, Volume 3, Issue 2, pp 87–91

New Concepts in Activation of the Clotting Cascade in Sepsis

  • Joost C.M. Meijers
  • Bonno N. Bouma


Systemic infection leads to activation of the coagulation system. The presence of endotoxins results in exposure of tissue factor. Tissue factor-mediated initiation of coagulation results in the generation of thrombin for fibrin formation. Thrombin formation continues after fibrin formation via feedback activation of factor XI, thereby propagating the intrinsic pathway of coagulation. The extra thrombin that is formed can lead to additional fibrin formation and protection of the fibrin clot from fibrinolysis. The activation of the coagulation system, with at the same time not fully working control mechanisms, induces a severe procoagulant state in sepsis.

coagulation sepsis fibrinolysis tissue factor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Robboy SJ, Major MC, Colman RW, Minna JD. Pathology of disseminated intravascular coagulation (DIC): Analysis of twenty-six cases. Hum Pathol 1972;3:327–343.Google Scholar
  2. 2.
    Regoeczi E, Brain MC. Organ distribution of fibrin in disseminated intravascular coagulation. Br J Haematol 1969;17:73–81.Google Scholar
  3. 3.
    Levi M, ten Cate H, van der Poll T, van Deventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993;270:975–979.Google Scholar
  4. 4.
    Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964;145:1310–1312.Google Scholar
  5. 5.
    MacFarlane RG. An enzyme cascade in the blood clotting mechanism and its function as biochemical amplifier. Nature 1964;202:498–499.Google Scholar
  6. 6.
    Rapaport SI, Rao LVM. The tissue factor pathway: How it has become a “prima ballerina.” Thromb Haemost 1995; 74:7–17.Google Scholar
  7. 7.
    Colman RW, Schmaier AH. Contact system: A vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997;90: 3819–3843.Google Scholar
  8. 8.
    Asakai R, Chung DW, Davie EW, Seligsohn U. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 1991;325:153–158.Google Scholar
  9. 9.
    Berliner S, Horowitz I, Martinowitz U, Brenner B, Seligsohn U. Dental surgery in patients with severe factor XI deficiency without plasma replacement. Blood Coagul Fibrinol 1992;3:465–468.Google Scholar
  10. 10.
    Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII. Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J Biol Chem 1991;266:7353–7358.Google Scholar
  11. 11.
    Gailani D, Broze GJ. Factor XI activation in a revised model of blood coagulation. Science 1991;253:909–912.Google Scholar
  12. 12.
    Von dem Borne PAK, Koppelman SJ, Bouma BN, Meijers JCM. Surface independent factor XI activation by thrombin in the presence of high molecular weight kininogen. Thromb Haemost 1994;72:397–402.Google Scholar
  13. 13.
    Von dem Borne PAK, Meijers JCM, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995;86:3035–3042.Google Scholar
  14. 14.
    Cawthern KM, van 't Veer C, Lock JB, DiLorenzo ME, Branda RF, Mann KG. Blood coagulation in hemophilia A and hemophilia C. Blood 1998;15:4581–4592.Google Scholar
  15. 15.
    Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol 1999;19:170–177.Google Scholar
  16. 16.
    Bouma BN, von dem Borne PAK, Meijers JCM. Factor XI and protection of the fibrin clot against lysis. A role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost 1998;80:24–27.Google Scholar
  17. 17.
    Østerud B, Rapaport SI. Activation of factor IX by the reaction product of tissue factor and factor VII: Additional pathway for initiating blood coagulation. Proc Natl Acad Sci USA 1977;74:5260–5264.Google Scholar
  18. 18.
    Marlar RA, Kleiss AJ, Griffin JH. An alternative pathway of human blood coagulation. Blood 1982;60:1353–1358.Google Scholar
  19. 19.
    Broze GJ. The role of tissue factor pathway inhibitor in a revised coagulation cascade. Semin Hematol 1992;29: 59–169.Google Scholar
  20. 20.
    Rand MD, Lock JB, van 't Veer C, Gaffney DP, Mann KG. Blood clotting in minimally altered whole blood. Blood 1996;88:3432–3445.Google Scholar
  21. 21.
    Ichinose A. The physiology and biochemistry of factor XIII. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and Thrombosis. Edinburgh: Churchill Livingstone, 1994:531–546.Google Scholar
  22. 22.
    Ichinose A, Fujikawa K, Suyama T. The activation of prourokinase by plasma kallikrein and its inactivation by thrombin. J Biol Chem 1986;261:3486–3490.Google Scholar
  23. 23.
    Gurewich V, Pannell R. Inactivation of single-chain urokinase (pro-urokinase) by thrombin and thrombin-like enzymes: Relevance of the findings to the interpretation of fibrin-binding experiments. Blood 1987;69:769–772.Google Scholar
  24. 24.
    Lijnen HR, van Hoef B, Collen D. Activation with plasmin of two-chain urokinase-type plasminogen activator derived from single-chain urokinase-type activator by treatment with thrombin. Eur J Biochem 1987;169:359–364.Google Scholar
  25. 25.
    Nesheim M, Wang W, Boffa M, Nagashima M, Morser J, Bajzar L. Thrombin, thrombomodulin and TAFI in the molecular link between coagulation and fibrinolysis. Thromb Haemost 1997;78:386–391.Google Scholar
  26. 26.
    Braat EAM, Los P, Rijken DC. The inactivation of singlechain urokinase plasminogen activator by thrombin in a plasma milieu: The effect of thrombomodulin. Blood Coag Fibrinol 1998;9:419–427.Google Scholar
  27. 27.
    Braat EAM, Rijken DC. The inactivation of single-chain urokinase type-plasminogen activator by thrombin may provide an additional explanation for the antifibrinolytic effect of factor XI. Thromb Haemostas 1999;81:657.Google Scholar
  28. 28.
    Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem 1995;270:14477–14484.Google Scholar
  29. 29.
    Tan AK, Eaton DL. Activation and characterization of procarboxypeptidase B from human plasma. Biochemistry 1995;34:5811–5816.Google Scholar
  30. 30.
    Hendriks D, Scharpe S, van Sande M, Lommaert MP. Characterisation of a carboxypeptidase in human serum distinct from carboxypeptidase N. J Clin Chem Clin Biochem 1989;27:277–285.Google Scholar
  31. 31.
    Wang W, Hendriks DF, Scharpe SS. Carboxypeptidase U, a plasma carboxypeptidase with high affinity for plasminogen. J Biol Chem 1994;269:15937–15944.Google Scholar
  32. 32.
    Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995;96:2534–2538.Google Scholar
  33. 33.
    Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem 1998;273:27176–27181.Google Scholar
  34. 34.
    Von dem Borne PAK, Bajzar L, Meijers JCM, Nesheim ME, Bouma BN. Thrombin-mediated activation of factor XI results in a thrombin-activable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest 1997;99:2323–2327.Google Scholar
  35. 35.
    Minnema MC, Friederich PW, Levi M, von dem Borne PAK, Mosnier LO, Meijers JCM, Biemond BJ, Hack CE, Bouma BN, ten Cate H. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an antifibrinolytic factor. J Clin Invest 1998;101:10–14.Google Scholar
  36. 36.
    Nuijens JH, Huijbregts CCM, Eerenberg-Belmer AJM, Abbink JJ, Strack van Schijndel RJM, Felt-Bersma RJF, Thijs LG, Hack CE. Quantification of plasma factor XII-C1–inhibitor and kallikrein-C1–inhibitor complexes in sepsis. Blood 1988;72:1841–1848.Google Scholar
  37. 37.
    Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, van Deventer SJ, 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. 38.
    Pixley RA, De La Cadena R, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor FB Jr, Colman RW. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest 1993;91:61–68.Google Scholar
  39. 39.
    Pixley RA, DeLa Cadena RA, Page JD, Kaufman N, Wyshock EG, Colman RW, Chang A, Taylor FB Jr. Activation of the contact system in lethal hypotensive bacteremia in a baboon model. Am J Pathol 1992;140:897–906.Google Scholar
  40. 40.
    Minnema M, Pajkrt D, Wuillemin WA, Roem D, Bleeker WK, Levi M, van Deventer SJH, Hack CE, ten Cate H. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood 1998;92:3294–3301.Google Scholar
  41. 41.
    Rivers RPA, Hathaway WE, Weston WL. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 1975;30:311–316.Google Scholar
  42. 42.
    Colucci M, Balconi R, Lorenzet A, Pietra A, Locati D, Donati MB, Semararo N. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest 1983;71:1893–1896.Google Scholar
  43. 43.
    Østerud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: Related to an unfavourable prognosis. Thromb Haemost 1983;49:5–7.Google Scholar
  44. 44.
    Giesen PLA, Rauch U, Bohrman B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA 1999;96:2311–2315.Google Scholar
  45. 45.
    Warr TA, Rao LVM, Rapaport SI. Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: Effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 1990;75:1481–1489.Google Scholar
  46. 46.
    Biemond BJ, Levi M, ten Cate H, 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 amonoclonal Fab fragment against factor VII/VIIa. ThrombHaemost 1995;73:223–230.Google Scholar
  47. 47.
    Taylor FB, Chang A, Ruf W, Morrissey 6JH, 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
  48. 48.
    Day KC, Hoffman LC, Palmier MO, Kretzmer KK, Huang MD, Pyla EY, Spokas E, Broze 6GJ, Warren TG, Wun TC. Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 1990;76:1538–1545.Google Scholar
  49. 49.
    Creasey AA, Chang AC, Feigen L, Wun TC, Taylor 6FB, Hinshaw 6LB. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993;91:2850–2856.Google Scholar
  50. 50.
    Sandset PM, Warn-Cramer BJ, Maki SL, Rapaport SI. Immunodepletion of extrinsic pathway inhibitor sensitizes rabbits to endotoxin-induced intravascular coagulation and the generalized Shwartzman reaction. Blood 1991;78:1496–1502.Google Scholar
  51. 51.
    Sandset PM, Warn-Cramer BJ, Rao LV, Maki SL, Rapaport SI. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: Evidence supporting a physiological role for EPI as a natural anticoagulant. Proc Natl Acad Sci USA 1991;88:708–712.Google Scholar
  52. 52.
    Carr C, Bild GS, Chang ACK, Peer GT, Palmier MO, Frazier RB, et al. 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.Google Scholar
  53. 53.
    Van Deventer SJH, Buller 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

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • Joost C.M. Meijers
    • 1
  • Bonno N. Bouma
    • 1
  1. 1.Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center, Utrecht, and Institute of BiomembranesUtrecht UniversityUtrechtthe Netherlands

Personalised recommendations