Disturbances of hemostasis in sepsis

Česká verzia

Authors: J. Novotný; M. Penka
Authors place of work: Oddělení klinické hematologie FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Miroslav Penka, CSc.
Published in the journal: Vnitř Lék 2012; 58(6): 439-447
Category: Reviews

Summary

Immune system and hemostasis are closely bound together. When one of these systems is activated, another is set in motion too. This is especially noticeable in polytraumas, inflammation, shocks etc. The most important activator of immune system and hemostasis is sepsis. In sepsis there is a vigorous stimulation of immune response because of a liberation of a lot of cytokines and proinflammatory molecules. This may lead to an extrem picture of systemic inflammatory response syndrome. In systemic inflammatory response syndrome a downregulation of thrombomodulin and endothelial protein C receptor on the surface of intact endothel may be detected and there is an upregulation of release of the tissue-type plasminogen activator with a switch to plasminogen activator inhibitor 1 release. There is lowering of activated protein C and fibrinolytic activation followed by fibrinolytic inhibition in septic patients. Consequently we can see consumption of coagulation factors, inhibitors (antithrombin, protein C, and tissue factor pathway inhibitor), microangiopatic hemolysis and thrombocytopenia with a picture of disseminated intravascular coagulation in these patients. The diagnosis of disseminated intravascular coagulation is not uniforme in the literature. Expression of tissue factor on monocytes and endothelium may aggravate this “circulus vitiosus” with serious microcirculatory failure in sense of MOF/MODS (mutliorgan failure/multiorgan dysfunction syndrome). The first steps in the therapy of sepsis represent the treatment of cause of sepsis, vigorous hydratation and maintenance of circulation and pulmonary function, glycemic control etc, the prevention and blocking of the undesirable activation of hemostasis and inflammation being equally important. The treatment with minidoses of heparin was implemented in the past and the question, if this therapy is indicated is not answered yet. The clinical studies of the suitability of the treatment with natural inhibitors of hemostasis (antithrombin, recombinant human activated PC or drotrecogin α activated, rhTFPI) were evaluated in the past and are still under way recently. The unequivocal contribution of these therapies was not proven and recombinant human activated PC was even pulled from the worldvide market.

Key words:
sepsis – SIRS – protein C system – disseminated intravascular coagulation – recombinant human activated protein C – drotrecogin α activated

Zdroje

1. Dhainaut JF, Shorr AF, Macias WL et al. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med 2005; 33: 341–348.

2. Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–710.

3. Niessen F, Schaffner F, Furlan-Freguia C et al. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 2008; 452: 654–658.

4. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131: 417–430.

5. Levi M, Lowenberg E, Meijers JC. Recombinant anticoagulant factors for adjutant treatment of sepsis. Semin Thromb Hemost 2010; 36: 550–557.

6. Diehl JL, Borgel D. Sepsis and coagulation. Curr Opin Crit Care 2005; 11: 454–460.

7. Knoebl P. Blood coagulation disorders in septic patients. Wien Med Wochenschr 2010; 160: 129–138.

8. Levi M. The coagulant response in sepsis and inflammation. Hamostaseologie 2010; 30: 14–16.

9. Petäjä J. Inflammation and coagulation. An overview. Tromb Res 2011; 15 (Suppl 2): S34–S37.

10. Leon LR, Helwig BG. Role of endotoxin and cytokines in the systemic inflammatory response to heat injury. Front Biosci 2010; 2: 910–938.

11. Burdette SD, Pario MA, Kaplan LJ et al. Systemic Inflammatory Response Syndrome. 2010 [online]. Available from: https://www.emedicine.medscape.com./crit.care.

12. Wang H, Ma S. The cytokine storm and factors determining the sequence and severity of organ dysfunction in MODS. Am J Emerg Med 2008; 26: 711–715.

13. Cambien B, Wagner DD. A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med 2004; 10: 179–186.

14. Ait-Oufella H, Lehoux S, Guidet B et al. The endothelium: physiological functions and role in microcirculatory failure during severe sepsis. Intensive Care Med 2010; 36: 1286–1298.

15. Silasi-Mansat R, Zhu H, Popescu NI et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 2010; 116: 1002–1010.

16. Davis AE 3rd, Lu F, Mejia P. C1 inhibitor, a multi-functional serin protease inhibitor. Thromb Haemost 2010; 104: 886–893.

17. Anas AA, Wiersinga WJ, de Vos AF et al. Recent insights into the pathogenesis of bacterial sepsis. Neth J Med 2010; 68: 147–152.

18. Wada H, Gabazza EC, Asakura H et al. Comparison of diagnostic criteria for DIC: diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol 2003; 74: 17–22.

19. Levi M. Current understanding of disseminated intravascular coagulation. Br J Haematol 2004; 124: 567–576.

20. Gris JC, Faillie LJ, Cochery-Nouvellon E et al. ISTH overt intravascular coagulation score in patients with septic shock: automated immunoturbidimetric solubile fibrin assay vs. D-dimer assay. J Thromb Haemost 2011; 9: 1252–1255.

21. Bick RL. Disseminated intravascular coagulation: a review of etiology, pathophysiology, diagnosis, and management: guidelines for care. Clin Appl Thromb Hemost 2002; 8: 1–31.

22. Toh CH, Samis J, Downey C et al. Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca(++)-dependent complex of CRP with VLD lipoprotein and is a novel marker of impeding DIC. Blood 2002; 100: 2522–2529.

23. Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost 2001; 27: 585–592.

24. Madoiwa S, Tanaka H, Nagahama Y et al. Degradation of cross-linked fibrin by leukocyte elastase as alternative pathway for plasmin-mediated fibrinolysis in sepsis-induced DIC. Thromb Res 2011; 127: 349–355.

25. Levi M, Toh CH, Thachil J et al. Guidelines for the diagnosis and management of DIC. British Committee for Standards in Haematology. Br J Haematol 2009; 145: 24–33.

26. Schöchl H, Solomon C, Schulz A et al. Thromboelastometry (TEM) findings in DIC in a pig model of endotoxinemia. Mol Med 2011; 17: 266–272.

27. Durila M, Bureš J, Pelichovská M et al. Hypocoagulation state in severe systemic inflammatory response syndrome/sepsis is consistent with endogenous heparinoid effect as detected by TEG. Anaesth Intensive Care 2011; 39: 508–509.

28. Kienast J, Juers M, Wiedermann CJ et al. Treatments effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost 2005; 4: 90–97.

29. Hirsh J, Guyatt G, Albers GW et al. Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (Suppl 6): 71S–109S.

30. Joyce DE, Nelson DR, Grinnell BW. Leukocyte and endothelial cell interaction in sepsis: relevance of the protein C pathway. Crit Care Med 2004; 32 (Suppl 5): S280–S286.

31. Levi M. Activated protein C in sepsis: a critical review. Curr Opin Hematol 2008; 15: 481–486.

32. Rezaie AR. Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr Med Chem 2010; 17: 2059–2069.

33. Levi M, van der Poll T, Büller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004; 109: 2698–2704.

34. Weiler H. Regulation of inflammation by the protein C system. Crit Care Med 2010; 38 (Suppl 2): S18–S25.

35. Schouten M, van’t Veer C, Levi M et al. Endogenous protein C inhibits activation of coagulation and transiently lowers bacterial outgrowth in murine Escherichia coli peritonitis. J Thromb Haemost 2011; 9: 1072–1075.

36. Camporota L, Wyncoll D. Practical aspects of treatment with drotrecogin alfa (activated). Crit Care 2007; 11 (Suppl 5): S7.

37. Liaw PC, Esmon CT, Kahnamoui R et al. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood 2004; 104: 3958–3964.

38. Warren BL, Eid A, Singer P et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869–1878.

39. Gårlund B. Activated protein C (Xigris) treatment in sepsis: a drug in trouble. Acta Anaesthesiol Scand 2006; 50: 907–910.

40. Hecksher CH, Lacerda HR, Maciel MA. Characteristics and outcomes of patients treated with drotrecogin alfa activated and other interventions of the „Surviving Sepsis“ campaign in clinical practice. Revista Brasieila de Terapia Intensive 2008; 20: 135–143.

41. Vincent JL, Bernard GR, Beale R et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med 2005; 33: 2266–2277.

42. Abraham E, Laterre PF, Garg R et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353: 1332–1341.

43. Short MA, Schlichting D, Qualy RL. From bench to bedside: a review of the clinical trial development plan of drotrecogin alfa (activated). Curr Med Res Opin 2006; 22: 2525–2540.

44. Kula R, Chylek V, Szturz P et al. A response to infection in patients with severe sepsis – do we need a “stage-directed therapy concept“? Bratisl Lék Listy 2009; 110: 459–464.

45. Muriová K, Maláska J, Otevřel F et al. Myokardiální dysfunkce v sepsi – charakteristika a patogenetické mechanizmy. Vnitř Lék 2010; 56: 220–225.

46. Maláska J, Slezák M, Muriová K et al. Myokardiální dysfunkce v sepsi – diagnostika a terapie. Vnitř Lék 2010; 56: 226–232.

47. Navrátil M, Tomíška M, Kořístek Z et al. Sepse a septický šok u onkologických a imunokompromitovaných pacientů – diagnostika, terapie. Vnitř Lék 2010; 56: 557–569.

48. Shorr AF, Nelson DR, Wyncoll DL et al. Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated). Crit Care 2008; 12: R45.

49. Macias WL, Nelson DR. Severe protein C deficiently predicts early death in severe sepsis. Crit Care Med 2004; 32 (Suppl 5): S223–S228.

50. Knaus WA, Draper EA, Wagner DP et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 10: 818–829.

51. Riou Franca L, Launois R, Le Lay K et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis with multiple organ failure. Int J Technol Assess Health Care 2006; 22: 101–108.

52. Levi M, Levy M, Williams MD et al. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176: 483–490.

53. Lowes R. Sepsis drug Xigris pulled from worldwide market. Medscape Medical News [online]. Available from: https://www.medscape.com/viewarticle/752169.

54. Schellongowski P, Bauer P, Holzinger U et al. Treatment of adult with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin). Vox Sang 2006; 90: 294–301.

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

56. Schuster DP, Metzler M, Opal S et al. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase IIb, multicenter, randomized, placebo-controlled, clinical trial. Crit Care Med 2003; 31: 1612–1619.

57. Grypioti AD, Mykoniatis M, Demopoulos CA et al. Recombinant PAF-acetylhydrolase attenuates paracetamol-induced liver oxidative stress, injury and regeneration. Digest Dis Sci 2007; 52: 192–199.

58. Mosnier LO, Gale AJ, Yegneswaran S et al. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 2004; 104: 1740–1744.

59. Saito H, Maruyama I, Shimazaki S et al. Efficacy and safety of recombinant soluble thrombomodulin (ART-123) in DIC: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5: 31–41.

60. Nakamura M, Oda S, Sadahiro T et al. Treatment of severe sepsis and septic shock by CHDF using a PMMA membrane hemofilter as a cytokine modulator. Contrib Nephrol 2010; 166: 73–82.

61. Deasy A, Read RC. Genetic variations in pro-inflammatory cytokines and meningococcal sepsis. Curr Opin Infect Dis 2010; 23: 255–258.

62. Chylek V, Kula R, Holub M et al. Anticytokine therapy in sepsis and why it fails. Klin Mikrobiol Infekc Lek 2008; 14: 209–212.

63. Leone M, Textoris J, Michel F et al. Emerging drugs in sepsis. Expert Opin Emerg Drugs 2010; 15: 41–52.