Download PDF
Semin Liver Dis 2012; 32(01): 039-048
DOI: 10.1055/s-0032-1306425
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hypercoagulation and Thrombophilia in Nonalcoholic Fatty Liver Disease: Mechanisms, Human Evidence, Therapeutic Implications, and Preventive Implications

Patrick G. Northup
1   Coagulation in Liver Disease Study Group, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia.
,
Curtis K. Argo
1   Coagulation in Liver Disease Study Group, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia.
,
Neeral Shah
1   Coagulation in Liver Disease Study Group, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia.
,
Stephen H. Caldwell
1   Coagulation in Liver Disease Study Group, Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia.
› Author Affiliations
Further Information

Publication History

Publication Date:
13 March 2012 (online)

    Permissions and Reprints

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders with a high prevalence in the industrialized world. Despite the high prevalence, the etiology and fundamental pathophysiology for the disease process is poorly understood. There is now a growing fund of knowledge suggesting that the ongoing inflammatory state associated with NAFLD leads to a low-level activation of the coagulation system. Although the data supporting this activation of the coagulation system are significant, the link with end-organ disease, mainly cardiovascular disease, is less firm and mostly epidemiological. In this review, we will explore the evidence for and against a hypercoagulable or thrombophilic state in NAFLD. We will examine possible pathophysiologic explanations and mechanisms, human epidemiologic and population-based data, and the possible therapeutic and preventative implications for treatment of thrombophilia in patients with this disease process.

Keywords

Thrombosis - steatohepatitis - coagulopathy - hepatitis - coagulopathy
 

  • References

  • 1 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
    CrossrefPubMedSearch in Google Scholar
  • 2 Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008; 28 (4) 339-350
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Williams CD, Stengel J, Asike MI , et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (1) 124-131
    CrossrefPubMedSearch in Google Scholar
  • 4 Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007; 132 (6) 2169-2180
    CrossrefPubMedSearch in Google Scholar
  • 5 Adams LA, Harmsen S, St Sauver JL , et al. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study. Am J Gastroenterol 2010; 105 (7) 1567-1573
    CrossrefPubMedSearch in Google Scholar
  • 6 Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA 2010; 303 (3) 235-241
    CrossrefPubMedSearch in Google Scholar
  • 7 Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141 (4) 1249-1253
    CrossrefPubMedSearch in Google Scholar
  • 8 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
  • 9 Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000; 343 (20) 1467-1476
    CrossrefPubMedSearch in Google Scholar
  • 10 Targher G, Zoppini G, Moghetti P, Day CP. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin Thromb Hemost 2010; 36 (1) 41-48
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Thuy S, Ladurner R, Volynets V , et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 2008; 138 (8) 1452-1455
    PubMedSearch in Google Scholar
  • 12 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
  • 13 Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Agostino G, De Sandre G. Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. Arterioscler Thromb Vasc Biol 1996; 16 (3) 368-374
    CrossrefPubMedSearch in Google Scholar
  • 14 Cigolini M, Targher G, Agostino G, Tonoli M, Muggeo M, De Sandre G. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men—role of the metabolic syndrome. Thromb Haemost 1996; 76 (1) 69-73
    PubMedSearch in Google Scholar
  • 15 Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007; 46 (6) 1126-1132
    CrossrefPubMedSearch in Google Scholar
  • 16 Targher G, Bertolini L, Padovani R , et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30 (5) 1212-1218
    CrossrefPubMedSearch in Google Scholar
  • 17 Targher G, Bertolini L, Rodella S , et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007; 30 (8) 2119-2121
    CrossrefPubMedSearch in Google Scholar
  • 18 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363 (14) 1341-1350
    CrossrefPubMedSearch in Google Scholar
  • 19 Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (4) 511-531
    CrossrefPubMedSearch in Google Scholar
  • 20 Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134 (2) 424-431
    CrossrefPubMedSearch in Google Scholar
  • 21 Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 2002; 35 (4) 898-904
    CrossrefPubMedSearch in Google Scholar
  • 22 Fujita K, Nozaki Y, Wada K , et al. Dysfunctional very-low-density lipoprotein synthesis and release is a key factor in nonalcoholic steatohepatitis pathogenesis. Hepatology 2009; 50 (3) 772-780
    CrossrefPubMedSearch in Google Scholar
  • 23 Musso G, Gambino R, De Michieli F , et al. Association of liver disease with postprandial large intestinal triglyceride-rich lipoprotein accumulation and pro/antioxidant imbalance in normolipidemic non-alcoholic steatohepatitis. Ann Med 2008; 40 (5) 383-394
    CrossrefPubMedSearch in Google Scholar
  • 24 Ohsaki Y, Cheng J, Suzuki M, Fujita A, Fujimoto T. Lipid droplets are arrested in the ER membrane by tight binding of lipidated apolipoprotein B-100. J Cell Sci 2008; 121 (Pt 14) 2415-2422
    CrossrefPubMedSearch in Google Scholar
  • 25 Caldwell S, Ikura Y, Dias D , et al. Hepatocellular ballooning in NASH. J Hepatol 2010; 53 (4) 719-723
    CrossrefPubMedSearch in Google Scholar
  • 26 Ikura Y, Ohsawa M, Suekane T , et al. Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: impact on disease progression. Hepatology 2006; 43 (3) 506-514
    CrossrefPubMedSearch in Google Scholar
  • 27 Lackner C, Gogg-Kamerer M, Zatloukal K, Stumptner C, Brunt EM, Denk H. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol 2008; 48 (5) 821-828
    CrossrefPubMedSearch in Google Scholar
  • 28 Itabe H, Takeshima E, Iwasaki H , et al. A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides. J Biol Chem 1994; 269 (21) 15274-15279
    PubMedSearch in Google Scholar
  • 29 García-Monzón C, Martín-Pérez E, Iacono OL , et al. Characterization of pathogenic and prognostic factors of nonalcoholic steatohepatitis associated with obesity. J Hepatol 2000; 33 (5) 716-724
    CrossrefPubMedSearch in Google Scholar
  • 30 Malaguarnera L, Madeddu R, Palio E, Arena N, Malaguarnera M. Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol 2005; 42 (4) 585-591
    CrossrefPubMedSearch in Google Scholar
  • 31 Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver diseases. J Hepatol 2002; 37 (1) 56-62
    CrossrefPubMedSearch in Google Scholar
  • 32 Albano E, Mottaran E, Vidali M , et al. Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 2005; 54 (7) 987-993
    CrossrefPubMedSearch in Google Scholar
  • 33 Puri P, Wiest MM, Cheung O , et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009; 50 (6) 1827-1838
    CrossrefPubMedSearch in Google Scholar
  • 34 Alessi MC, Bastelica D, Mavri A , et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol 2003; 23 (7) 1262-1268
    CrossrefPubMedSearch in Google Scholar
  • 35 Allison BA, Nilsson L, Karpe F, Hamsten A, Eriksson P. Effects of native, triglyceride-enriched, and oxidatively modified LDL on plasminogen activator inhibitor-1 expression in human endothelial cells. Arterioscler Thromb Vasc Biol 1999; 19 (5) 1354-1360
    CrossrefPubMedSearch in Google Scholar
  • 36 Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol 2003; 14 (5) 421-430
    CrossrefPubMedSearch in Google Scholar
  • 37 Bochkov VN, Mechtcheriakova D, Lucerna M , et al. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca(++)/NFAT. Blood 2002; 99 (1) 199-206
    CrossrefPubMedSearch in Google Scholar
  • 38 Sommeijer DW, Hansen HR, van Oerle R , et al. Soluble tissue factor is a candidate marker for progression of microvascular disease in patients with Type 2 diabetes. J Thromb Haemost 2006; 4 (3) 574-580
    CrossrefPubMedSearch in Google Scholar
  • 39 Li Z, Berk M, McIntyre TM, Gores GJ, Feldstein AE. The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity. Hepatology 2008; 47 (5) 1495-1503
    CrossrefPubMedSearch in Google Scholar
  • 40 Singh R, Kaushik S, Wang Y , et al. Autophagy regulates lipid metabolism. Nature 2009; 458 (7242) 1131-1135
    CrossrefPubMedSearch in Google Scholar
  • 41 Lemasters JJ. Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology 2005; 129 (1) 351-360
    CrossrefPubMedSearch in Google Scholar
  • 42 Owens III AP, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011; 108 (10) 1284-1297
    CrossrefPubMedSearch in Google Scholar
  • 43 Baron M, Leroyer AS, Majd Z , et al. PPARα activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH. Atherosclerosis 2011; 18 (1) 69-76
    PubMedSearch in Google Scholar
  • 44 Leroyer AS, Isobe H, Lesèche G , et al. Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques. J Am Coll Cardiol 2007; 49 (7) 772-777
    CrossrefPubMedSearch in Google Scholar
  • 45 Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care 2004; 27 (10) 2498-2500
    CrossrefPubMedSearch in Google Scholar
  • 46 Targher G, Bertolini L, Padovani R , et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29 (6) 1325-1330
    CrossrefPubMedSearch in Google Scholar
  • 47 Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49 (4) 600-607
    CrossrefPubMedSearch in Google Scholar
  • 48 Villanova N, Moscatiello S, Ramilli S , et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005; 42 (2) 473-480
    CrossrefPubMedSearch in Google Scholar
  • 49 Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol 2008; 28 (1) 27-38
    CrossrefPubMedSearch in Google Scholar
  • 50 Targher G, Bertolini L, Poli F , et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005; 54 (12) 3541-3546
    CrossrefPubMedSearch in Google Scholar
  • 51 Marchesini G, Moscatiello S, Di Domizio S, Forlani G. Obesity-associated liver disease. J Clin Endocrinol Metab 2008; 93 (11, Suppl 1) S74-S80
    CrossrefPubMedSearch in Google Scholar
  • 52 Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol 2005; 11 (31) 4838-4842
    CrossrefPubMedSearch in Google Scholar
  • 53 Mirbagheri SA, Rashidi A, Abdi S, Saedi D, Abouzari M. Liver: an alarm for the heart?. Liver Int 2007; 27 (7) 891-894
    CrossrefPubMedSearch in Google Scholar
  • 54 Hamaguchi M, Kojima T, Takeda N , et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13 (10) 1579-1584
    CrossrefPubMedSearch in Google Scholar
  • 55 Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50 (5) 1403-1411
    CrossrefPubMedSearch in Google Scholar
  • 56 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
    CrossrefPubMedSearch in Google Scholar
  • 57 Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 2008; 49 (4) 608-612
    CrossrefPubMedSearch in Google Scholar
  • 58 Rafiq N, Bai C, Fang Y , et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009; 7 (2) 234-238
    CrossrefPubMedSearch in Google Scholar
  • 59 Northup PG, McMahon MM, Ruhl AP , 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
  • 60 Forssen U, Kobayashi M, Moylan CA, Ludema CM, Theodore D. Nash increases the risk of portal vein thrombosis in patients on the liver transplant waiting list. Hepatology 2010; 52 (4) 911a-911a , abstract
    PubMedSearch in Google Scholar
  • 61 Northup PG, Sundaram V, Fallon MB , et al; Coagulation in Liver Disease Group. Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost 2008; 6 (1) 2-9
    PubMedSearch in Google Scholar
  • 62 Laryea M, Watt KD, Molinari M , et al. Metabolic syndrome in liver transplant recipients: prevalence and association with major vascular events. Liver Transpl 2007; 13 (8) 1109-1114
    CrossrefPubMedSearch in Google Scholar
  • 63 Malik SM, deVera ME, Fontes P, Shaikh O, Ahmad J. Outcome after liver transplantation for NASH cirrhosis. Am J Transplant 2009; 9 (4) 782-793
    CrossrefPubMedSearch in Google Scholar
  • 64 Bhagat V, Mindikoglu AL, Nudo CG, Schiff ER, Tzakis A, Regev A. Outcomes of liver transplantation in patients with cirrhosis due to nonalcoholic steatohepatitis versus patients with cirrhosis due to alcoholic liver disease. Liver Transpl 2009; 15 (12) 1814-1820
    CrossrefPubMedSearch in Google Scholar
  • 65 Dirckx JH, Armand J. Quick: pioneer and prophet of coagulation research. Ann Intern Med 1980; 92 (4) 553-558
    CrossrefPubMedSearch in Google Scholar
  • 66 Tripodi A, Caldwell SH, Hoffman M, Trotter JF, Sanyal AJ. Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease. Aliment Pharmacol Ther 2007; 26 (2) 141-148
    CrossrefPubMedSearch in Google Scholar
  • 67 Lisman T, van Leeuwen Y, Adelmeijer J , et al. Interlaboratory variability in assessment of the model of end-stage liver disease score. Liver Int 2008; 28 (10) 1344-1351
    CrossrefPubMedSearch in Google Scholar
  • 68 Trotter JF, Olson J, Lefkowitz J, Smith AD, Arjal R, Kenison J. Changes in international normalized ratio (INR) and model for endstage liver disease (MELD) based on selection of clinical laboratory. Am J Transplant 2007; 7 (6) 1624-1628
    CrossrefPubMedSearch in Google Scholar
  • 69 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
    CrossrefPubMedSearch in Google Scholar
  • 70 Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004; 99 (6) 1160-1174
    CrossrefPubMedSearch in Google Scholar
  • 71 Germani G, Hytiroglou P, Fotiadu A, Burroughs AK, Dhillon AP. Assessment of fibrosis and cirrhosis in liver biopsies: an update. Semin Liver Dis 2011; 31 (1) 82-90
    Thieme ConnectPubMedSearch in Google Scholar
  • 72 Ratziu V, Charlotte F, Heurtier A , et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128 (7) 1898-1906
    CrossrefPubMedSearch in Google Scholar
  • 73 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
  • 74 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
  • 75 Dahlbäck B. Progress in the understanding of the protein C anticoagulant pathway. Int J Hematol 2004; 79 (2) 109-116
    CrossrefPubMedSearch in Google Scholar
  • 76 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
  • 77 Lisman T, Adelmeijer J, de Groot PG, Janssen HL, Leebeek FW. No evidence for an intrinsic platelet defect in patients with liver cirrhosis—studies under flow conditions. J Thromb Haemost 2006; 4 (9) 2070-2072
    CrossrefPubMedSearch in Google Scholar
  • 78 Lisman T, Bongers TN, 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
  • 79 Basili S, Ferro D, Leo R , et al. Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis. The CALC Group. Coagulation abnormalities in liver cirrhosis. J Hepatol 1996; 24 (5) 574-580
    CrossrefPubMedSearch in Google Scholar
  • 80 Despotis GJ, Levine V, Filos KS , et al. Evaluation of a new point-of-care test that measures PAF-mediated acceleration of coagulation in cardiac surgical patients. Anesthesiology 1996; 85 (6) 1311-1323
    CrossrefPubMedSearch in Google Scholar
  • 81 Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992; 69 (3) 307-313
    CrossrefPubMedSearch in Google Scholar
  • 82 Spiess BD. Thromboelastography and cardiopulmonary bypass. Semin Thromb Hemost 1995; 21 (Suppl 4) 27-33
    PubMedSearch in Google Scholar
  • 83 Viola F, Mauldin Jr FW, Lin-Schmidt X, Haverstick DM, Lawrence MB, Walker WF. A novel ultrasound-based method to evaluate hemostatic function of whole blood. Clin Chim Acta 2010; 411 (1-2) 106-113
    CrossrefPubMedSearch in Google Scholar
  • 84 Amitrano L, Guardascione MA, Ames PR. Coagulation abnormalities in cirrhotic patients with portal vein thrombosis. Clin Lab 2007; 53 (9-12) 583-589
    PubMedSearch in Google Scholar
  • 85 Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. 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
  • 86 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31 (3) 366-374
    CrossrefPubMedSearch in Google Scholar
  • 87 Qi X, Han G, Wu K, Fan D. Anticoagulation for portal vein thrombosis in cirrhosis. Am J Med 2010; 123 (9) e19-e20 , author reply e21
    PubMedSearch in Google Scholar
  • 88 Lauer MS. Clinical practice. Aspirin for primary prevention of coronary events. N Engl J Med 2002; 346 (19) 1468-1474
    CrossrefPubMedSearch in Google Scholar
  • 89 Mohr JP, Thompson JL, Lazar RM , et al; Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345 (20) 1444-1451
    CrossrefPubMedSearch in Google Scholar
  • 90 Menguy R, Desbaillets L, Okabe S, Masters YF. Abnormal aspirin metabolism in patients with cirrhosis and its possible relationship to bleeding in cirrhotics. Ann Surg 1972; 176 (3) 412-418
    CrossrefPubMedSearch in Google Scholar
  • 91 Rainsford KD, Ford NL, Brooks PM, Watson HM. Plasma aspirin esterases in normal individuals, patients with alcoholic liver disease and rheumatoid arthritis: characterization and the importance of the enzymic components. Eur J Clin Invest 1980; 10 (5) 413-420
    CrossrefPubMedSearch in Google Scholar
  • 92 Kalaitzakis E, Rosengren A, Skommevik T, Björnsson E. Coronary artery disease in patients with liver cirrhosis. Dig Dis Sci 2010; 55 (2) 467-475
    CrossrefPubMedSearch in Google Scholar
  • 93 Song JY, Choi JY, Ko JT , et al. Long-term aspirin therapy for hepatopulmonary syndrome. Pediatrics 1996; 97 (6 Pt 1) 917-920
    PubMedSearch in Google Scholar
  • 94 Ridker PM, Cook NR, Lee IM , et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005; 352 (13) 1293-1304
    CrossrefPubMedSearch in Google Scholar
  • 95 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
    CrossrefPubMedSearch in Google Scholar
  • 96 Bechmann LP, Sichau M, Wichert M, Gerken G, Kröger K, Hilgard P. Low-molecular-weight heparin in patients with advanced cirrhosis. Liver Int 2011; 31 (1) 75-82
    CrossrefPubMedSearch in Google Scholar
  • 97 Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. Hepatology 2011; 54 (5) 1631-1639
    CrossrefPubMedSearch in Google Scholar
  • 98 Sanyal AJ, Chalasani N, Kowdley KV , et al; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362 (18) 1675-1685
    CrossrefPubMedSearch in Google Scholar
  • 99 Adams LA, Angulo P, Petz J, Keach J, Lindor KD. A pilot trial of high-dose ursodeoxycholic acid in nonalcoholic steatohepatitis. Hepatol Int 2010; 4 (3) 628-633
    CrossrefPubMedSearch in Google Scholar
  • 100 Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Therap Adv Gastroenterol 2009; 2 (3) 157-163
    CrossrefPubMedSearch in Google Scholar
  • 101 Chalasani NP, Sanyal AJ, Kowdley KV , et al; NASH CRN Research Group. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials 2009; 30 (1) 88-96
    CrossrefPubMedSearch in Google Scholar
  • 102 Targher G. Pioglitazone in nonalcoholic steatohepatitis. N Engl J Med 2007; 356 (10) 1067 , author reply 1068–1069
    CrossrefPubMedSearch in Google Scholar
  • 103 Belfort R, Harrison SA, Brown K , et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355 (22) 2297-2307
    CrossrefPubMedSearch in Google Scholar
  • 104 Sanyal AJ, Mofrad PS, Contos MJ , et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004; 2 (12) 1107-1115
    CrossrefPubMedSearch in Google Scholar
  • 105 Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98 (11) 2485-2490
    CrossrefPubMedSearch in Google Scholar
  • 106 Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995; 21 (5) 1238-1247
    CrossrefPubMedSearch in Google Scholar
  • 107 Goodman ZD, Stoddard AM, Bonkovsky HL , et al; HALT-C Trial Group. Fibrosis progression in chronic hepatitis C: morphometric image analysis in the HALT-C trial. Hepatology 2009; 50 (6) 1738-1749
    CrossrefPubMedSearch in Google Scholar
  • 108 McHutchison J, Goodman Z, Patel K , et al; Farglitizar Study Investigators. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology 2010; 138 (4) 1365-1373 , 1373, e1–e2
    CrossrefPubMedSearch in Google Scholar
  • 109 Muir AJ, Sylvestre PB, Rockey DC. Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection. J Viral Hepat 2006; 13 (5) 322-328
    CrossrefPubMedSearch in Google Scholar
  • 110 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9) 526-533
    CrossrefPubMedSearch in Google Scholar
  • 111 Anstee QM, Goldin RD, Wright M, Martinelli A, Cox R, Thursz MR. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J Thromb Haemost 2008; 6 (8) 1336-1343
    CrossrefPubMedSearch in Google Scholar
  • 112 Duplantier JG, Dubuisson L, Senant N , et al. A role for thrombin in liver fibrosis. Gut 2004; 53 (11) 1682-1687
    CrossrefPubMedSearch in Google Scholar
  • 113 Ibrahim M, Farghaly E, Gomaa W, Kelleni M, Abdelrahman AM. Nitro-aspirin is a potential therapy for non alcoholic fatty liver disease. Eur J Pharmacol 2011; 659 (2-3) 289-295
    CrossrefPubMedSearch in Google Scholar
  • 114 Assy N, Hussein O, Khalil A , et al. The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. Dig Dis Sci 2007; 52 (5) 1187-1193
    CrossrefPubMedSearch in Google Scholar
  • 115 Papatheodoridis GV, Papakonstantinou E, Andrioti E , et al. Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 2003; 52 (3) 404-409
    CrossrefPubMedSearch in Google Scholar
  • 116 Poujol-Robert A, Boëlle PY, Poupon R, Robert A . Factor V. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology 2004; 39 (4) 1174-1175
    CrossrefPubMedSearch in Google Scholar
  • 117 Goulding C, O'Brien C, Egan H , et al. The impact of inherited prothrombotic risk factors on individuals chronically infected with hepatitis C virus from a single source. J Viral Hepat 2007; 14 (4) 255-259
    CrossrefPubMedSearch in Google Scholar
  • 118 Shi J, Hao JH, Ren WH, Zhu JR. Effects of heparin on liver fibrosis in patients with chronic hepatitis B. World J Gastroenterol 2003; 9 (7) 1611-1614
    CrossrefPubMedSearch in Google Scholar
  • 119 Papatheodoridis GV, Chrysanthos N, Cholongitas E , et al. Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease. J Hepatol 2009; 51 (5) 931-938
    CrossrefPubMedSearch in Google Scholar
  • 120 Dhar A, Anstee QM, Cobbold JF , et al. Anticoagulation for liver fibrosis: a pilot study in hepatitis C infected patients. Hepatology 2010; 52 (4) 1133a-1133a
    PubMedSearch in Google Scholar
  • 121 Northup PG, Caldwell SH. New concepts of coagulation and bleeding in liver disease. Intern Emerg Med 2010; 5 (1) 3-6
    CrossrefPubMedSearch in Google Scholar