Disturbances and Modulators of Coagulation and Fibrinolysis in Sepsis

  • L. G. Thijs
Conference paper


In patients with sepsis abnormalities in hemostatic variables indicating systemic activation of coagulation and early activation with subsequent inhibition of fibrinolysis, are common features [1-5]. The most important clinical manifestation of these processes is disseminated intravascular coagulation (DIC), which is characterized by generation and deposition of fibrin in the microvasculature with widespread microvascular thrombosis in various organ systems. The bipha- sic effect on the fibrinolytic system may result in impaired fibrin dissolution and aggravate the formation of microthrombi. There is evidence that DIC contributes to the development of (multiple) organ dysfunction and failure [3, 5]. In addition, depletion of coagulation proteins and platelets, mainly due to the extensive and ongoing coagulation activation, may induce severe bleeding complications [6]. The impressive extreme of the clinical spectrum of manifestations of DIC is purpura fulminans, which presents with hemorrhagic skin necrosis and peripheral gangrene and is most often seen in meningococcal sepsis [7].


Septic Shock Tissue Factor Plasminogen Activator Inhibitor Disseminate Intravascular Coagulation Thrombin Generation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hesselvik JF, Blomback M, Brodin B et al (1989) Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome. Crit Care Med 17:724–733PubMedCrossRefGoogle Scholar
  2. 2.
    Voss R, Matthias FR, Borkowski G et al (1990) Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit. Br J Haematol 75:99–105PubMedCrossRefGoogle Scholar
  3. 3.
    Fourrier F, Chopin C, Goudemand J et al (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816–823PubMedCrossRefGoogle Scholar
  4. 4.
    Lorente JA, Garcia-Frade LJ, Landin L et al (1993) Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest 103:1536–1542PubMedCrossRefGoogle Scholar
  5. 5.
    Kidokoro A, Iba T, Fukunaga M et al (1996) Alterations in coagulation and fibrinolysis during sepsis. Shock 5:223–228PubMedCrossRefGoogle Scholar
  6. 6.
    Levi M, ten Cate H, van der Poll T et al (1993) Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 270:975–979PubMedCrossRefGoogle Scholar
  7. 7.
    Fijnvandraat K, Derkx B, Peters M et al (1995) Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 73:15–20PubMedGoogle Scholar
  8. 8.
    Ziegler EJ, Fisher CJ, Sprung CL et al (1991) Treatment of gram-negative bacteremia and septic shock with HA-IA human monoclonal antibody against endotoxin. N Engl J Med 324: 429–436PubMedCrossRefGoogle Scholar
  9. 9.
    Greenman RL, Schein RMH, Martin MA et al (1991) A controlled clinical trial of E5 Murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 266: 1097–1102PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher CJ, Dhainaut JFA, Opal SM et al (1994) Recombinant human Interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. JAMA 271:1836–1843PubMedCrossRefGoogle Scholar
  11. 11.
    Abraham E, Wunderink R, Silverman H et al (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor a in patients with sepsis syndrome. JAMA 273:934–941PubMedCrossRefGoogle Scholar
  12. 12.
    Bone RC, Baik RA, Fein AM et al (1995) A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: Results of a prospective, multicenter, randomized, controlled trial. Crit Care Med 23:994–1005PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen J, Carlet J, Intersept study group (1996) INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-a in patients with sepsis. Crit Care Med 24:1431–1440PubMedCrossRefGoogle Scholar
  14. 14.
    Rangel-Frausto MS, Pittet D, Costigan M et al (1995) The natural history of the systemic inflanmiatory response syndrome (SIRS). A prospective study. JAMA 273:117–123PubMedCrossRefGoogle Scholar
  15. 15.
    Levi M, ten Cate H, Bauer KA et al (1994) Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 93:114–120PubMedCrossRefGoogle Scholar
  16. 16.
    Biemond BJ, ten Cate H, Levi M et al (1995) Complete inhibition of endotoxin-induced coagulation activation in chimpanzees with a monoclonal Fab fragment against factor VlWIIa. Thromb Haemost 73:223–230PubMedGoogle Scholar
  17. 17.
    Pixley RA, DeLa Cadena R, Page JD et al (1993) The contact system contributes to hypotension but not to disseminated intravascular coagulation in lethal bacteremia. J Clin Invest 91: 61–68PubMedCrossRefGoogle Scholar
  18. 18.
    Ten Cate H, Brandjes DPM, Wolters HJ et al (1993) Disseminated intravascular coagulation: pathophysiology, diagnosis, and treatment. New Horizons 1:312–323PubMedGoogle Scholar
  19. 19.
    Gregory SA, Morrissey JH, Edgington TS (1989) Regulation of tissue factor gene expression in the monocyte procoagulant response to endotoxin. Mol Cell Biol 9:2752–2755PubMedGoogle Scholar
  20. 20.
    0sterud B, Flaegstad T (1983) Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost 49:5–7Google Scholar
  21. 21.
    Moore KL, Andreoli SP, Esmon NL et al (1987) Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest 79:124–130PubMedCrossRefGoogle Scholar
  22. 22.
    Colucci M, Balconi G, Lorenzet R et al (1983) Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest 71:1893–1896PubMedCrossRefGoogle Scholar
  23. 23.
    Furie B, Furie BC (1992) Molecular and cellular biology of blood coagulation. N Engl J Med 326:800–806PubMedCrossRefGoogle Scholar
  24. 24.
    Wada H, Minamikawa K, Wakita Y et al (1993) Hemostatic study before onset of disseminated intravascular coagulation. Am J Hematol 43:190–194PubMedCrossRefGoogle Scholar
  25. 25.
    Kobayashi M, Shimada K, Ozawa T (1990) Human recombinant interleukin 1-beta and tumor necrosis factor alfa-mediated suppression of heparin-like compounds on cultured porcine aortic endothelial cells. J Cell Physiol 144:383–390PubMedCrossRefGoogle Scholar
  26. 26.
    Abe H, Okajima K, Okabe H et al (1994) Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro. J Lab Clin Med 123:874–881PubMedGoogle Scholar
  27. 27.
    Alcaraz A, España F, Sánchez-Cuenca J et al (1995) Activation of the protein C pathway in acute sepsis. Thromb Res 79:83–93PubMedCrossRefGoogle Scholar
  28. 28.
    Rapaport SI (1991) The extrinsic pathway inhibitor: a regulator of tissue factor-dependent blood coagulation. Thromb Haemost 66:6–15PubMedGoogle Scholar
  29. 29.
    Girard TJ, Warren LA, Novotny WF et al (1989) Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 338:518–520PubMedCrossRefGoogle Scholar
  30. 30.
    Taylor Jr FB, Emerson Jr TE, Jordan R et al (1988) Antithrombin-EI prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 26:227–235PubMedGoogle Scholar
  31. 31.
    Taylor Jr FB, Chang A, Esmon CT et al (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in baboons. J Clin Invest 79:918–925PubMedCrossRefGoogle Scholar
  32. 32.
    Creasey AA, Chang ACK, Feigen L et al (1993) Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J CHn Invest 91:2850–2860CrossRefGoogle Scholar
  33. 33.
    Carr C, Bild GS, Chang ACK et al (1995) Recombinant E. coli-derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon Gram-negative model of septic shock. Circ Shock 44:126–137Google Scholar
  34. 34.
    Taylor F, Chang A, Ferrel G et al (1991) C4b-binding protein exacerbates the host response to Escherichia coli. Blood 78:357–363PubMedGoogle Scholar
  35. 35.
    Philippe J, Offner F, Declerck PJ et al (1991) Fibrinolysis and coagulation in patients with infectious disease and sepsis. Thromb Haemost 65:291–295PubMedGoogle Scholar
  36. 36.
    Jansen PM, Pixley RA, Brouwer M et al (1996) Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interieukin-6 and neutrophil elastase. Blood 87:2337–2344PubMedGoogle Scholar
  37. 37.
    Sprengers ED, Kluft C (1987) Plasminogen activator inhibitors. Blood 62:381–387Google Scholar
  38. 38.
    Emeis JJ, Kooistra T (1986) Interleukin-1 and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 163: 1260–1266PubMedCrossRefGoogle Scholar
  39. 39.
    Hanss M, Collen D (1987) Secretion of tissue-type plasminogen activator and plasminogen activator inhibitor by cultured human endothelial cells: modulation by thrombin, endotoxin, and histamine. J Lab Clin Med 109:97–104PubMedGoogle Scholar
  40. 40.
    Colluci M, Paramo JA, Collen D (1985) Generation in plasma of a fast acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 75:818–824CrossRefGoogle Scholar
  41. 41.
    Van Deventer SJH, Buller HR, Ten Cate JW et al (1990) Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways. Blood 76:2520–2526PubMedGoogle Scholar
  42. 42.
    Van der Poll T, Levi M, van Deventer SJH et al (1994) Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 83:446–451PubMedGoogle Scholar
  43. 43.
    Van der Poll T, Levi M, Hack CE et al (1994) Elimination of Interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 179:1253–1259PubMedCrossRefGoogle Scholar
  44. 44.
    Suffredini AF, Harpel PC, Parrillo JE (1989) Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 320:1165–1172PubMedCrossRefGoogle Scholar
  45. 45.
    Biemond BJ, Levi M, ten Cate H et al (1995) Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokines and coagulation cascades. Clin Science 88:587–594Google Scholar
  46. 46.
    De Boer JP, Creasy AA, Chang A et al (1993) Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. Circ Shock 39:59–67PubMedGoogle Scholar
  47. 47.
    Hack CE, Thijs LG (1991) The orchestra of mediators in the pathogenesis of septic shock: A review. In: Vincent JL (ed) Update in Intensive Care and Emergency Medicine. Springer, New York, pp 232–246Google Scholar
  48. 48.
    Redl H, Schiag G, Bahrami S et al (1991) Plasma neutrophil-activating peptide-1/ Interleukin-8 and neutrophil elastase in a primate bacteremia model. J Infect Dis 164:383–388PubMedCrossRefGoogle Scholar
  49. 49.
    Bevilacqua MP, Pober JS, Majeau GR et al (1984) Interleukin-1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 160:618–623PubMedCrossRefGoogle Scholar
  50. 50.
    Conway EM, Back R, Rosenberg RD et al (1989) Tumor necrosis factor enhances expression of tissue factor in RNA in endothehal cells. Thromb Res 53:231–241PubMedCrossRefGoogle Scholar
  51. 51.
    Conkling PR, Greenberg CS, Weinberg JB (1988) Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 72:128–133PubMedGoogle Scholar
  52. 52.
    Nawroth PP, Handley DA, Esmon CT et al (1986) Interleukin-1 induces endothelial cell procoagulant while suppressing cell surface anticoagulant activity. Proc Natl Acad Sci USA 83: 3460–3464PubMedCrossRefGoogle Scholar
  53. 53.
    Conway EM, Rosenberg RD (1988) Tumor necrosis factor suppresses transcription of thrombomodulin gene in endothelial cells. Mol Cell Biol 8:5588–5592PubMedGoogle Scholar
  54. 54.
    Schleef RR, Bevilacqua MP, Sawdey M et al (1988) Cytokine activation of vascular endothelium: effects on tissue-type plasminogen activator and type I plasminogen activator inhibitor. J Biol Chem 263:5797–5803PubMedGoogle Scholar
  55. 55.
    Van der Poll T, Buller HR, ten Cate H et al (1990) Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 322:1622–1627PubMedCrossRefGoogle Scholar
  56. 56.
    Van der Poll T, Levi M, Buller HR et al (1991) Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med 174:729–732PubMedCrossRefGoogle Scholar
  57. 57.
    Bauer KA, ten Cate H, Barzegar S et al (1989) Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans. Blood 74:165–172PubMedGoogle Scholar
  58. 58.
    Van Hinsbergh VWM, Bauer KA, Kooistra T et al (1990) Progress of fibrinolysis during tumor necrosis factor infusion in humans, concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 76: 2284–2289PubMedGoogle Scholar
  59. 59.
    Jansen PM, Boermeester MA, Fischer E et al (1995) Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: Studies in nonhuman primates after interleukin-la administration and during lethal bacteremia. Blood 86:1027–1034PubMedGoogle Scholar
  60. 60.
    Boermeester MA, van Leeuwen PAM, Coyle SM et al (1995) Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 130:739–748PubMedCrossRefGoogle Scholar
  61. 61.
    Giles AR, Nesheim ME, Herring SW et al (1990) The fibrinolytic potential of the normal primate following the generation of thrombin in vivo. Thromb Haemost 63:476–481PubMedGoogle Scholar
  62. 62.
    Mesters RM, Mannuccio PM, Coppola R et al (1996) Factor Vila and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 88:881–886PubMedGoogle Scholar
  63. 63.
    Mesters RM, Florke N, Ostermann et al (1996) Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 75:902–907PubMedGoogle Scholar
  64. 64.
    Leclerc F, Hazelzet J, Jude B et al (1992) Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases. Intensive Care Med 18:202–205PubMedCrossRefGoogle Scholar
  65. 65.
    Thijs LG, de Boer JP, de Groot MCM et al (1993) Coagulation disorders in septic shock. Intensive CareMed l9:S8-S15CrossRefGoogle Scholar
  66. 66.
    Takahashi H, Tatewaki W, Wada K et al (1990) Thrombin versus plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. Am J Hematol 33:90–95PubMedCrossRefGoogle Scholar
  67. 67.
    Hesselvik JF, Malm J, Dahlback B et al (1991) Protein C, Protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 65:126–129PubMedGoogle Scholar
  68. 68.
    Wuillemin WA, Fijnvandraat K, Derkx BHF et al (1995) Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost 74:1436–1441PubMedGoogle Scholar
  69. 69.
    Brandtzaeg P, Sandset PM, Jo0 GB et al (1989) The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide A in systemic meningococcal disease. Thromb Res 55:459–470PubMedCrossRefGoogle Scholar
  70. 70.
    Warr TA, Rao LVM, Rapaport SI (1989) Human plasma extrinsic pathway inhibitor activity: II. Plasma levels in disseminated intravascular coagulation and hepatocellular disease. Blood 74:994–998Google Scholar
  71. 71.
    Nuijens JH, Huijbregts CC, Eerenberg-Belmer AJ et al (1988) Quantification of plasma factor Xlla-Cl-inhibitor and kallikrein-Cl-inhibitor complexes in sepsis. Blood 72:1841–1848PubMedGoogle Scholar
  72. 72.
    Kaufman N, Page JD, Pixley RA et al (1991) oc2-macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 77:2660–2667PubMedGoogle Scholar
  73. 73.
    Pralong G, Calandra T, Glauser MP et al (1989) Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 61:459–462PubMedGoogle Scholar
  74. 74.
    Gando S, Kameue T, Nanzaki S et al (1996) Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 75: 224–228PubMedGoogle Scholar
  75. 75.
    Kruithof EKO, Calandra T, Pralong G et al (1993) Evolution of plasminogen activator inhibitor type I in patients with septic shock — correlation with cytokine concentrations. Fibrinolysis 7:117–121CrossRefGoogle Scholar
  76. 76.
    Brandtzaeg P, Jo0 GB, Bmsletto B et al (1990) Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 57:271–278PubMedCrossRefGoogle Scholar
  77. 77.
    Okajima K, Yang W-P, Okabe H et al (1991) Role of leukocytes in the activation of intravascular coagulation in patients with septicemia. Am J Hemat 36:265–271PubMedCrossRefGoogle Scholar
  78. 78.
    Ono S, Mochizuki H, Tamakuma S (1996) A clinical study on the significance of platelet-acti- vating factor in the pathophysiology of septic disseminated intravascular coagulation in surgery. Am J Surg 171:409–415PubMedCrossRefGoogle Scholar
  79. 79.
    Idell S, James KK, Levin EG et al (1989) Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 84:695–705PubMedCrossRefGoogle Scholar
  80. 80.
    Bertozzi P, Astedt B, Zenzius L et al (1990) Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 322:890–897PubMedCrossRefGoogle Scholar
  81. 81.
    Tanaka T, Tsujinaka T, Kambayashi J-I et al (1990) The effect of heparin on multiple organ failure and disseminated intravascular coagulation in a sepsis model. Thromb Res 60:321–330PubMedCrossRefGoogle Scholar
  82. 82.
    Coalson JJ, Benjamin B, Archer LT et al (1978) Prolonged shock in the baboon subjected to infusion of E. coH endotoxin. Circ Shock 5:423–437Google Scholar
  83. 83.
    Emerson TE Jr, Fournel MA, Redens TB et al (1989) Efficacy of antithrombin III supplementation in animal models of fulminant Escherichia coli endotoxemia or bacteremia. Am J Med 87:27S-33SPubMedCrossRefGoogle Scholar
  84. 84.
    Blauhut B, Kramar H, Vinazzer H et al (1985) Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 39:81–89PubMedCrossRefGoogle Scholar
  85. 85.
    Maki M, Terao T, Ikenoue T et al (1987) Clinical evaluation of antithrombin EI concentrate and BI 6.013 for disseminated intravascular coagulation in obstetrics. Gynecol Obstet Invest 23:230–240CrossRefGoogle Scholar
  86. 86.
    Fourrier F, Chopin C, Huart JJ et al (1993) Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104:882–888PubMedCrossRefGoogle Scholar
  87. 87.
    Yamauchi T, Umed F, Inoguche T (1991) Antithrombin EI stimulates prostacyclin production by cultured aortic endothelial cells. Biochem Biophys Res Comm 163:1404–1411CrossRefGoogle Scholar
  88. 88.
    Okajima K, Imamura H, Koga S et al (1990) Treatment of patients with disseminated intravascular coagulation by protein C. Am J Hemat 33:277–278PubMedCrossRefGoogle Scholar
  89. 89.
    Salat C, Boekstegers P, Holler E et al (1996) Hemostatic parameters in sepsis patients treated with anti-TNFa-monoclonal antibodies. Shock 6:233–237PubMedCrossRefGoogle Scholar
  90. 90.
    Taylor Jr FB, Chang A, Ruf W et al (1991) Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 33:127–134PubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia, Milano 1998

Authors and Affiliations

  • L. G. Thijs

There are no affiliations available

Personalised recommendations