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Pathogenesis of DIC in Sepsis

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Sepsis

Abstract

Sepsis can be associated with profound alterations in the hemostatic mechanism. In this article we discuss recent insights into which mediators are involved in the activation of the coagulation system. We focus on studies performed in healthy humans intravenously injected with a low dose of endotoxin, and investigations in nonhuman primates infused with either endotoxin or live gram-negative bacteria. Special emphasis is given to the role of cytokines, in particular tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-10 and IL-12. Moreover, the roles of tissue factor, activated protein C, and the fibrinolytic system are briefly addressed. Disseminated intravascular coagulation likely is the result of complex interactions between several host mediator systems.

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References

  1. Levi M, ten Cate H, van der Poll T, van Deventer SJH. New insights in the pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993;270:975–979.

    Google Scholar 

  2. Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infections related to unfavourable prognosis. Thromb Haemostas 1983;49:5–7.

    Google Scholar 

  3. Van Deventer SJH, Büller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: Analysis of cytokine release and coagulation, fibrinolytic and complement pathways. Blood 1990;76:2520–2526.

    Google Scholar 

  4. De Boer JP, Creasy AA, Chang A, Roem D, Brouwer MC, Eerenberg AJM, Hack CE, Taylor FB Jr. Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. Circ Shock 1993;39:59–67.

    Google Scholar 

  5. Taylor FB Jr. Studies on the inflammatory-coagulant axis in the baboon response to E. coli: Regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. Prog Clin Biol Res 1994;388:175–194.

    Google Scholar 

  6. Van der Poll T, van Deventer SJH. Cytokines and anti-cytokines in the pathogenesis of sepsis. Infect Dis Clin N Am 1999; 13:413–426.

    Google Scholar 

  7. Lowry SF, Calvano SE, 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-Verlag, 1995:86–105.

    Google Scholar 

  8. Hazelzet JA, Kornelisse RF, van der Pouw Kraan TCTM, JoostenKMF, Van derVoort E, Van Mierlo G, Suur MH, Hop WCJ, De Groot R, Hack CE. Interleukin 12 levels during the initial phase of septic shock with purpura in children: Relation to severity of disease. Cytokine 1997;9:711–716.

    Google Scholar 

  9. Marchant A, Deviere J, Byl B, de Groote D, Vincent JL, Goldman M. Interleukin-10 production during septicaemia. Lancet 1994;343:707–710.

    Google Scholar 

  10. Van Zee KJ, Kohno T, Fischer E, Rock SC, Moldawer LL, Lowry SF. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor a in vitro and in vivo. Proc Natl Acad Sci USA 1992;89:4845–4849.

    Google Scholar 

  11. Van der Poll T, de Waal Malefyt R, Coyle SM, Lowry SF. 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.

    Google Scholar 

  12. Dehoux MS, Boutten A, Ostinelli J, Seta N, Dombret MC, Crestani B, Deschenes M, Trouillet JL, Aubier M. Compartimentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 1994;150: 710–716.

    Google Scholar 

  13. Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KR, Kenney JS, Lee AT, Kuo GC, Allison AC, Lowry SF, Cerami A. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1b and interleukin 6 appearance during lethal bacteremia. J Exp Med 1989;170:1627–1633.

    Google Scholar 

  14. Van der Poll T, Levi M, van Deventer SJH, ten Cate H, Haagmans BL, Biemond BJ, Büller HR, Hack CE, ten Cate JW. Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 1994;83:446–451.

    Google Scholar 

  15. Van der Poll T, Coyle SM, Levi M, Jansen PM, Dentener M, Barbosa K, Buurman WA, Hack CE, ten Cate JW, Agosti JM, Lowry SF. Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. Blood 1997;89:3727–3734.

    Google Scholar 

  16. Van der Poll T, Jansen J, Levi M, ten Cate H, ten Cate JW, van Deventer SJH. Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees. J Exp Med 1994;180:1985–1988.

    Google Scholar 

  17. Jansen PM, van der Pouw Kraan TCTM, de Jong IW, Van Mierlo G,Wijdenes J, Chang AA, Aarden LA, Taylor FB Jr, Hack CE. Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: Relation to plasma levels of interleukin-10 and interferon-c. Blood 1996;87:5144–5151.

    Google Scholar 

  18. Jansen J, van der Poll T, Levi M, ten Cate H, Gallati H, ten Cate JW, van Deventer SJH. Inhibition of the release of soluble tumour necrosis factor receptors in experimental endotoxemia by an anti-tumor necrosis factor-a antibody. J Clin Immunol 1995;15:45–50.

    Google Scholar 

  19. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–664.

    Google Scholar 

  20. Hinshaw LB, Tekamp-Olson P, Chang ACK, Lee PA, Taylor FB Jr, Murray CK, Peer GT, Emerson TE Jr, Passey B, Kuo GC. Survival of primates in LD 100 septic shock following therapy with antibody to tumor necrosis factor (TNF). Circ Shock 1990;30:279–292.

    Google Scholar 

  21. Ohlsson K, Björk P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin 1 receptor antagonist reduces mortality from endotoxin shock. Nature 1990;348:550–552.

    Google Scholar 

  22. Fischer E, Marano MA, Van Zee KJ, Rock CS, Hawes AS, Thompson WA, DeForge L, Kenney JS, Remick DG, Bloedow DC, Thompson RC, Lowry SF, Moldawer LL. 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.

    Google Scholar 

  23. Fattori E, Cappelletti M, Costa P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V. Defective inflammatory response in interleukin-6–deffcient mice. J Exp Med 1994;180:1243–1250.

    Google Scholar 

  24. Wysocka M, Kubin M, Vieira LQ, Ozmen L, Garotta G, Scott P, Trinchieri G. Interleukin-12 is required for interferon-c production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol 1995;25:672–676.

    Google Scholar 

  25. Berg DJ, Kühn R, Rajewsky K, Müller W, Menon S, Davidson N, Grünig G, Rennick D. 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.

    Google Scholar 

  26. Marchant A, Bruyns C, Vandenabeele P, Ducarme M, Gérard C, Delvaux A, de Groote D, Abramowicz D, Velu T, Goldman M. IL-10 controls IFN-c and TNF production during experimental endotoxemia. Eur J Immunol 1994;24: 1167–1171.

    Google Scholar 

  27. Van der Poll T, Büller HR, Ten Cate H, Wortel CH, Bauer KA, Van Deventer SJH, Hack CE, Sauerwein HP, Rosenberg RD, ten Cate JW. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990;322:1622–1627.

    Google Scholar 

  28. DeLa Cadena RA, Majluf-Cruz A, Stadnicki A, Tropea M, Reda D, Agosti JM, Colman RW, Suffredini AF. 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 Haemostas 1998;80:114–118.

    Google Scholar 

  29. Jansen PM, Boermeester MA, Fischer E, de Jong IW, van der Poll T, Moldawer LL, Hack CE, Lowry SF. 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-1a administration and during lethal bacteremia. Blood 1995;86:1027–1034.

    Google Scholar 

  30. Stouthard JML, Levi M, Hack CE, Veenhof CHN, Romijn JA, Sauerwein HP, van der Poll T. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemostas 1996;76:738–742.

    Google Scholar 

  31. Van der Poll T, Levi M, Hack CE, Ten Cate H, Van Deventer SJH, Eerenberg AJM, De Groot ER, Jansen J, Gallati H, Büller HR, Ten Cate JW, Aarden LA. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994;179: 1253–1259.

    Google Scholar 

  32. Lauw FN, Dekkers PEP, te Velde AA, Speelman P, Levi M, Kurimoto M, Hack CE, van Deventer SJH, van der Poll T. Interleukin 12 induces sustained activation of multiple host inflammatory mediator systems in chimpanzees. J Infect Dis 1999;179:646–652.

    Google Scholar 

  33. Pradier O, Gérard C, Delvaux A, Lybin M, Abramowicz D, Capel P, Velu T, Goldman M. Interleukin-10 inhibits the induction of monocyte procoagulant activity by bacterial lipopolysaccharide. Eur J Immunol 1993;23:2700–2703.

    Google Scholar 

  34. Pajkrt D, van der Poll T, Levi M, Cutler DL, Affrime MB, van den Ende A, ten Cate JW, van Deventer SJH. Interleukin 10 inhibits activation of coagulation and fibrinolysis during human endotoxemia. Blood 1997;89:2701–2705.

    Google Scholar 

  35. Van der Poll T, Jansen PM, Montegut WJ, Braxton CC, Calvano SE, Stackpole SA, Smith SM, Swanson SW, Hack CE, Lowry SF, Moldawer LL. Effects of IL-10 on systemic inflammatory responses during sublethal primate endotoxemia. J Immunol 1997;158:1971–1975.

    Google Scholar 

  36. Taylor FB Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991;33:127–134.

    Google Scholar 

  37. Levi M, Ten Cate H, Bauer KA, Van der Poll T, Edgington TS, Büller HR, Van Deventer SJH, Hack CE, Ten Cate JW, Rosenberg RD. 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.

    Google Scholar 

  38. Biemond BJ, ten Cate H, Levi M, Soule HR, Morris LD, Foster DL, Bogowitz CA, van der Poll T, Büller HR, ten Cate JW. Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VII/VIIa. Thromb Haemostas 1995;73:223–230.

    Google Scholar 

  39. Taylor FB Jr, Chang ACK, 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.

    Google Scholar 

  40. Creasey AA, Chang ACK, Feigen L, Wün TC, Taylor FB Jr, Hinshaw LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993;91:2850–2860.

    Google Scholar 

  41. Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, Gustafson ME, Wun TC, Creasey AA, Hinshaw LB. Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gramnegative model of septic shock. Circ Shock 1995;44:126–137.

    Google Scholar 

  42. Taylor FB Jr, Chang ACK, Peer GT, Mather T, Blick K, Catlett R, Lockhart MS, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991;78:364–368.

    Google Scholar 

  43. Taylor FB Jr, Chang A, Esmon T, 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.

    Google Scholar 

  44. Uchiba M, Okajima K, Murakami K, Nawa K, Okabe H, Takatsuki K. Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats. Thromb Haemostas 1995;74: 1265–1270.

    Google Scholar 

  45. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 1996;87:642–647.

    Google Scholar 

  46. Hancock WW, Tsuchida A, Hau H, Thomson NM, Salem HH. 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.

    Google Scholar 

  47. 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-c, or phorbol ester. J Immunol 1994;153:3664–3672.

    Google Scholar 

  48. Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 1989;320:1165–1172.

    Google Scholar 

  49. Van der Poll T, Levi M, Büller HR, Van Deventer SJH, De Boer JP, Hack CE, Ten Cate JW. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 1991;174:729–732.

    Google Scholar 

  50. Johnson K, Aarden LA, Choi Y, De Groof E, Creasey A. The proinflammatory cytokine response to coagulation and endotoxin in whole blood. Blood 1996;87:5051–5060.

    Google Scholar 

  51. Johnson K, Choi Y, De Groof E, Samuels I, Creasey A, Aarden LA. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998;160:5130–5135.

    Google Scholar 

  52. Sower LE, Froelich CJ, Fenton JW, Klimpel GR. 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.

    Google Scholar 

  53. Qi J, Goralnick S, Kreutzer DL. Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells. Blood 1997;90:3595–3602.

    Google Scholar 

  54. Senden NMH, Jeunhomme TMAA, Heemskerk JWM, Wagenvoord R, Van't Veer C, Hemker HC, Buurman WA. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol 1998;161:4318–4324.

    Google Scholar 

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van der Poll, T., de Jonge, E., Levi, M. et al. Pathogenesis of DIC in Sepsis. Sepsis 3, 103–109 (1999). https://doi.org/10.1023/A:1009843331372

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