Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Disseminated intravascular coagulation

Abstract

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation that can be caused by infectious insults (such as sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient control of anticoagulant pathways and plasminogen activator inhibitor 1-mediated suppression of fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent observations have pointed to an important role for extracellular DNA and DNA-binding proteins, such as histones, in the pathogenesis of DIC. The International Society on Thrombosis and Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test parameters. This scoring system has now been well validated in diverse clinical settings. The theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH guidance for the treatment of DIC recommends treatment strategies that are based on current evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and management of DIC and discuss the future directions of basic and clinical research in this field.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of coagulation physiology.
Figure 2: Interaction of inflammation and coagulation in DIC.
Figure 3: Diverse and opposing effects of thrombin.
Figure 4: Purpura fulminans in a patient with DIC due to meningococcal septicaemia.
Figure 5: Management strategies for DIC.
Figure 6: Anticoagulant factor concentrate treatment for DIC.

Similar content being viewed by others

References

  1. Lasch, H. G., Heene, D. L., Huth, K. & Sandritter, W. Pathophysiology, clinical manifestations and therapy of consumption-coagulopathy (“Verbrauchskoagulopathie”). Am. J. Cardiol. 20, 381–391 (1967).

    Article  CAS  PubMed  Google Scholar 

  2. Spero, J. A., Lewis, J. H. & Hasiba, U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb. Haemost. 43, 28–33 (1980).

    Article  CAS  PubMed  Google Scholar 

  3. Taylor, F. B. Jr et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb. Haemost. 86, 1327–1330 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Wada, H. et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J. Thromb. Haemost. 11, 761–767 (2013). Together with reference 3, these were important landmarks in standardizing and harmonizing the diagnosis of DIC.

    Article  CAS  Google Scholar 

  5. [No authors listed.] American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 20, 864–874 (1992).

  6. Gando, S., Kameue, T., Nanzaki, S. & Nakanishi, Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb. Haemost. 75, 224–228 (1996). This paper links DIC to the systemic inflammatory state.

    CAS  PubMed  Google Scholar 

  7. Bakhtiari, K., Meijers, J. C. M., de Jonge, E. & Levi, M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit. Care Med. 32, 2416–2421 (2004).

    Article  PubMed  Google Scholar 

  8. Gando, S. et al. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: Results of a multicenter, prospective survey. Crit. Care Med. 36, 145–150 (2008).

    Article  PubMed  Google Scholar 

  9. Matsuda, T. et al. in Annual Report of the Research Committee on DIC 1992. (ed. Matsuda, T. ) 17–30 (Ministry of Health and Welfare of Japan, 1993).

    Google Scholar 

  10. Nakagawa, M. in Annual Report of the Research Committee on DIC 1998. (ed. Nakagawa, M. ) 57–64 (Ministry of Health and Welfare of Japan, 1999).

    Google Scholar 

  11. Murata, A., Okamoto, K., Mayumi, T., Muramatsu, K. & Matsuda, S. The recent time trend of outcomes of disseminated intravascular coagulation in Japan: an observational study based on a national administrative database. J. Thromb. Thromblysis 38, 364–371 (2014).

    Article  Google Scholar 

  12. Cartin-Ceba, R. et al. Epidemiology of critical care syndromes, organ failures, and life-support interventions in a suburban US community. Chest 140, 1447–1445 (2011).

    Article  PubMed  Google Scholar 

  13. Singh, B. et al. Trends in the incidence and outcomes of disseminated intravascular coagulation in critically ill patients (2004–2010): a population-based study. Chest 143, 1235–1242 (2013).

    Article  PubMed  Google Scholar 

  14. Rangel-Frausto, M. S. et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273, 117–123 (1995). A clinical study that elucidated the interaction between inflammation and coagulation.

    Article  CAS  PubMed  Google Scholar 

  15. Ogura, H. et al. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J. Infect. Chemother. 20, 157–162 (2014).

    Article  PubMed  Google Scholar 

  16. Dhainaut, J. F. et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J. Thromb. Haemost. 2, 1924–1933 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Kienast, J. et al. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J. Thromb. Haemostasis 4, 90–97 (2006).

    Article  CAS  Google Scholar 

  18. Gando, S. et al. A multicenter, prospective validation study of the Japanese association for acute medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit. Care 17, R111 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sawamura, A. et al. Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma. Thromb. Res. 124, 706–710 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Oshiro, A. et al. Hemostasis during the early stage of trauma: comparison with disseminated intravascular coagulation. Crit. Care 18, R61 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Rattray, D., O'Connell, C. M. & Baskett, T. F. Acute disseminated intravascular coagulation in obstetrics: a tertiary center population review (1980 to 2009). J. Obstet. Gynaecol. Can. 34, 341–347 (2012).

    Article  PubMed  Google Scholar 

  22. Esmon, C. T., Xu, J. & Lupu, F. Innate immunity and coagulation. J. Thromb. Haemost. 9 (Suppl. 1), 182–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Engelmann, B. & Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 13, 34–45 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Levi, M., van der Poll, T., ten Cate, H. & van Deventer, S. J. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur. J. Clin. Invest. 27, 3–9 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Levi, M., van der Poll, T. & Buller, H. R. The bidirectional relationshiop between coagulation and inflammation. Circulation 109, 2698–2704 (2004).

    Article  PubMed  Google Scholar 

  26. Aird, W. C. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit. Care Med. 29, S28–S34 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Falanga, A., Schieppati, F. & Russo, D. Cancer tissue procoagulant mechanisms and the hypercoagulable state of patients with cancer. Semin. Thromb. Hemost. 41, 756–764 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Levi, M. Pathogenesis and management of peripartum coagulopathic calamities (disseminated intravascular coagulation and amniotic fluid embolism). Thromb. Res. 131, S32–S34 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Franco, R. F. et al. The in vivo kinetics of tissue factor messenger RNA expression during human endotoxemia: relationship with activation of coagulation. Blood 96, 554–559 (2000).

    CAS  PubMed  Google Scholar 

  30. Osterud, B. & Flaegstad, T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb. Haemost. 49, 5–7 (1983).

    Article  CAS  PubMed  Google Scholar 

  31. Taylor, F. B. Jr et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ. Shock 33, 127–134 (1991).

    PubMed  Google Scholar 

  32. Levi, M. et al. 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, 114–120 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gando, S. Hemostasis and thrombosis in trauma patients. Semin. Thromb. Hemost. 41, 26–34 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Falanga, A., Marchetti, M. & Vignoli, A. Coagulation and cancer: biological and clinical aspects. J. Thromb. Haemost. 11, 223–233 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Delabranche, X. et al. Microparticles are new biomarkers of septic shock-induced disseminated intravascular coagulopathy. Intensive Care Med. 39, 1695–1703 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Levi, M. & van der Poll, T. Inflammation and coagulation. Crit. Care Med. 38, S26–S34 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Giesen, P. L. et al. Blood-borne tissue factor: another view of thrombosis. Proc. Natl Acad. Sci. USA 96, 2311–2315 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Osterud, B., Rao, L. V. & Olsen, J. O. Induction of tissue factor expression in whole blood — lack of evidence for the presence of tissue factor expression on granulocytes. Thromb. Haemost. 83, 861–867 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Rauch, U. et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood 96, 170–175 (2000).

    CAS  PubMed  Google Scholar 

  40. Zimmerman, G. A., McIntyre, T. M., Prescott, S. M. & Stafforini, D. M. The platelet-activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit. Care Med. 30, S294–S301 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Versteeg, H. H., Heemskerk, J. W., Levi, M. & Reitsma, P. H. New fundamentals in hemostasis. Physiol. Rev. 93, 327–358 (2013). A comprehensive paper providing new insights in coagulation physiology and pathology.

    Article  CAS  PubMed  Google Scholar 

  42. Shebuski, R. J. & Kilgore, K. S. Role of inflammatory mediators in thrombogenesis. J. Pharmacol. Exp. Ther. 300, 729–735 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Eerenberg, E. S. & Levi, M. The potential therapeutic benefit of targeting ADAMTS13 activity. Semin. Thromb. Hemost. 40, 28–33 (2014).

    CAS  PubMed  Google Scholar 

  44. Bockmeyer, C. L. et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 93, 137–140 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Booth, K. K., Terrell, D. R., Vesely, S. K. & George, J. N. Systemic infections mimicking thrombotic thrombocytopenic purpura. Am. J. Hematol. 86, 743–751 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Kremer Hovinga, J. A. et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J. Thromb. Haemost. 5, 2284–2290 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Bartlett, A. H., Hayashida, K. & Park, P. W. Molecular and cellular mechanisms of syndecans in tissue injury and inflammation. Mol. Cells 24, 153–166 (2007).

    CAS  PubMed  Google Scholar 

  48. Esmon, C. T. The regulation of natural anticoagulant pathways. Science 235, 1348–1352 (1987).

    Article  CAS  PubMed  Google Scholar 

  49. Griffin, J. H., Fernandez, J. A., Gale, A. J. & Mosnier, L. O. Activated protein C. J. Thromb. Haemost. 5 (Suppl. 1), 73–80 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Esmon, C. T. Inflammation and the activated protein C anticoagulant pathway. Semin. Thromb. Hemost 32 (Suppl. 1), 49–60 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Fijnvandraat, K. et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb. Haemost. 73, 15–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Taylor, F. B. Jr et al. Role of free protein S and C4b binding protein in regulating the coagulant response to Escherichia coli. Blood 86, 2642–2652 (1995).

    CAS  PubMed  Google Scholar 

  53. Taylor, F. B. et al. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood 97, 1685–1688 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Levi, M. & van der Poll, T. Coagulation in patients with severe sepsis. Semin. Thromb. Hemost. 41, 9–15 (2015).

    Article  PubMed  Google Scholar 

  55. Sandset, P. M., Warn-Cramer, B. J., Rao, L. V., Maki, S. L. & Rapaport, S. I. Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant. Proc. Natl Acad. Sci. USA 88, 708–712 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Creasey, A. A. et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J. Clin. Invest. 91, 2850–2856 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. de Jonge, E. et al. Tissue factor pathway inhibitor (TFPI) dose-dependently inhibits coagulation activtion without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 95, 1124–1129 (2000).

    CAS  PubMed  Google Scholar 

  58. Levi, M. & van der Poll, T. A short contemporary history of disseminated intravascular coagulation. Semin. Thromb. Hemost. 40, 874–880 (2014).

    Article  PubMed  Google Scholar 

  59. Biemond, B. J. et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin. Sci. (Lond.) 88, 587–594 (1995).

    Article  CAS  Google Scholar 

  60. Hack, C. E. Fibrinolysis in disseminated intravascular coagulation. Semin. Thromb. Hemost. 27, 633–638 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Hinshaw, L. B. et al. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ. Shock 30, 279–292 (1990).

    CAS  PubMed  Google Scholar 

  62. Abraham, E. et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factorα in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-α MAb Sepsis Study Group. JAMA 273, 934–941 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. van der Poll, T. et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J. Exp. Med. 179, 1253–1259 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Stouthard, J. M. et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb. Haemost. 76, 738–742 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Boermeester, M. A. et al. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch. Surg. 130, 739–748 (1995).

    Article  CAS  PubMed  Google Scholar 

  66. Coughlin, S. R. Thrombin signalling and protease-activated receptors. Nature 407, 258–264 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Kannemeier, C. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc. Natl Acad. Sci. USA 104, 6388–6393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Semeraro, F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118, 1952–1961 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fuchs, T. A., Brill, A. & Wagner, D. D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler. Thromb. Vasc. Biol. 32, 1777–1783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004). This study highlighted the importance of innate immune activation and its coupling to DIC. The study described important pathophysiological roles of NETs.

    Article  CAS  PubMed  Google Scholar 

  71. Brinkmann, V. & Zychlinsky, A. Neutrophil extracellular traps: is immunity the second function of chromatin? J. Cell Biol. 198, 773–783 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. von Bruhl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Iba, T., Miki, T., Hashiguchi, N., Tabe, Y. & Nagaoka, I. Combination of antithrombin and recombinant thrombomodulin modulates neutrophil cell-death and decreases circulating DAMPs levels in endotoxemic rats. Thromb. Res. 134, 169–173 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Saffarzadeh, M. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS ONE 7, e32366 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kaneider, N. C., Forster, E., Mosheimer, B., Sturn, D. H. & Wiedermann, C. J. Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thromb. Haemost. 90, 1150–1157 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Esmon, C. T. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J. Exp. Med. 196, 561–564 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yuksel, M., Okajima, K., Uchiba, M., Horiuchi, S. & Okabe, H. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb. Haemost. 88, 267–273 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Murakami, K. et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87, 642–647 (1996).

    CAS  PubMed  Google Scholar 

  81. Taylor, F. B. Jr et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 95, 1680–1686 (2000).

    CAS  PubMed  Google Scholar 

  82. Levi, M. et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein C deficient mice. Blood 101, 4823–4827 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Toh, C. H. & Hoots, W. K. & SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J. Thromb. Haemost. 5, 604–606 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Sivula, M., Tallgren, M. & Pettila, V. Modified score for disseminated intravascular coagulation in the critically ill. Intensive Care Med. 31, 1209–1214 (2005).

    Article  PubMed  Google Scholar 

  85. Cauchie, P. et al. Diagnosis and prognosis of overt disseminated intravascular coagulation in a general hospital — meaning of the ISTH score system, fibrin monomers, and lipoprotein–C-reactive protein complex formation. Am. J. Hematol. 81, 414–419 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Venugopal, A. Disseminated intravascular coagulation. Indian J. Anaesth. 58, 603–608 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Toh, C. H. & Dennis, M. Disseminated intravascular coagulation: old disease, new hope. BMJ 327, 974–977 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Toh, C. H. & Alhamdi, Y. Current consideration and management of disseminated intravascular coagulation. Hematology Am. Soc. Hematol. Educ. Program 2013, 286–291 (2013).

    Article  PubMed  Google Scholar 

  89. Narayanan, S. Multifunctional roles of thrombin. Ann. Clin. Lab. Sci. 29, 275–280 (1999).

    CAS  PubMed  Google Scholar 

  90. Kjalke, M. et al. Active site-inactivated factors VIIa, Xa, and IXa inhibit individual steps in a cell-based model of tissue factor-initiated coagulation. Thromb. Haemost. 80, 578–584 (1998).

    CAS  PubMed  Google Scholar 

  91. Rezaie, A. R. Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr. Med. Chem. 17, 2059–2069 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Levin, E. G., Marzec, U., Anderson, J. & Harker, L. A. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J. Clin. Invest. 74, 1988–1995 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gelehrter, T. D. & Sznycer-Laszuk, R. Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J. Clin. Invest. 77, 165–169 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, W., Boffa, M. B., Bajzar, L., Walker, J. B. & Nesheim, M. E. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J. Biol. Chem. 273, 27176–27181 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Satta, N. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J. Immunol. 153, 3245–3255 (1994).

    CAS  PubMed  Google Scholar 

  96. Moxon, C. A. et al. Laboratory evidence of disseminated intravascular coagulation is associated with a fatal outcome in children with cerebral malaria despite an absence of clinically evident thrombosis or bleeding. J. Thromb. Haemost. 13, 1653–1664 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Moxon, C. A. et al. Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 122, 842–851 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Turner, L. et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498, 502–505 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mosnier, L. O., Zlokovic, B. V. & Griffin, J. H. The cytoprotective protein C pathway. Blood 109, 3161–3172 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Gando, S., Wada, H., Thachil, J. & Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis (ISTH). Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J. Thromb. Haemost. 11, 826–835 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Gando, S., Sawamura, A. & Hayakawa, M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann. Surg. 254, 10–19 (2011).

    Article  PubMed  Google Scholar 

  102. Geerts, W. H., Code, K. I., Jay, R. M., Chen, E. & Szalai, J. P. A prospective study of venous thromboembolism after major trauma. N. Engl. J. Med. 331, 1601–1606 (1994).

    Article  CAS  PubMed  Google Scholar 

  103. Osterud, B. & Bjorklid, E. The production and availability of tissue thromboplastin in cellular populations of whole blood exposed to various concentrations of endotoxin. An assay for detection of endotoxin. Scand. J. Haematol. 29, 175–184 (1982).

    Article  CAS  PubMed  Google Scholar 

  104. Hellum, M. et al. Microparticle-associated tissue factor activity correlates with plasma levels of bacterial lipopolysaccharides in meningococcal septic shock. Thromb. Res. 133, 507–514 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Muller, F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139, 1143–1156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nesheim, M. E., Tracy, R. P. & Mann, K. G. “Clotspeed,” a mathematical simulation of the functional properties of prothrombinase. J. Biol. Chem. 259, 1447–1453 (1984).

    CAS  PubMed  Google Scholar 

  107. Giles, A. R., Mann, K. G. & Nesheim, M. E. A combination of factor Xa and phosphatidylcholine-phosphatidylserine vesicles bypasses factor VIII in vivo. Br. J. Haematol. 69, 491–497 (1988).

    Article  CAS  PubMed  Google Scholar 

  108. Barranco-Medina, S., Pozzi, N., Vogt, A. D. & Di Cera, E. Histone H4 promotes prothrombin autoactivation. J. Biol. Chem. 288, 35749–35757 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Eltzschig, H. K. & Collard, C. D. Vascular ischaemia and reperfusion injury. Br. Med. Bull. 70, 71–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Darbousset, R. et al. P2X1 expressed on polymorphonuclear neutrophils and platelets is required for thrombosis in mice. Blood 124, 2575–2585 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Abrams, S. T. et al. Circulating histones are mediators of trauma-associated lung injury. Am. J. Respir. Crit. Care Med. 187, 160–169 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Alhamdi, Y. et al. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit. Care Med. 43, 2094–2103 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Xu, J., Zhang, X., Monestier, M., Esmon, N. L. & Esmon, C. T. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J. Immunol. 187, 2626–2631 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15, 1318–1321 (2009). This study highlighted the importance of innate immune activation and its coupling to DIC. In addition, the study described important pathophysiological roles for extracellular DNA and histones in sepsis and related organ failure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nakahara, M. et al. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. PLoS ONE 8, e75961 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Alhamdi, Y. et al. Circulating histone concentrations differentially affect the predominance of left or right ventricular dysfunction in critical illness. Crit. Care Med. 44, e278–e288 (2016).

    Article  PubMed  Google Scholar 

  117. Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Fuchs, T. A., Bhandari, A. A. & Wagner, D. D. Histones induce rapid and profound thrombocytopenia in mice. Blood 118, 3708–3714 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Longstaff, C. et al. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J. Biol. Chem. 288, 6946–6956 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kim, J. E., Lee, N., Gu, J. Y., Yoo, H. J. & Kim, H. K. Circulating levels of DNA–histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation. Thromb. Res. 135, 1064–1069 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Levi, M., Toh, C., Thachil, J. & Watson, H. Guidelines for the diagnosis and management of disseminated intravascular coagulation. Br. J. Haematol. 145, 24–33 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. Mesters, R. M. et al. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 88, 881–886 (1996).

    CAS  PubMed  Google Scholar 

  123. Dhainaut, J. F. et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit. Care Med. 33, 341–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Kobayashi, N., Maekawa, T., Takada, M., Tanaka, H. & Gonmori, H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl. Haematol. 49, 265–275 (1983).

    Google Scholar 

  125. Wada, H. et al. Outcome of disseminated intravascular coagulation in relation to the score when treatment was begun. Mie DIC Study Group. Thromb. Haemost. 74, 848–852 (1995).

    Article  CAS  PubMed  Google Scholar 

  126. Dempfle, C. E. & Borggrefe, M. Point of care coagulation tests in critically ill patients. Semin. Thromb. Hemost 34, 445–450 (2008).

    Article  PubMed  Google Scholar 

  127. Levi, M. & Hunt, B. J. A critical appraisal of point-of-care coagulation testing in critically ill patients. J. Thromb. Haemost. 13, 1960–1967 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Zuckerman, L., Cohen, E., Vagher, J. P., Woodward, E. & Caprini, J. A. Comparison of thrombelastography with common coagulation tests. Thromb. Haemost. 46, 752–756 (1981).

    Article  CAS  PubMed  Google Scholar 

  129. Fourrier, F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way? Crit. Care Med. 40, 2704–2708 (2012).

    Article  PubMed  Google Scholar 

  130. Grottke, O. et al. Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model. PLoS ONE 8, e64100 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Grundman, C. et al. Prothrombin overload causes thromboembolic complications in prothrombin complex concentrates: in vitro and in vivo evidence. Thromb. Haemost. 94, 1338–1339 (2005).

    Article  PubMed  Google Scholar 

  132. Grottke, O. et al. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood 118, 1943–1951 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Schochl, H., Voelckel, W., Maegele, M., Kirchmair, L. & Schlimp, C. J. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit. Care 18, R147 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Simpson, E. et al. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst. Rev. 3, CD005011 (2012).

    Google Scholar 

  135. Jaimes, F. et al. Unfractioned heparin for treatment of sepsis: a randomized clinical trial (the HETRASE study). Crit. Care Med. 37, 1185–1196 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Sakuragawa, N., Hasegawa, H., Maki, M., Nakagawa, M. & Nakashima, M. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC) — a multicenter co-operative double-blind trial in comparison with heparin. Thromb. Res. 72, 475–500 (1993).

    Article  CAS  PubMed  Google Scholar 

  137. Samama, M. M. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N. Engl. J. Med. 341, 793–800 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Hoffman, M. & Monroe, D. M. 3rd. A cell-based model of hemostasis. Thromb. Haemost. 85, 958–965 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Levi, M. & van der Poll, T. The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. Semin. Thromb. Hemost. 34, 459–468 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Warren, B. L. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286, 1869–1878 (2001).

    Article  CAS  PubMed  Google Scholar 

  141. Abraham, E. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290, 238–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Ranieri, V. M. et al. Drotrecogin alfa (activated) in adults with septic shock. N. Engl. J. Med. 366, 2055–2064 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Aoki, N. et al. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int. J. Hematol. 75, 540–547 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Afshari, A., Wetterslev, J., Brok, J. & Moller, A. M. Antithrombin III for critically ill patients. Cochrane Database Syst. Rev. 3, CD005370 (2008).

    Google Scholar 

  145. Levi, M., de Jonge, E., van der Poll, T. & ten Cate, H. Disseminated intravascular coagulation. Thromb. Haemost. 82, 695–705 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Wiedermann, C. J. & Kaneider, N. C. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. Blood Coagul. Fibrinolysis 17, 521–526 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Gando, S. et al. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit. Care 17, R297 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Iba, T., Saitoh, D., Wada, H. & Asakura, H. Efficacy and bleeding risk of antithrombin supplementation in septic disseminated intravascular coagulation: a secondary survey. Crit. Care 18, 497 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Tagami, T., Matsui, H., Horiguchi, H., Fushimi, K. & Yasunaga, H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J. Thromb. Haemost. 12, 1470–1479 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Tagami T. Matsui H. Fushimi K. & Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis. Thromb. Haemost. 114, 537–545 (2015).

    Article  PubMed  Google Scholar 

  151. Saito, H. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a Phase III, randomized, double-blind clinical trial. J. Thromb. Haemost. 5, 31–41 (2007). This was the first study that showed efficacy and safety of rhTM.

    Article  CAS  PubMed  Google Scholar 

  152. Tagami, T., Matsui, H., Horiguchi, H., Fushimi, K. & Yasunaga, H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J. Thromb. Haemost. 13, 31–40 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Yamakawa, K. et al. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study. Crit. Care 15, R123 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Yamakawa, K. et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med. 39, 644–652 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Yamakawa, K. et al. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J. Thromb. Haemost. 13, 508–519 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Yoshimura, J. et al. Benefit profile of recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Crit. Care 19, 78 (2015). The results reported in this paper indirectly support the concept that the target of anticoagulant factor concentrates is not severe sepsis, but severe sepsis with established DIC.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Vincent, J. L. et al. A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit. Care Med. 41, 2069–2079 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Marder, V. J., Feinstein, D. I., Colman, R. W. & Levi, M. in Hemostasis and Thrombosis. Basic Principles and Clinical Practice 5th edn (eds Colman, R. W., Marder, V. J., Clowes, A. W., George, J. N. & Goldhaber, S. Z. ) 1571–1600 (Lippincott Williams & Wilkins, 2006).

    Google Scholar 

  159. Asakura, H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J. Intensive Care 2, 20 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Menell, J. S. et al. Annexin II and bleeding in acute promyelocytic leukemia. N. Engl. J. Med. 340, 994–1004 (1999).

    Article  CAS  PubMed  Google Scholar 

  161. Avvisati, G., ten Cate, J. W., Buller, H. R. & Mandelli, F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 2, 122–124 (1989).

    Article  CAS  PubMed  Google Scholar 

  162. de la Serna, J. et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 111, 3395–3402 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Brown, J. E. et al. All-trans retinoic acid (ATRA) and tranexamic acid: a potentially fatal combination in acute promyelocytic leukaemia. Br. J. Haematol. 110, 1010–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Arbuthnot, C. & Wilde, J. T. Haemostatic problems in acute promyelocytic leukaemia. Blood Rev. 20, 289–297 (2006).

    Article  CAS  PubMed  Google Scholar 

  165. Lowenstein, C. J., Morrell, C. N. & Yamakuchi, M. Regulation of Weibel–Palade body exocytosis. Trends Cardiovasc. Med. 15, 302–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  166. 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. 320, 1165–1172 (1989).

    Article  CAS  PubMed  Google Scholar 

  167. Shakur, H. et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 376, 23–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Roberts, I. et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 377, 1096–1101, 1101.e1–1101.e2 (2011). Together with reference 167, these two consecutive studies nicely demonstrated that tranexamic acid given within 3 hours from injury can safely reduce the risk of death in patients with bleeding trauma.

    Article  CAS  PubMed  Google Scholar 

  169. Roberts, I. & Prieto-Merino, D. Applying results from clinical trials: tranexamic acid in trauma patients. J. Intensive Care 2, 56 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Fourrier, F. et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104, 882–888 (1993).

    Article  CAS  PubMed  Google Scholar 

  171. Sawamura, A. et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb. Res. 124, 608–613 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Levi, M., van der Poll, T. & Schultz, M. Systemic versus localized coagulation activation contributing to organ failure in critically ill patients. Semin. Immunopathol. 34, 167–179 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Rosenberg, R. D. & Aird, W. C. Vascular-bed-specific hemostasis and hypercoagulable states. N. Engl. J. Med. 340, 1555–1564 (1999).

    Article  CAS  PubMed  Google Scholar 

  174. Texereau, J., Pene, F., Chiche, J. D., Rousseau, C. & Mira, J. P. Importance of hemostatic gene polymorphisms for susceptibility to and outcome of severe sepsis. Crit. Care Med. 32, S313–S319 (2004).

    Article  PubMed  Google Scholar 

  175. Schouten, M., van 't Veer, C., van der Poll, T. & Levi, M. Effect of the factor V Leiden mutation on the incidence and outcome of severe infection and sepsis. Neth. J. Med. 70, 306–310 (2012).

    CAS  PubMed  Google Scholar 

  176. Hermans, P. W. et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 354, 556–560 (1999).

    Article  CAS  PubMed  Google Scholar 

  177. US National Library of Science. Phase 3 safety and efficacy study of ART-123 in subjects with severe sepsis and coagulopathy. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT01598831 (2012).

Download references

Acknowledgements

C.-H.T. has received funding from the US National Institute of Health Research. The authors thank Y. Alhamdi (University of Liverpool, UK) for assistance in preparing the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (S.G.); Epidemiology (S.G.); Mechanisms/pathophysiology (C.-H.T. and M.L.); Diagnosis, screening and prevention (C.-H.T.); Management (S.G.); Quality of life (S.G.); Outlook (M.L.); Overview of Primer (S.G.).

Corresponding author

Correspondence to Satoshi Gando.

Ethics declarations

Competing interests

The authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gando, S., Levi, M. & Toh, CH. Disseminated intravascular coagulation. Nat Rev Dis Primers 2, 16037 (2016). https://doi.org/10.1038/nrdp.2016.37

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2016.37

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing