Hemorrhagic syndrome at liver cirrhosis

The aim of review. To demonstrate different points of view on hemorrhagic complications in patients with liver cirrhosis (LC), relation of these complications to disorders of hemostatic system.

Key points. Physiology of hemostatic system is intimately related to liver function because parenchymatous cells produce the majority of coagulating and fibrinolytic systems factors. Hence, chronic or acute diseases of this organ frequently have profound effect the system of hemostasis. Bleeding developing at invasive procedures in LC patients, bleeding from varicose esophageal veins, hematomas, hemorrhagic purpura, nasal bleeding, odontorrhagia, menorrhagias are actual clinical problems. Laboratory diagnostics of disorders in «hemostasisfibrinolysis» system in patients with the LC underwent essential changes at the last decade. Standard complex tests for hemostasis lose their diagnostic value in this group of patients. Active search of the laboratory methods is conducted, allowing to estimate the risk of bleeding in liver cirrhosis patients. Strategy in treatment of hemorrhagic complications in LC is directed on prevention of pending bleedings and well-timed onset of medical actions in the case of its development. Basic principles of therapy are: application of erythrocytes, plasma, platelets concentrate, recombinant factor VIIa, concentrates of prothrombin complex, desmopressin, antifibrinolytic drugs, thrombo-and erythropoietin, antibiotics. The relation to prescription of components of blood is cautious now, there are no definite indications to their application and criteria of efficacy.

Conclusion. The problem of prediction of hemorrhagic complications in patients with LC by modern laboratory tests remains open. There is no conventional strategy of treatment and prophylaxis of bleedings for these patients. Carrying out of randomized controlled studies for evaluation of laboratory tests in prediction of bleedings or thromboses at patients with cirrhoses, for studying efficacy of modern concentrates of factors of coagulation, for assessment of restrictive policy of decantation of blood components is necessary.

1. Болезни печени и желчевыводящих путей: Руководство для врачей / Под ред. В.Т. Ивашкина. – М.: Изд. Дом «М-Вести», 2002. – С. 84–85.

2. Буланова Е.Л., Буланов А.Ю., Гацолаева Д.С. Тромбоэластография как метод обследования гемостаза у пациента с циррозом печени // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2011. – Т. 21, № 5. – С. 41–51.

3. Герман Е.Н., Маевская М.В., Андрейцева О.И. и др. Возможности лечения терминальных стадий заболевания печени в исходе хронической инфекции вирусом гепатита С в условиях дефицита донорских органов // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2011. – Т. 21, № 2. – С. 14–21.

4. Ильченко Л.Ю., Решетняк В.И. Клинико-лабораторные критерии диагностики первичного билиарного цирроза и современная терапия // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2011. – Т. 21, № 6. – С. 82–85.

5. Маевская М.В., Морозова М.А., Ивашкин В.Т. Алгоритм ведения пациентов с алкогольной болезнью печени // Рос. журн. гастроэнтерол. гепатол. колопроктол. – 2007. – Т. 17, № 6. – С. 1–10.

6. Abdel-Wahab OI, Healy B, Dzik WH. Effect of freshfrozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006; 46 (8): 1279–85.

7. Alter HJ, Klein HG. The hazards of blood transfusion in historical perspective. Blood 2008; 112 (7): 2617–26.

8. Amarapurkar Pooja D, Amarapurkar Deepak N. Management of coagulopathy in patients with decompensated liver cirrhosis. Int J Hepatol 2011, Article ID 695470, 5 pages, 2011. doi:10.4061/2011/695470.

9. AuBuchan JP. Meeting transfusion safety expectations. Ann Intern Med 2005; 143: 537–8.

10. Aytac S, Turkay C, Bavbek N, Kosar A. Hemostasis and global fibrinolytic capacity in chronic liver disease. Blood Coagul Fibrinolysis 2007; 18 (7): 623–6.

11. Basili S, Raparelli V, Riggio O, et al. NADPH oxidasemediated platelet isoprostane over-production in cirrhotic patients: implication for platelet activation. Liver Int 2011; 31 (10): 1533–40.

12. Bernstein DE, Jeffers L, Erhardtsen E, et al. Recombinant factor VIIa corrects prothrombin time in cirrhotic patients: A preliminary study. Gastroenterology 1997; 113: 1930–7.

13. Blonski W, Siropaides T, Reddy KR. Coagulopathy in liver disease. Curr Treat Options Gastroenterol 2007; 10 (6): 464–73.

14. Boberg KM, Brosstad F, Egeland T, et al. Is a prolonged bleeding time associated with an increased risk of hemorrhage after liver biopsy? Thromb Haemost 1999; 81: 378–81.

15. Boks AL, Brommer EJP, Schalm SW, Van Vliet HHDM. Hemostasis and fibrinolysis in severe liver failure and their relation to hemorrhage. Hepatology 1986; 6: 79–86.

16. Boylan JF, Klinck JR, Sandler AN, et al. Tranexamic acid reduces blood loss, transfusion requirements, and coagulation factor use in primary orthotopic liver transplantation. Anesthesiology 1996; 85 (5): 1043–8.

17. Caldwell SH, Chang C, Macik BG. Recombinant activated factor VII (rFVIIa) as a hemostatic agent in liver disease: A break with tradition in need of controlled trials. Hepatology 2004; 39: 592–8.

18. Carmen MSt, Andre HM, Advemi L, et al. Intranasal desmopressin versus blood transfusion in cirrhotic patients with coagulopathy undergoing dental extraction: a randomized controlled trial. J Oral Maxillofac Surg 2010; 68 (1): 138–43.

19. De Franchis R, Arcidiacono PG, Carpinelli L, et al. Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian Endoscopic Club. Hepatology 1993; 18: 1102–7.

20. Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981; 26: 388–93.

21. Francis JL, Armstrong DJ. Acquired dysfibrinogenemia in liver disease. J Clin Pathol 1982; 35: 667–72.

22. Gatt A, Riddell A, Calvaruso V, et al. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. Thromb Haemost 2010; 8 (9): 1994–2000.

23. Grant A, Neuberger J. Guidelines on the use of liver biopsy in clinical practice. British Society of Gastroenterology. Gut 1999; 43 (suppl 4): IV1–IV11.

24. Gresele P, Binetti BM, Branca G, et al. TAFI deficiency in liver cirrhosis: relation with plasma fibrinolysis and survival. Thromb Res 2008; 121 (6): 763–8.

25. Gunawan B, Runyon B. The efficacy and safety of epsilon-aminocaproic acid treatment in patients with cirrhosis and hyperfibrinolysis. Aliment Pharmacol Ther 2006; 23 (1): 115–20.

26. Hendriks HG, Meijer K, de Wolf J, et al. Effects of recombinant activated factor VII on coagulation measured by thromboelastography in liver transplantation. Blood Coagul Fibrinolysis 2002; 13: 309–13.

27. Hernandez AJ, Northup PG. Factor VII versus FFP for bleeding after liver biopsy: A cost-effectiveness evaluation (Submitted).

28. Hoffman M, Monroe DM, 3rd. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958–65.

29. Hollestelle MJ, Geertzen HGM, Straatsburg IH, et al. Factor VIII expression in liver disease. Thromb Haemost 2004; 91: 267–75.

30. Homoncik M, Jilma-Stohlawetz P, Schmid M, et al. Erythropoietin increases platelet reactivity and platelet counts in patients with alcoholic liver cirrhosis: a randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2004; 20 (4): 437–43.

31. Hou MC, Lin HC, Liu TT, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004; 39 (3): 746–53.

32. Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res 1999; 95 (4) suppl 1: 13–17.

33. Laffi G, Marra F. Complications of cirrhosis: Is the endothelium guilty? J Hepatol 1999; 30: 532–5.

34. Levi M, Peters M, Buller HR. Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: A systematic review. Crit Care Med 2005; 33: 883–90.

35. Lisman T, Leebeek FWG, de Groot PG. Haemostatic abnormalities in patients with liver disease. J Hepatol 2002; 37 (2): 280–7.

36. Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (6): 878–85.

37. López P, Otaso JC, Alvarez D, et al. Hemostatic and hemodynamic effects of vasopressin analogue DDAVP in patients with cirrhosis. Acta Gastroenterol Latinoam 1997; 27 (2): 59–62.

38. Lorenz R, Kienast J, Otto U, et al. Efficacy and safety of a prothrombin complex concentrate with two virusinactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol 2003; 15 (1): 15–20.

39. Mancuso A, Fung K, Cox D, et al. Assessment of blood coagulation in severe liver disease using thromboelastography: use of citrate storage versus native blood. Blood Coagul Fibrinolysis 2003; 14: 211–6.

40. Monroe DM, Hoffman M. The coagulation cascade in cirrhosis. Clin Liver Dis 2009; 13 (1): 1–9.

41. O’Shaughnessy DF, Atterbury C, Bolton MP, et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126 (1): 11–28.

42. Panasiuk A, Zak J, Panasiuk B, Prokopowicz D. Blood Coagul Fibrinolysis 2007; 18 (7): 739–44.

43. Pluta A, Gutkowski K, Hartleb M. Coagulopathy in liver diseases. Adv Med Sci. 2010; 55 (1): 16–21.

44. Porte RJ, Molenaar IQ, Begliomini B, et al. Aprotinin and transfusion requirements in orthotopic liver transplantation: a multicentrerandomised doubleblind study. EMSALT Study Group. Lancet 2000; 355 (9212):1303–9.

45. Prelipsean CC, Fierbinteanu-Braticevici C, Drug VL, et al. Liver cirrhosis-procoagulant stasis. Rev Med ChirSoc Med Nat Iasi 2011; 115 (3): 678–85.

46. Roberts HR, Monroe DM, Oliver JA, et al. Newer concepts of blood coagulation. Haemophilia 1998; 4:331–4.

47. Segal JB, Dzik WH. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005; 45 (9): 1413–25.

48. Sharara AI, Rockey DC. Gastroesophagealvariceal hemorrhage. N Engl J Med; 2001; 345 (9): 669–81.

49. Sherlock S, Dooly J. Haematology of liver disease // Diseases of Liver and Biliary System / Eds. Sherlock S, Dooly J. 10th ed. London, UK: Blackwell Science; 1997. 43–62.

50. Tripodi A, Primignani M, Chantarangkul V, et al. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Tromb Res 2009; 124 (1):132–6.

51. Tripodi A, Primignani M, Mannucci PM. Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged. Intern Emerg Med 2010; 5 (1):7– 12.

52. Tripodi A, Primignani M, Lemma L, et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology 2010; 52 (1):249–55.

53. Tripodi A, Salerno F, Chantarangkul V, et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41:553–8.

54. Trotter JF, Brimhall B, Arjal R, Phillips C. Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl 2004; 10: 995–1000.

55. Tsochatzis E, Papatheodoridis GV, Elefsiniotis I, et al. Prophylactic and therapeutic use of recombinant activated factor VII in patients with cirrhosis and coagulation impairment. Dig Liver Dis 2007; 39 (5): 490–4.

56. Violi F, Basili S, Raparelli V, et al. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol 2011; 55 (6): 1415–27.

57. Violi F, Leo R, Vezza E, et al. Bleeding time in patients with cirrhosis: relation with degree of liver failure and clotting abnormalities. C.A.L.C. Group. Coagulation Abnormalities in Cirrhosis Study Group. J Hepatol 1994; 20: 531–6.

58. Vivas S, Rodriguez M, Palacio MA, et al. Presence of bacterial infection in bleeding cirrhotic patients is independently associated with early mortality and failure to control bleeding. Dig Dis Sci 2001; 46 (12): 2752–7.

59. Youssef WI, Salazar F, Dasarathy S, et al. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol 2003; 98 (6): 1391–4.