  • 88 Redl H, Schlag G, Schiesser A, Davies J. Thrombomodulin release in baboon sepsis: its dependence on the dose of Escherichia coli and the presence of tumor necrosis factor.  J Infect Dis . 1995;  171 1522-1527
  • 89 Yamamoto K, Shimokawa T, Kojima T, Loskutoff D J, Saito H. Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor-α, interleukin-1 and transforming growth factor-β.  Thromb Haemost . 1999;  82 1297-1301
  • 90 De Boer P J, Creasy A A, Chang A. Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli Circ Shock .  1993;  39 59-67
  • 91 Schleef R R, Bevilaqua M P, Sawdey M, Gimbrone Jr A M, Loskutoff D J. Cytokine activation of vascular endothelium. Effects on tissue-type plasminogen activator and type 1 plasminogen activator inhibitor.  J Biol Chem . 1988;  263 5797-5803
  • 92 Sawdey M, Podor T J, Loskutoff D J. Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-β, lipopolysaccharide, and tumor necrosis factor-α.  J Biol Chem . 1989;  264 10396-10401
  • 93 van Hinsbergh W V, van den Berg A E, Fiers W, Dooijewaard G. Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells.  Blood . 1990;  75 1991-1998
  • 94 Gallicchio M, Hufnagl P, Wojta J, Tipping P. IFN-γ inhibits thrombin- and endotoxin-induced plasminogen activator inhibitor type 1 in human endothelial cells.  J Immunol . 1996;  157 2610-2617
  • 95 Arnman V, Stemme S, Rymo L, Risberg B. Interferon-γ modulates the fibrinolytic response in cultured human endothelial cells.  Thromb Res . 1995;  77 431-440
  • 96 Takahashi K, Uwabe Y, Sawasaki Y. Increased secretion of urokinase-type plasminogen activator by human lung microvascular endothelial cells.  Am J Physiol . 1998;  275 L47-L54
  • 97 Niedbala M J, Picarella M S. Tumor necrosis factor induction of endothelial cell urokinase-type plasminogen activator mediated proteolysis of extracellular matrix and its antagonism by gamma-interferon.  Blood . 1992;  79 678-687
  • 98 Wojta J, Gallicchio M, Zoellner H. Interleukin-4 stimulates expression of urokinase-type-plasminogen activator in cultured human foreskin microvascular endothelial cells.  Blood . 1993;  81 3285-3292
  • 99 De Boer P J, Abbink J J, Brouwer M C. PAI-1 synthesis in the human hepatoma cell line HepG2 is increased by cytokines. Evidence that the liver contributes to acute phase behaviour of PAI-1.  Thromb Haemost . 1991;  65 181-185
  • 100 Healy A M, Gelehrter T D. Induction of plasminogen activator inhibitor-1 in HepG2 human hepatoma cells by mediators of the acute phase response.  J Biol Chem . 1994;  269 19095-19100
  • 101 Seki T, Gelehrter T D. Interleukin-1 induction of type-1 plasminogen activator inhibitor (PAI-1) gene expression in the mouse hepatocyte line, AML 12.  J Cell Physiol . 1996;  168 648-656
  • 102 Busso N, Nicodeme E, Chesne C. Urokinase and type 1 plasminogen activator inhibitor production by normal hepatocytes: modulation by inflammatory agents.  Hepatology . 1994;  20 189-190
  • 103 Suffredini A F, Harpel P C, Parrillo J E. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects.  N Engl J Med . 1989;  320 1165-1172
  • 104 van der Poll T, Levi M, Büller H R. Fibrinolytic response to tumor necrosis factor in healthy subjects.  J Exp Med . 1991;  174 729-732
  • 105 van Hinsbergh W V, Bauer K A, Kooistra T. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products.  Blood . 1990;  76 2284-2289
  • 106 Logan T F, Virji M A, Gooding W E. Plasminogen activator and its inhibitor in cancer patients treated with tumor necrosis factor.  J Natl Cancer Inst . 1992;  84 1802-1810
  • 107 Fearns C, Loskutoff D J. Induction of plasminogen activator inhibitor type 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-α.  Am J Pathol . 1997;  150 579-590
  • 108 Seki T, Healy A M, Fletcher D S, Noguchi T, Gelehrter T D. IL-1β mediates induction of hepatic type I plasminogen activator inhibitor in response to local tissue injury.  Am J Physiol . 1999;  277 G801-G809
  • 109 Mileno M D, Margolis N H, Clark B D. Coagulation of whole blood stimulates interleukin-1β gene expression.  J Infect Dis . 1995;  172 308-311
  • 110 Jones A, Geczy C L. Thrombin and factor Xa enhance the production of interleukin-1.  Immunology . 1990;  71 236-241
  • 111 Johnson K, Aarden L A, Choi Y, De Groot E, Creasey A. The proinflammatory cytokine response to coagulation and endotoxin in whole blood.  Blood . 1996;  87 5051-5060
  • 112 Johnson K, Choi Y, De Groot E. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation.  J Immunol . 1998;  160 5130-5135
  • 113 Suk K, Cha S H. Thrombin-induced interleukin-8 production and its regulation by interferon-γ and prostaglandin E2 in human monocytic U937 cells.  Immunol Lett . 1999;  67 223-227
  • 114 Sower L E, Froelich C J, Fenton J W, Klimpel G R. Thrombin induces IL-6 production in fibroblasts and epithelial cells. Evidence for the involvement of the seven-transmembrane domain (STD) receptor for alpha thrombin.  J Immunol . 1995;  155 895-901
  • 115 Qi J, Goralnick S, Kreutzer D L. Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells.  Blood . 1997;  90 3595-3602
  • 116 Senden N MH, Jeunhomme T A A M, Heemskerk J WM. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells.  J Immunol . 1998;  161 4318-4324
  • 117 Ueno A, Murakami K, Yamanouchi K, Watanabe M, Kondo T. Thrombin stimulates production of interleukin-8 in human endothelial cells.  Immunology . 1996;  88 76-81
  • 118 Anrather D, Millan M T, Palmetshofer A. Thrombin activates nuclear factor-κB and potentiates endothelial cell activation by TNF.  J Immunol . 1997;  159 5620-5628
  • 119 Hancock W W, Tsuchida A, Hau H, Thomson N M, Salem H H. The anticoagulants protein C and protein S display potent antiinflammatory and immunosuppressive effects relevant to transplant biology and therapy.  Transplant Proc . 1992;  24 2302-2303
  • 120 Grey S T, Tsuchida A, Hau H. Selective inhibitor effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-γ, or phorbol ester.  J Immunol . 1994;  153 3664-3672
  • 121 Murakami K, Okajima K, Uchiba M. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats.  Blood . 1996;  87 642-647
  • 122 Hancock W W, Bach F H. Immunobiology and therapeutic applications of protein C/protein S/thrombomodulin in human and experimental allotransplantation and xenotransplantation.  Trends Cardiovasc Med . 1997;  7 174-183
  • 123 Hooper W C, Phillips D J, Renshaw M A, Evatt B L, Benson J M. The up-regulation of IL-6 and IL-8 in human endothelial cells by activated protein C.  J Immunol . 1998;  161 2567-2573
  • 124 Robson S C, Saunders R, Kirsch R E. Monocyte-macrophage release of IL-1 is inhibited by type-1 plasminogen activator inhibitor.  J Clin Lab Immunol . 1990;  33 83-90
  • 125 Sitrin R G, Shollenberger S B, Strieter R M, Gyetko M R. Endogenously produced urokinase amplifies tumor necrosis factor-α secretion by THP-1 mononuclear phagocytes.  J Leukoc Biol . 1996;  59 302-311
  • 126 Parmely M J, Sterner K E, Gale A, Zhou W W. U937 cells can utilize plasminogen activator to regulate human interferon-γ.  J Interferon Res . 1993;  13 397-406
  • 127 Taylor Jr B F, Chang A CK, Peer G T. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage.  Blood . 1991;  78 364-368
  • 128 Uchiba M, Okajima K, Murakami K. Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats.  Thromb Haemost . 1995;  74 1265-1270
  • 129 Taoka Y, Okajima K, Uchiba M. Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes.  J Neurosci . 1998;  18 1393-1398