Drugs

, Volume 55, Issue 6, pp 767–777

Current Drug Treatment Strategies for Disseminated Intravascular Coagulation

  • Evert de Jonge
  • Marcel Levi
  • Christiaan P. Stoutenbeek
  • Sander J. H. van Deventer
Disease Management

Summary

Disseminated intravascular coagulation (DIC) can be caused by a variety of diseases. Experimental models of DIC have provided substantial insight into the pathogenesis of this disorder, which may ultimately result in improved treatment. Disseminated coagulation is the result of a complex imbalance of coagulation and fibrinolysis. Simultaneously occurring tissue factor-dependent activation of coagulation, depression of natural anticoagulant pathways and shutdown of endogenous fibrinolysis all contribute to the clinical picture of widespread thrombotic deposition in the microvasculature and subsequent multiple organ failure.

Cornerstone for the treatment of DIC is the optimal management of the underlying disorder. At present, specific treatment of the coagulation disorders themselves is not based on firm evidence from controlled clinical trials. Plasma and platelet transfusion are used in patients with bleeding or at risk for bleeding and low levels of coagulation factors or thrombocytopenia. The role of heparin and low molecular weight heparin is controversial, but their use may be justified in patients with active DIC and clinical signs of extensive fibrin deposition such as those with meningococcal sepsis. There is some evidence to indicate that low molecular weight heparin is as effective as unfractionated heparin but may be associated with a decreased bleeding risk.

Antithrombin III (AT III) replacement appears to be effective in decreasing the signs of DIC if high doses are administered, but effects on survival or other clinically significant parameters are at best uncertain. If AT III supplementation is used, the dosage should be selected to achieve normal or supranormal plasma levels of 100% or higher. Results of studies on protein C concentrate, thrombomodulin or inhibitors of tissue factor are promising, but the efficacy and safety of these novel strategies remains to be established in appropriate clinical trials.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Baglin T. Disseminated intravascular coagulation: diagnosis and treatment. BMJ 1996; 312: 683–7PubMedCrossRefGoogle Scholar
  2. 2.
    Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation: compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816–23PubMedCrossRefGoogle Scholar
  3. 3.
    Levi M, ten Cate H, van der Poll T, et al. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993; 270: 975–9PubMedCrossRefGoogle Scholar
  4. 4.
    Bick RL. Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemost 1996; 22: 69–88PubMedCrossRefGoogle Scholar
  5. 5.
    Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 3–9PubMedCrossRefGoogle Scholar
  6. 6.
    van Deventer SJ, Buller HR, ten Cate JW, et al. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 1990; 76: 2520–6PubMedGoogle Scholar
  7. 7.
    Levi M, ten Cate H, Bauer KA, et al. Inhibition of endotoxininduced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 1994; 93: 114–20PubMedCrossRefGoogle Scholar
  8. 8.
    Nuijens JH, Huijbregts CC, Eerenberg-Belmer AJ, et al. Quantification of plasma factor XIIa-Cl(−)-inhibitor and kallikrein-Cl (−)-inhibitor complexes in sepsis. Blood 1988; 72: 1841–8PubMedGoogle Scholar
  9. 9.
    Pixley RA, De La Cadena R, Page JD, et al. 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: 61–8PubMedCrossRefGoogle Scholar
  10. 10.
    Colucci M, Balconi G, Lorenzet R, et al. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest 1983; 71: 1893–6PubMedCrossRefGoogle Scholar
  11. 11.
    Bevilacqua MP, Pober JS, Majeau GR, et al. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 1986; 83: 4533–7PubMedCrossRefGoogle Scholar
  12. 12.
    Taylor Jr FB, Chang A, Ruf W, et al. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127–34PubMedGoogle Scholar
  13. 13.
    Biemond BJ, Levi M, ten Cate H, et al. Complete inhibition of endotoxin-induced coagulation in chimpanzees with monoclonal Fab fragment against factor VII/VIIa. Thromb Haemost 1995; 73: 223–30PubMedGoogle Scholar
  14. 14.
    van der Poll T, Buller HR, ten Cate H, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990; 322: 1622–7PubMedCrossRefGoogle Scholar
  15. 15.
    van der Poll T, Levi M, van Deventer SJ, et al. Differential effects of anti-tumor necrosis factor monoclonal antibodies on systemic inflammatory responses in experimental endotoxemia in chimpanzees. Blood 1994; 83: 446–51PubMedGoogle Scholar
  16. 16.
    van der Poll T, Levi M, Hack CE, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253–9PubMedCrossRefGoogle Scholar
  17. 17.
    Stouthard JM, Levi M, Hack CE, et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 1996; 76: 738–42PubMedGoogle Scholar
  18. 18.
    Mestries JC, Kruithof EK, Gascon MP, et al. In vivo modulation of coagulation and fibrinolysis by recombinant glycosylated human interleukin-6 in baboons. Eur Cytokine Netw 1994; 5: 275–81PubMedGoogle Scholar
  19. 19.
    Boermeester MA, van Leeuwen PA, Coyle SM, et al. Interleukin-I blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg 1995; 130: 739–48PubMedCrossRefGoogle Scholar
  20. 20.
    Jansen PM, Boermeester MA, Fischer E, et al. 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-1 alpha administration and during lethal bacteremia. Blood 1995; 86: 1027–34PubMedGoogle Scholar
  21. 21.
    Tanaka H, Kobayashi N, Maekawa T. Studies on production of antithrombin III with special reference to endotoxin-induced DIC in rats. Thromb Haemost 1986; 56: 137–43PubMedGoogle Scholar
  22. 22.
    Buller HR, ten Cate JW. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate. Am J Med 1989; 87: 44S–48SPubMedCrossRefGoogle Scholar
  23. 23.
    Seitz R, Wolf M, Egbring R, et al. The disturbance of hemostasis in septic shock: role of neutrophil elastase and thrombin, effects of antithrombin and plasma substitution. Eur J Haematol 1989; 43: 22–8PubMedCrossRefGoogle Scholar
  24. 24.
    Furie B, Furie BC. Molecular and cellular biology of blood coagulation. N Engl J Med 1992; 326: 800–6PubMedCrossRefGoogle Scholar
  25. 25.
    Hesselvik JF, Malm J, Dahlback B, et al. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991; 65: 126–9PubMedGoogle Scholar
  26. 26.
    Nawroth PP, Handley DA, Esmon CT, et al. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci USA 1986; 83: 3460–4PubMedCrossRefGoogle Scholar
  27. 27.
    Nawroth PP, Stern DM. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 1986; 163: 740–5PubMedCrossRefGoogle Scholar
  28. 28.
    Broze Jr GJ. Tissue factor pathway inhibitor. Thromb Haemost 1995; 74: 90–3PubMedGoogle Scholar
  29. 29.
    Sabharwal AK, Bajaj SP, Ameri A, et al. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis. Am J Respir Crit Care Med 1995; 151: 758–67PubMedGoogle Scholar
  30. 30.
    Creasey AA, Chang AC, Feigen L, et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850–6PubMedCrossRefGoogle Scholar
  31. 31.
    Biemond BJ, Levi M, ten Cate H, 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 1995; 88: 587–94PubMedGoogle Scholar
  32. 32.
    Wong VK, Hitchcock W, Mason WH, et al. Meningococcal infection in children: a review of 100 cases. Pediatr Infect Dis J 1989; 8: 224–7PubMedGoogle Scholar
  33. 33.
    Gross SJ, Filston HC. Controlled study of treatment for disseminated intravascular coagulation in the neonate. J Pediatr 1982; 100: 445–8PubMedCrossRefGoogle Scholar
  34. 34.
    Rubin RN, Colman RW. Disseminated intravascular coagulation: approach to treatment. Drugs 1992; 44: 963–71PubMedCrossRefGoogle Scholar
  35. 35.
    Hiller E, Heim M. Indikationen für die Therapie mit frischgefrorenem Plasma. Dtsch Med Wochenschr 1989; 114: 1371–4PubMedCrossRefGoogle Scholar
  36. 36.
    Little JR. Purpura fulminans treated successfully with anticoagulation: report of a case. JAMA 1959; 169: 36–40CrossRefGoogle Scholar
  37. 37.
    Gaskins Jr RA, Dalldorf FG. Experimental meningococcal septicemia: effect of heparin therapy. Arch Pathol Lab Med 1976; 100: 318–24PubMedGoogle Scholar
  38. 38.
    Corrigan Jr JJ, Kiernat JF. Effect of heparin in experimental Gram-negative septicemia. J Infect Dis 1975; 131: 138–43PubMedCrossRefGoogle Scholar
  39. 39.
    Corrigan Jr JJ, Jordan CM. Heparin therapy in septicemia with disseminated intravascular coagulation: effect on mortality and on correction of hemostatic defects. N Engl J Med 1970; 283: 778–82PubMedCrossRefGoogle Scholar
  40. 40.
    Corrigan Jr JJ. Heparin therapy in bacterial septicemia. J Pediatrics 1977; 91: 695–700CrossRefGoogle Scholar
  41. 41.
    Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 1982; 60: 284–7PubMedGoogle Scholar
  42. 42.
    Tazawa S, Ichikawa K, Misawa K, et al. Effects of low molecular weight heparin on a severely antithrombin III-decreased disseminated intravascular coagulation model in rabbits. Thromb Res 1995; 80: 391–8PubMedCrossRefGoogle Scholar
  43. 43.
    Takahashi Y, Hosaka Y, Imada K, et al. Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting bleeding time in rats: comparison with low molecular weight heparin. Thromb Haemost 1997; 77: 789–95PubMedGoogle Scholar
  44. 44.
    Audibert G, Lambert H, Toulemonde F, et al. Utilisation d’une héparine de bas poids moléculaire, la CY 222, dans le traitement des coagulopathies de consommation. J Mal Vasc 1987; 12 Suppl. B: 147–51PubMedGoogle Scholar
  45. 45.
    Gillis S, Dann EJ, Eldor A. Low molecular weight heparin in the prophylaxis and treatment of disseminated intravascular coagulation in acute promyelocytic leukemia. Eur J Haematol 1995; 54: 59–60PubMedCrossRefGoogle Scholar
  46. 46.
    Sakuragawa N, Hasegawa H, Maki M, et al. 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 1993; 72: 475–500PubMedCrossRefGoogle Scholar
  47. 47.
    Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385–91PubMedCrossRefGoogle Scholar
  48. 48.
    Freund M, Cazenave JP, Courtney M, et al. Inhibition by recombinant hirudins of experimental venous thrombosis and disseminated intravascular coagulation induced by tissue factor in rats. Thromb Haemost 1990; 63: 187–92PubMedGoogle Scholar
  49. 49.
    Zawilska K, Zozulinska M, Turowiecka Z, et al. The effect of a long-acting recombinant hirudin (PEG-hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. Thromb Res 1993; 69: 315–20PubMedCrossRefGoogle Scholar
  50. 50.
    Dickneite G, Czech J. Combination of antibiotic treatment with the thrombin inhibitor recombinant hirudin for the therapy of experimental Klebsiella pneumoniae sepsis. Thromb Haemost 1994; 71: 768–72PubMedGoogle Scholar
  51. 51.
    Saito M, Asakura H, Jokaji H, et al. Recombinant hirudin for the treatment of disseminated intravascular coagulation in patients with haematological malignancy. Blood Coagul Fibrinolysis 1995; 6: 60–4PubMedCrossRefGoogle Scholar
  52. 52.
    Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. Acomparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335(11): 775–82CrossRefGoogle Scholar
  53. 53.
    Taylor Jr FB, Emerson Jr TE, Jordan R, et al. Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988; 26: 227–35PubMedGoogle Scholar
  54. 54.
    Maki M, Terao T, Ikenoue T, et al. Clinical evaluation of antithrombin III concentrate (BI 6.013) for disseminated intravascular coagulation in obstetrics: well-controlled multicenter trial. Gynecol Obstet Invest 1987; 23: 230–40PubMedCrossRefGoogle Scholar
  55. 55.
    Blauhut B, Kramar H, Vinazzer H, et al. Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 1985; 39: 81–9PubMedCrossRefGoogle Scholar
  56. 56.
    Fourrier F, Chopin C, Huart JJ, et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104: 882–8PubMedCrossRefGoogle Scholar
  57. 57.
    Vinazzer HA. Antithrombin III in shock and disseminated intravascular coagulation. Clin Appl Thrombosis/Hemostasis 1995; 1: 62–5CrossRefGoogle Scholar
  58. 58.
    Kessler CM, Tang Z, Jacobs HM, et al. The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. Blood 1997; 89: 4393–401PubMedGoogle Scholar
  59. 59.
    Blauhut B, Necek S, Vinazzer H, et al. Substitution therapy with antithrombin III in shock and DIC. Thromb Res 1982; 27: 271–78PubMedCrossRefGoogle Scholar
  60. 60.
    Taylor Jr FB, Chang AC, Peer GT, et al. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 364–8PubMedGoogle Scholar
  61. 61.
    Fijnvandraad K, Derkx B, Peters M, et al. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73: 15–20Google Scholar
  62. 62.
    Taylor Jr FB, Chang A, Esmon CT, et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918–25PubMedCrossRefGoogle Scholar
  63. 63.
    Katsuura Y, Aoki K, Tanabe H, et al. Characteristic effects of activated human protein C on tissue thromboplastin-induced disseminated intravascular coagulation in rabbits. Thromb Res 1994; 76: 353–62PubMedCrossRefGoogle Scholar
  64. 64.
    Gerson WT, Dickerman JD, Bovill EG, et al. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics 1993; 91: 418–22PubMedGoogle Scholar
  65. 65.
    Dreyfus M, Magny JF, Bridey F, et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325: 1565–8PubMedCrossRefGoogle Scholar
  66. 66.
    Rintala E, Seppala O, Kotilainen P, et al. Protein C in the treatment of coagulopathy in meningococcal disease [letter]. Lancet 1996; 347: 1767PubMedCrossRefGoogle Scholar
  67. 67.
    Gonda Y, Hirata S, Saitoh H, et al. Antithrombotic effect of recombinant human soluble thrombomodulin on endotoxininduced disseminated intravascular coagulation in rats. Thromb Res 1993; 71: 325–35PubMedCrossRefGoogle Scholar
  68. 68.
    Aoki Y, Ohishi R, Takei R, et al. Effects of recombinant human soluble thrombomodulin (rhs-TM) on a rat model of disseminated intravascular coagulation with decreased levels of antithrombin III. Thromb Haemost 1994; 71: 452–5PubMedGoogle Scholar
  69. 69.
    Uchiba M, Okajima K, Murakami K, et al. Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats. Am J Hematol 1997; 54: 118–23PubMedCrossRefGoogle Scholar
  70. 70.
    Elsayed YA, Nakagawa K, Kamikubo YI, et al. Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model. Am J Clin Pathol 1996; 106: 574–83PubMedGoogle Scholar
  71. 71.
    Bregengard C, Nordfang O, Wildgoose P, et al. The effect of two-domain tissue factor pathway inhibitor on endotoxininduced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis 1993; 4: 699–706PubMedGoogle Scholar
  72. 72.
    Avvisati G, ten Cate JW, Buller HR, et al. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet; 1989; II(8655): 122–4CrossRefGoogle Scholar
  73. 73.
    Levi M, Biemond BJ, van Zonneveld AI, et al. Inhibition of plasminogen activator inhibitor-1 (PAI-1) activity results in promotion of endogenous fibrinolysis and inhibition of thrombosis in experimental models. Circulation 1992; 83: 305–12CrossRefGoogle Scholar
  74. 74.
    Zenz W, Muntean W, Zobel G, et al. Treatment of fulminant meningococcemia with recombinant tissue plasminogen activator. Thromb Haemost 1995; 74: 802–3PubMedGoogle Scholar
  75. 75.
    Aiuto LT, Barone SR, Cohen PS, et al. Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 1997; 25: 1079–82PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Evert de Jonge
    • 1
  • Marcel Levi
    • 2
  • Christiaan P. Stoutenbeek
    • 1
  • Sander J. H. van Deventer
    • 3
  1. 1.Department of Intensive Care, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  2. 2.Center for Haemostasis, Thrombosis, Atherosclerosis and Inflammation Research, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  3. 3.Department of Experimental Internal Medicine, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

Personalised recommendations