Download PDF
Semin Thromb Hemost 2011; 37(1): 066-076
DOI: 10.1055/s-0030-1270073
© Thieme Medical Publishers

Venous Thromboembolism in Chronic Liver Disease

Giuseppe Lippi1 , Giovanni Targher2 , Emmanuel J. Favaloro3 , Massimo Franchini4
  • 1U.O. di Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Italy
  • 2Sezione di Endocrinologia, Dipartimento di Medicina, Università di Verona, Verona, Italy
  • 3Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia
  • 4U.O. di Immunoematologia e Trasfusione, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
Further Information

Publication History

Publication Date:
09 February 2011 (online)

    Permissions and Reprints

ABSTRACT

The liver plays a central role in the maintenance of a normal hemostatic balance by synthesizing several factors belonging to the pathways of coagulation, anticoagulation, and fibrinolysis. It is thereby unsurprising that patients with chronic liver disease (CLD) or cirrhosis may experience a kaleidoscope of hemostatic disorders. A bleeding tendency represents the most frequent and clinically severe hemostatic complication of CLD or cirrhosis. Perhaps less anticipated, growing evidence now suggests that a procoagulant state may be also associated with CLD, so that patients with CLD or cirrhosis, irrespective of its etiology, rather than be “naturally anticoagulated” might also experience a large spectrum of spontaneous or unprovoked venous thrombotic complications. The clinical significance of an increased risk of venous thromboembolism in CLD is an important topic for future research, and the initiation of new randomized studies of potential treatments for this complication is needed.

KEYWORDS

Thrombosis - liver - chronic liver disease - coagulation - cirrhosis

REFERENCES

  • 1 DeFrances C J, Cullen K A, Kozak L J. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data.  Vital Health Stat 13. 2007;  (165) 1-209
    PubMedSearch in Google Scholar
  • 2 Heron M P, Hoyert D L, Murphy S L, Xu J Q, Kochanek K D, Tejada-Vera B. Deaths: final data for 2006. National Vital Statistics Reports. Vol 57, No 14 Hyattsville, MD: National Center for Health Statistics; 2009
    Search in Google Scholar
  • 3 Pugh R N, Murray-Lyon I M, Dawson J L, Pietroni M C, Williams R. Transection of the oesophagus for bleeding oesophageal varices.  Br J Surg. 1973;  60 (8) 646-649
    CrossrefPubMedSearch in Google Scholar
  • 4 Wiesner R H, McDiarmid S V, Kamath P S et al.. MELD and PELD: application of survival models to liver allocation.  Liver Transpl. 2001;  7 (7) 567-580
    CrossrefPubMedSearch in Google Scholar
  • 5 Favaloro E J, Adcock D M. Standardization of the INR: how good is your laboratory's INR and can it be improved?.  Semin Thromb Hemost. 2008;  34 (7) 593-603
    Thieme ConnectPubMedSearch in Google Scholar
  • 6 Tripodi A. How to implement the modified international normalized ratio for cirrhosis (INR(liver)) for model for end-stage liver disease calculation.  Hepatology. 2008;  47 (4) 1423-1424; author reply 1424
    CrossrefPubMedSearch in Google Scholar
  • 7 Tripodi A, Chantarangkul V, Mannucci P M. The international normalized ratio to prioritize patients for liver transplantation: problems and possible solutions.  J Thromb Haemost. 2008;  6 (2) 243-248
    CrossrefPubMedSearch in Google Scholar
  • 8 Trotter J F. Coagulation abnormalities in patients who have liver disease.  Clin Liver Dis. 2006;  10 (3) 665-678, x–xi
    CrossrefPubMedSearch in Google Scholar
  • 9 Craxì A, Cammà C, Giunta M. Clinical aspects of bleeding complications in cirrhotic patients.  Blood Coagul Fibrinolysis. 2000;  11 ((Suppl 1)) S75-S79
    CrossrefPubMedSearch in Google Scholar
  • 10 Roberts L N, Patel R K, Arya R. Haemostasis and thrombosis in liver disease.  Br J Haematol. 2010;  148 (4) 507-521
    CrossrefPubMedSearch in Google Scholar
  • 11 Wada H, Usui M, Sakuragawa N. Hemostatic abnormalities and liver diseases.  Semin Thromb Hemost. 2008;  34 (8) 772-778
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Monroe D M, Hoffman M. The coagulation cascade in cirrhosis.  Clin Liver Dis. 2009;  13 (1) 1-9
    CrossrefPubMedSearch in Google Scholar
  • 13 Witters P, Freson K, Verslype C et al.. Review article: blood platelet number and function in chronic liver disease and cirrhosis.  Aliment Pharmacol Ther. 2008;  27 (11) 1017-1029
    CrossrefPubMedSearch in Google Scholar
  • 14 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
    CrossrefPubMedSearch in Google Scholar
  • 15 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
    CrossrefPubMedSearch in Google Scholar
  • 16 Berntorp E, Salvagno G L. Standardization and clinical utility of thrombin-generation assays.  Semin Thromb Hemost. 2008;  34 (7) 670-682
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Tripodi A, Primignani M, Chantarangkul V et al.. Thrombin generation in patients with cirrhosis: the role of platelets.  Hepatology. 2006;  44 (2) 440-445
    CrossrefPubMedSearch in Google Scholar
  • 18 Tripodi A, Primignani M, Chantarangkul V et al.. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.  Gastroenterology. 2009;  137 (6) 2105-2111
    CrossrefPubMedSearch in Google Scholar
  • 19 Ho C H, Hou M C, Lin H C, Lee F Y, Wu J C, Lee S D. Hemostatic changes in patients with liver cirrhosis.  Zhonghua Yi Xue Za Zhi (Taipei). 1999;  62 (6) 376-382
    PubMedSearch in Google Scholar
  • 20 Cong Y L, Wei Y X, Zhang L W, Yin Z J, Bai J. The relationship between hemostatic changes in liver cirrhosis patients with different degrees of liver lesions in reference to Child-Pugh scores [in Chinese].  Zhonghua Gan Zang Bing Za Zhi. 2005;  13 (1) 31-34
    PubMedSearch in Google Scholar
  • 21 Hollestelle M J, Geertzen H GM, Straatsburg I H, van Gulik T M, van Mourik J A. Factor VIII expression in liver disease.  Thromb Haemost. 2004;  91 (2) 267-275
    PubMedSearch in Google Scholar
  • 22 Tacke F, Schöffski P, Trautwein C, Manns M P, Ganser A, von Depka M. Tissue factor and thrombomodulin levels are correlated with stage of cirrhosis in patients with liver disease.  Blood Coagul Fibrinolysis. 2001;  12 (7) 539-545
    CrossrefPubMedSearch in Google Scholar
  • 23 Oksüzoğlu G, Simsek H, Haznedaroğlu I C, Kirazli S. Tissue factor pathway inhibitor concentrations in cirrhotic patients with and without portal vein thrombosis.  Am J Gastroenterol. 1997;  92 (2) 303-306
    PubMedSearch in Google Scholar
  • 24 Biagini M R, Tozzi A, Marcucci R et al.. Hyperhomocysteinemia and hypercoagulability in primary biliary cirrhosis.  World J Gastroenterol. 2006;  12 (10) 1607-1612
    PubMedSearch in Google Scholar
  • 25 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.  Semin Thromb Hemost. 2009;  35 (3) 277-287
    Thieme ConnectPubMedSearch in Google Scholar
  • 26 Targher G, Bertolini L, Rodella S et al.. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men.  Obesity (Silver Spring). 2008;  16 (6) 1394-1399
    CrossrefPubMedSearch in Google Scholar
  • 27 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
    CrossrefPubMedSearch in Google Scholar
  • 28 Pereboom I T, Lisman T, Porte R J. Platelets in liver transplantation: friend or foe?.  Liver Transpl. 2008;  14 (7) 923-931
    CrossrefPubMedSearch in Google Scholar
  • 29 Tacke F, Schöffski P, Trautwein C et al.. Plasma P-selectin levels are elevated in patients with chronic liver disease.  Blood Coagul Fibrinolysis. 2003;  14 (4) 319-325
    CrossrefPubMedSearch in Google Scholar
  • 30 Vardareli E, Saricam T, Demirustu C, Gulbas Z. Soluble P selectin levels in chronic liver disease: relationship to disease severity.  Hepatogastroenterology. 2007;  54 (74) 466-469
    PubMedSearch in Google Scholar
  • 31 Pihusch R, Rank A, Göhring P, Pihusch M, Hiller E, Beuers U. Platelet function rather than plasmatic coagulation explains hypercoagulable state in cholestatic liver disease.  J Hepatol. 2002;  37 (5) 548-555
    CrossrefPubMedSearch in Google Scholar
  • 32 Ferro D, Celestini A, Violi F. Hyperfibrinolysis in liver disease.  Clin Liver Dis. 2009;  13 (1) 21-31
    CrossrefPubMedSearch in Google Scholar
  • 33 Caldwell S H, Sanyal A J. Coagulation disorders and bleeding in liver disease: future directions.  Clin Liver Dis. 2009;  13 (1) 155-157
    CrossrefPubMedSearch in Google Scholar
  • 34 Hu K Q, Yu A S, Tiyyagura L, Redeker A G, Reynolds T B. Hyperfibrinolytic activity in hospitalized cirrhotic patients in a referral liver unit.  Am J Gastroenterol. 2001;  96 (5) 1581-1586
    CrossrefPubMedSearch in Google Scholar
  • 35 Aytac S, Turkay C, Bavbek N, Kosar A. Hemostasis and global fibrinolytic capacity in chronic liver disease.  Blood Coagul Fibrinolysis. 2007;  18 (7) 623-626
    CrossrefPubMedSearch in Google Scholar
  • 36 Ferguson J W, Helmy A, Ludlam C, Webb D J, Hayes P C, Newby D C. Hyperfibrinolysis in alcoholic cirrhosis: relative plasminogen activator inhibitor type 1 deficiency.  Thromb Res. 2008;  121 (5) 675-680
    CrossrefPubMedSearch in Google Scholar
  • 37 Kahl B S, Schwartz B S, Mosher D F. Profound imbalance of pro-fibrinolytic and anti-fibrinolytic factors (tissue plasminogen activator and plasminogen activator inhibitor type 1) and severe bleeding diathesis in a patient with cirrhosis: correction by liver transplantation.  Blood Coagul Fibrinolysis. 2003;  14 (8) 741-744
    CrossrefPubMedSearch in Google Scholar
  • 38 Violi F, Ferro D, Basili S et al.. Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis.  Hepatology. 1993;  17 (1) 78-83
    CrossrefPubMedSearch in Google Scholar
  • 39 Gresele P, Binetti B M, Branca G et al.. TAFI deficiency in liver cirrhosis: relation with plasma fibrinolysis and survival.  Thromb Res. 2008;  121 (6) 763-768
    CrossrefPubMedSearch in Google Scholar
  • 40 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
    PubMedSearch in Google Scholar
  • 41 Fimognari F L, Violi F. Portal vein thrombosis in liver cirrhosis.  Intern Emerg Med. 2008;  3 (3) 213-218
    CrossrefPubMedSearch in Google Scholar
  • 42 Amitrano L, Brancaccio V, Guardascione M A et al.. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis.  Hepatology. 2000;  31 (2) 345-348
    CrossrefPubMedSearch in Google Scholar
  • 43 Murata M, Tamura Y, Ohsawa M, Hirano T, Matsuo T, Murata T. Central retinal vein occlusion in hypertensive patients with chronic hepatitis C treated with interferon alpha and ribavirin.  Jpn J Ophthalmol. 2008;  52 (6) 511-513
    CrossrefPubMedSearch in Google Scholar
  • 44 Okuse C, Adachi K, Katakura Y et al.. A case of deep venous thrombosis associated with pegylated interferon alpha2b plus ribavirin treatment of chronic hepatitis C.  J Gastroenterol. 2006;  41 (12) 1231-1236
    CrossrefPubMedSearch in Google Scholar
  • 45 Zandieh I, Adenwalla M, Cheong-Lee C, Ma P E, Yoshida E M. Retinal vein thrombosis associated with pegylated-interferon and ribavirin combination therapy for chronic hepatitis C.  World J Gastroenterol. 2006;  12 (30) 4908-4910
    PubMedSearch in Google Scholar
  • 46 Caiado A H, Blasbalg R, Marcelino A S et al.. Complications of liver transplantation: multimodality imaging approach.  Radiographics. 2007;  27 (5) 1401-1417
    CrossrefPubMedSearch in Google Scholar
  • 47 Senzolo M, Burra P, Cholongitas E, Burroughs A K. New insights into the coagulopathy of liver disease and liver transplantation.  World J Gastroenterol. 2006;  12 (48) 7725-7736
    PubMedSearch in Google Scholar
  • 48 Tripodi A, Primignani M, Mannucci P M. Abnormalities of hemostasis and bleeding in chronic liver disease: the paradigm is challenged.  Intern Emerg Med. 2010;  5 (1) 7-12
    CrossrefPubMedSearch in Google Scholar
  • 49 Roberts L N, Patel R K, Arya R. Haemostasis and thrombosis in liver disease.  Br J Haematol. 2010;  148 (4) 507-521
    CrossrefPubMedSearch in Google Scholar
  • 50 Valla D C. Thrombosis and anticoagulation in liver disease.  Hepatology. 2008;  47 (4) 1384-1393
    CrossrefPubMedSearch in Google Scholar
  • 51 Søgaard K K, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen H T. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study.  Am J Gastroenterol. 2009;  104 (1) 96-101
    CrossrefPubMedSearch in Google Scholar
  • 52 Heit J A, Silverstein M D, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study.  Arch Intern Med. 2000;  160 (6) 809-815
    CrossrefPubMedSearch in Google Scholar
  • 53 Huerta C, Johansson S, Wallander M A, García Rodríguez L A. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom.  Arch Intern Med. 2007;  167 (9) 935-943
    CrossrefPubMedSearch in Google Scholar
  • 54 Northup P G, McMahon M M, Ruhl A P et al.. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism.  Am J Gastroenterol. 2006;  101 (7) 1524-1528; quiz 1680
    CrossrefPubMedSearch in Google Scholar
  • 55 García-Fuster M J, Abdilla N, Fabiá M J, Fernández C, Oliver V, Forner M J. Forner M J . Venous thromboembolism and liver cirrhosis [in Spanish].  Rev Esp Enferm Dig. 2008;  100 (5) 259-262
    PubMedSearch in Google Scholar
  • 56 Gulley D, Teal E, Suvannasankha A, Chalasani N, Liangpunsakul S. Deep vein thrombosis and pulmonary embolism in cirrhosis patients.  Dig Dis Sci. 2008;  53 (11) 3012-3017
    CrossrefPubMedSearch in Google Scholar
  • 57 Dabbagh O, Oza A, Prakash S, Sunna R, Saettele T M. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease.  Chest. 2010;  137 (5) 1145-1149
    CrossrefPubMedSearch in Google Scholar
  • 58 DeLeve L D, Valla D C, Garcia-Tsao G. American Association for the Study Liver Diseases . Vascular disorders of the liver.  Hepatology. 2009;  49 (5) 1729-1764
    CrossrefPubMedSearch in Google Scholar
  • 59 Senzolo M, Sartori M T, Lisman T. Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy?.  HPB (Oxford). 2009;  11 (6) 459-464
    CrossrefPubMedSearch in Google Scholar
  • 60 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over.  Semin Thromb Hemost. 2008;  34 (8) 747-761
    Thieme ConnectPubMedSearch in Google Scholar

Professor Giuseppe LippiM.D. U.O. 

Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma

Via Gramsci 14, 43126 - Parma, Italy

Email: glippi@ao.pr.it; ulippi@tin.it