Venous Thromboembolism in Chronic Liver Disease

Giuseppe Lippi; Giovanni Targher; Emmanuel J Favaloro; Massimo Franchini

doi:10.1055/s-0030-1270073

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2011; 37(1): 066-076
DOI: 10.1055/s-0030-1270073

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

Abstract

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

Full Text

References

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
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
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
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
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
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
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
8 Trotter J F. Coagulation abnormalities in patients who have liver disease. Clin Liver Dis. 2006; 10 (3) 665-678, x–xi
9 Craxì A, Cammà C, Giunta M. Clinical aspects of bleeding complications in cirrhotic patients. Blood Coagul Fibrinolysis. 2000; 11 ((Suppl 1)) S75-S79
10 Roberts L N, Patel R K, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol. 2010; 148 (4) 507-521
11 Wada H, Usui M, Sakuragawa N. Hemostatic abnormalities and liver diseases. Semin Thromb Hemost. 2008; 34 (8) 772-778
12 Monroe D M, Hoffman M. The coagulation cascade in cirrhosis. Clin Liver Dis. 2009; 13 (1) 1-9
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
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
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
16 Berntorp E, Salvagno G L. Standardization and clinical utility of thrombin-generation assays. Semin Thromb Hemost. 2008; 34 (7) 670-682
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
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
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
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
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
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
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
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
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
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
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
28 Pereboom I T, Lisman T, Porte R J. Platelets in liver transplantation: friend or foe?. Liver Transpl. 2008; 14 (7) 923-931
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
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
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
32 Ferro D, Celestini A, Violi F. Hyperfibrinolysis in liver disease. Clin Liver Dis. 2009; 13 (1) 21-31
33 Caldwell S H, Sanyal A J. Coagulation disorders and bleeding in liver disease: future directions. Clin Liver Dis. 2009; 13 (1) 155-157
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
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
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
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
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
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
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
41 Fimognari F L, Violi F. Portal vein thrombosis in liver cirrhosis. Intern Emerg Med. 2008; 3 (3) 213-218
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
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
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
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
46 Caiado A H, Blasbalg R, Marcelino A S et al.. Complications of liver transplantation: multimodality imaging approach. Radiographics. 2007; 27 (5) 1401-1417
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
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
49 Roberts L N, Patel R K, Arya R. Haemostasis and thrombosis in liver disease. Br J Haematol. 2010; 148 (4) 507-521
50 Valla D C. Thrombosis and anticoagulation in liver disease. Hepatology. 2008; 47 (4) 1384-1393
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
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
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
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
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
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
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
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
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
60 Lippi G, Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost. 2008; 34 (8) 747-761

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