Download PDF
Semin Thromb Hemost 2010; 36(4): 437-443
DOI: 10.1055/s-0030-1254052
© Thieme Medical Publishers

Activation and Regulation of Hemostasis in Acute Liver Failure and Acute Pancreatitis

Ton Lisman1 , Robert J. Porte1
  • 1Section Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Further Information

Publication History

Publication Date:
07 July 2010 (online)

    Permissions and Reprints

ABSTRACT

Acute liver failure and acute pancreatitis are accompanied by substantial changes in the hemostatic system. In acute liver failure, defective synthesis of coagulation factors and intravascular activation of coagulation results in thrombocytopenia and reduced levels of proteins involved in coagulation and fibrinolysis. Acute pancreatitis may be accompanied by intravascular activation of hemostasis mediated by inflammation and exposure of pancreatic tissue factor to the bloodstream. In animal models for both diseases, activation of hemostasis appears to contribute to the progression of the disease. Consequently, the use of anticoagulants may, in theory, be beneficial in humans. In practice, however, clinical use of anticoagulants in these patients is likely hampered by a substantial bleeding risk.

KEYWORDS

Liver - platelet - coagulation - hemostasis - fibrin - pancreatitis

REFERENCES

  • 1 Lisman T, Leebeek F W. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment.  Dig Surg. 2007;  24(4) 250-258
    CrossrefPubMedGoogle Scholar
  • 2 Tripodi A, Salerno F, Chantarangkul V et al.. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.  Hepatology. 2005;  41(3) 553-558
    CrossrefPubMedGoogle Scholar
  • 3 Lisman T, Bongers T N, Adelmeijer J et al.. Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity.  Hepatology. 2006;  44(1) 53-61
    CrossrefPubMedGoogle Scholar
  • 4 de Boer M T, Molenaar I Q, Hendriks H G, Slooff M J, Porte R J. Minimizing blood loss in liver transplantation: progress through research and evolution of techniques.  Dig Surg. 2005;  22(4) 265-275
    CrossrefPubMedGoogle Scholar
  • 5 Warnaar N, Lisman T, Porte R J. The two tales of coagulation in liver transplantation.  Curr Opin Organ Transplant. 2008;  13(3) 298-303
    CrossrefPubMedGoogle Scholar
  • 6 Caldwell S H, Hoffman M, Lisman T Coagulation in Liver Disease Group et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.  Hepatology. 2006;  44(4) 1039-1046
    CrossrefPubMedGoogle Scholar
  • 7 Kakafika A, Papadopoulos V, Mimidis K, Mikhailidis D P. Coagulation, platelets, and acute pancreatitis.  Pancreas. 2007;  34(1) 15-20
    CrossrefPubMedGoogle Scholar
  • 8 Maeda K, Hirota M, Ichihara A et al.. Applicability of disseminated intravascular coagulation parameters in the assessment of the severity of acute pancreatitis.  Pancreas. 2006;  32(1) 87-92
    CrossrefPubMedGoogle Scholar
  • 9 Stravitz R T, Kramer A H, Davern T Acute Liver Failure Study Group et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group.  Crit Care Med. 2007;  35(11) 2498-2508
    CrossrefPubMedGoogle Scholar
  • 10 Munoz S J, Stravitz R T, Gabriel D A. Coagulopathy of acute liver failure.  Clin Liver Dis. 2009;  13(1) 95-107
    CrossrefPubMedGoogle Scholar
  • 11 Anand A C, Nightingale P, Neuberger J M. Early indicators of prognosis in fulminant hepatic failure: an assessment of the King's criteria.  J Hepatol. 1997;  26(1) 62-68
    CrossrefPubMedGoogle Scholar
  • 12 Munoz S J, Rajender Reddy K, Lee W. Acute Liver Failure Study Group . The coagulopathy of acute liver failure and implications for intracranial pressure monitoring.  Neurocrit Care. 2008;  9(1) 103-107
    CrossrefPubMedGoogle Scholar
  • 13 Pernambuco J R, Langley P G, Hughes R D, Izumi S, Williams R. Activation of the fibrinolytic system in patients with fulminant liver failure.  Hepatology. 1993;  18(6) 1350-1356
    CrossrefPubMedGoogle Scholar
  • 14 Kerr R, Newsome P, Germain L et al.. Effects of acute liver injury on blood coagulation.  J Thromb Haemost. 2003;  1(4) 754-759
    CrossrefPubMedGoogle Scholar
  • 15 Lisman T, Leebeek F W, Mosnier L O et al.. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis.  Gastroenterology. 2001;  121(1) 131-139
    CrossrefPubMedGoogle Scholar
  • 16 Colucci M, Binetti B M, Branca M G et al.. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis.  Hepatology. 2003;  38(1) 230-237
    PubMedGoogle Scholar
  • 17 Cornillon B, Paul J, Belleville J, Aurousseau A M, Clendinnen G, Eloy R. Experimental DMNA induced hepatic necrosis: early course of haemostatic disorders in the rat.  Comp Biochem Physiol C. 1985;  80(2) 277-284
    CrossrefPubMedGoogle Scholar
  • 18 Hollestelle M J, Poyck P P, Hollestelle J M, Marsman H A, Mourik J A, Gulik T M. Extra-hepatic factor VIII expression in porcine fulminant hepatic failure.  J Thromb Haemost. 2005;  3(10) 2274-2280
    CrossrefPubMedGoogle Scholar
  • 19 Schiødt F V, Balko J, Schilsky M, Harrison M E, Thornton A, Lee W M. Acute Liver Failure Study Group . Thrombopoietin in acute liver failure.  Hepatology. 2003;  37(3) 558-561
    CrossrefPubMedGoogle Scholar
  • 20 Goulis J, Chau T N, Jordan S et al.. Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation.  Gut. 1999;  44(5) 754-758
    CrossrefPubMedGoogle Scholar
  • 21 Ganey P E, Luyendyk J P, Newport S W et al.. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice.  Hepatology. 2007;  46(4) 1177-1186
    CrossrefPubMedGoogle Scholar
  • 22 Kume M, Hayashi T, Yuasa H et al.. Bacterial lipopolysaccharide decreases thrombomodulin expression in the sinusoidal endothelial cells of rats—a possible mechanism of intrasinusoidal microthrombus formation and liver dysfunction.  J Hepatol. 2003;  38(1) 9-17
    PubMedGoogle Scholar
  • 23 Hillenbrand P, Parbhoo S P, Jedrychowski A, Sherlock S. Significance of intravascular coagulation and fibrinolysis in acute hepatic failure.  Gut. 1974;  15(2) 83-88
    CrossrefPubMedGoogle Scholar
  • 24 Hughes R D, Lane D A, Ireland H, Langley P G, Gimson A E, Williams R. Fibrinogen derivatives and platelet activation products in acute and chronic liver disease.  Clin Sci (Lond). 1985;  68(6) 701-707
    PubMedGoogle Scholar
  • 25 Langley P G, Forbes A, Hughes R D, Williams R. Thrombin-antithrombin III complex in fulminant hepatic failure: evidence for disseminated intravascular coagulation and relationship to outcome.  Eur J Clin Invest. 1990;  20(6) 627-631
    CrossrefPubMedGoogle Scholar
  • 26 Langley P G, Williams R. The effect of fulminant hepatic failure on protein C antigen and activity.  Thromb Haemost. 1988;  59(2) 316-318
    PubMedGoogle Scholar
  • 27 Tripodi A, Mannucci P M. Abnormalities of hemostasis in chronic liver disease: reappraisal of their clinical significance and need for clinical and laboratory research.  J Hepatol. 2007;  46(4) 727-733
    CrossrefPubMedGoogle Scholar
  • 28 Lisman T, Caldwell S H, Leebeek F WG, Porte R J. Is chronic liver disease associated with a bleeding diathesis?.  J Thromb Haemost. 2006;  4(9) 2059-2060
    CrossrefPubMedGoogle Scholar
  • 29 Mannucci P M. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No.  J Thromb Haemost. 2006;  4(4) 721-723
    CrossrefPubMedGoogle Scholar
  • 30 Northup P G, Sundaram V, Fallon M B Coagulation in Liver Disease Group et al. Hypercoagulation and thrombophilia in liver disease.  J Thromb Haemost. 2008;  6(1) 2-9
    PubMedGoogle Scholar
  • 31 Massicotte L, Beaulieu D, Thibeault L et al.. Coagulation defects do not predict blood product requirements during liver transplantation.  Transplantation. 2008;  85(7) 956-962
    CrossrefPubMedGoogle Scholar
  • 32 Gazzard B G, Henderson J M, Williams R. Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy.  Gut. 1975;  16(8) 617-620
    CrossrefPubMedGoogle Scholar
  • 33 Fujiwara K, Ogata I, Ohta Y et al.. Intravascular coagulation in acute liver failure in rats and its treatment with antithrombin III.  Gut. 1988;  29(8) 1103-1108
    CrossrefPubMedGoogle Scholar
  • 34 Gazzard B G, Clark R, Borirakchanyavat V, Williams R. A controlled trial of heparin therapy in the coagulation defect of paracetamol-induced hepatic necrosis.  Gut. 1974;  15(2) 89-93
    CrossrefPubMedGoogle Scholar
  • 35 Anstee Q M, Goldin R D, Wright M, Martinelli A, Cox R, Thursz M R. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies.  J Thromb Haemost. 2008;  6(8) 1336-1343
    CrossrefPubMedGoogle Scholar
  • 36 Wright M, Goldin R, Hellier S et al.. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection.  Gut. 2003;  52(8) 1206-1210
    CrossrefPubMedGoogle Scholar
  • 37 Bhatia M, Wong F L, Cao Y et al.. Pathophysiology of acute pancreatitis.  Pancreatology. 2005;  5(2–3) 132-144
    CrossrefPubMedGoogle Scholar
  • 38 Bhatia M. Inflammatory response on the pancreatic acinar cell injury.  Scand J Surg. 2005;  94(2) 97-102
    PubMedGoogle Scholar
  • 39 Levi M, ten Cate H, van der Poll T, van Deventer S J. Pathogenesis of disseminated intravascular coagulation in sepsis.  JAMA. 1993;  270(8) 975-979
    CrossrefPubMedGoogle Scholar
  • 40 Bockman D E, Büchler M, Beger H G. Ultrastructure of human acute pancreatitis.  Int J Pancreatol. 1986;  1(2) 141-153
    PubMedGoogle Scholar
  • 41 Moberg L, Johansson H, Lukinius A et al.. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation.  Lancet. 2002;  360(9350) 2039-2045
    CrossrefPubMedGoogle Scholar
  • 42 Radenkovic D, Bajec D, Ivancevic N et al.. D-dimer in acute pancreatitis: a new approach for an early assessment of organ failure.  Pancreas. 2009;  38(6) 655-660
    CrossrefPubMedGoogle Scholar
  • 43 Hackert T, Werner J, Gebhard M M, Klar E. Effects of heparin in experimental models of acute pancreatitis and post-ERCP pancreatitis.  Surgery. 2004;  135(2) 131-138
    CrossrefPubMedGoogle Scholar
  • 44 Hagiwara S, Iwasaka H, Shingu C, Matsumoto S, Uchida T, Noguchi T. Antithrombin III prevents cerulein-induced acute pancreatitis in rats.  Pancreas. 2009;  38(7) 746-751
    CrossrefPubMedGoogle Scholar
  • 45 Hackert T, Sperber R, Hartwig W et al.. P-selectin inhibition reduces severity of acute experimental pancreatitis.  Pancreatology. 2009;  9(4) 369-374
    CrossrefPubMedGoogle Scholar
  • 46 Andersson E, Axelsson J, Pedersen L C, Elm T, Andersson R. Treatment with anti-factor VIIa in acute pancreatitis in rats: blocking both coagulation and inflammation?.  Scand J Gastroenterol. 2007;  42(6) 765-770
    CrossrefPubMedGoogle Scholar
  • 47 Ping C, Yongping Z, Minmin Q, Weiyan Y, Yaozong Y. Activated protein C improves the severity of severe acute pancreatitis via up-regulating the expressions of endothelial cell protein C receptor and thrombomodulin.  Dig Dis Sci. 2009;  , August 13 (Epub ahead of print)
    PubMedGoogle Scholar
  • 48 Alsfasser G, Warshaw A L, Thayer S P et al.. Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis.  Arch Surg. 2006;  141(7) 670-676 discussion 676-677
    CrossrefPubMedGoogle Scholar
  • 49 Jamdar S, Siriwardena A K. Drotrecogin alfa (recombinant human activated protein C) in severe acute pancreatitis.  Crit Care. 2005;  9(4) 321-322
    CrossrefPubMedGoogle Scholar
  • 50 Kerschen E J, Fernandez J A, Cooley B C et al.. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C.  J Exp Med. 2007;  204(10) 2439-2448
    CrossrefPubMedGoogle Scholar

Ton LismanPh.D. 

Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen

BA44, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands

Email: j.a.lisman@chir.umcg.nl