Semin Thromb Hemost 2015; 41(05): 514-519
DOI: 10.1055/s-0035-1550436
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Anticoagulant Therapy in Patients with Cirrhosis

Nicolas M. Intagliata
1   Division of Gastroenterology and Hepatology, University of Virginia Health System, University of Virginia, Charlottesville, Virginia
,
Patrick G. Northup
1   Division of Gastroenterology and Hepatology, University of Virginia Health System, University of Virginia, Charlottesville, Virginia
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
06. Juni 2015 (online)

Abstract

Recent studies have greatly expanded our understanding of the coagulopathy of cirrhosis. It is clear that cirrhosis patients are at a risk of both bleeding and thrombosis. While prediction of these events remains challenging, cirrhosis patients are not protected from the development of venous and arterial thrombosis. In fact, studies show that hypercoagulability may promote hepatic decompensation and development of fibrosis. Anticoagulation for thrombosis is now becoming a common prospect in many clinical situations. Our understanding of the efficacy and safety of commonly used therapeutics is only beginning to emerge and the risks and benefits remain unclear in this unique population. In this review, we discuss the role of anticoagulation in the treatment and prevention peripheral and splanchnic thrombosis in patients with cirrhosis, as well as examine the potential role of anticoagulants in altering the progression of chronic liver disease.

 
  • References

  • 1 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
  • 2 Lisman T, Caldwell SH, Burroughs AK , et al; Coagulation in Liver Disease Study Group. Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 2010; 53 (2) 362-371
  • 3 Amitrano L, Guardascione MA, Brancaccio V , et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004; 40 (5) 736-741
  • 4 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
  • 5 Francoz C, Belghiti J, Vilgrain V , et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005; 54 (5) 691-697
  • 6 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
  • 7 Englesbe MJ, Kubus J, Muhammad W , et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010; 16 (1) 83-90
  • 8 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
  • 9 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
  • 10 Tripodi A, Primignani M, Lemma L, Chantarangkul V, Mannucci PM. Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis. J Hepatol 2013; 59 (2) 265-270
  • 11 Gatt A, Riddell A, Calvaruso V, Tuddenham EG, Makris M, Burroughs AK. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost 2010; 8 (9) 1994-2000
  • 12 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) 249-255
  • 13 Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52 (3) 355-361
  • 14 Vivarelli M, Zanello M, Zanfi C , et al. Prophylaxis for venous thromboembolism after resection of hepatocellular carcinoma on cirrhosis: is it necessary?. World J Gastroenterol 2010; 16 (17) 2146-2150
  • 15 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
  • 16 Villa E, Cammà C, Marietta M , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (5) 1253-60.e1 , 4
  • 17 Intagliata NM, Henry ZH, Shah N, Lisman T, Caldwell SH, Northup PG. Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding. Liver Int 2014; 34 (1) 26-32
  • 18 Amitrano L, Guardascione MA, Menchise A , et al. Safety and efficacy of anticoagulation therapy with low molecular weight heparin for portal vein thrombosis in patients with liver cirrhosis. J Clin Gastroenterol 2010; 44 (6) 448-451
  • 19 Delgado MG, Seijo S, Yepes I , et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012; 10 (7) 776-783
  • 20 Maruyama H, Takahashi M, Shimada T, Yokosuka O. Emergency anticoagulation treatment for cirrhosis patients with portal vein thrombosis and acute variceal bleeding. Scand J Gastroenterol 2012; 47 (6) 686-691
  • 21 Senzolo M, , M Sartori T, Rossetto V. , et al. Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management of portal vein thrombosis in cirrhosis. Liver Int 2012; 32 (6) 919-927
  • 22 Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis - possibilities and caveats. J Hepatol 2013; 59 (2) 358-366
  • 23 Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology 2014; 60 (1) 425-426
  • 24 Intagliata NM, Maitland H, Northup PG, Caldwell SH. Treating thrombosis in cirrhosis patients with new oral agents: Ready or not?. Hepatology 2014;
  • 25 Lisman T, Porte RJ. Towards a rational use of low-molecular-weight heparin in patients with cirrhosis. Liver Int 2011; 31 (7) 1063
  • 26 Senzolo M, Rodriguez-Castro KI, Rossetto V , et al. Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis. J Thromb Haemost 2012; 10 (9) 1823-1829
  • 27 Potze W, Arshad F, Adelmeijer J , et al. Routine coagulation assays underestimate levels of antithrombin-dependent drugs but not of direct anticoagulant drugs in plasma from patients with cirrhosis. Br J Haematol 2013; 163 (5) 666-673
  • 28 Potze W, Arshad F, Adelmeijer J , et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS ONE 2014; 9 (2) e88390
  • 29 Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981; 26 (5) 388-393
  • 30 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
  • 31 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
  • 32 Porte RJ, Lisman T, Tripodi A, Caldwell SH, Trotter JF ; Coagulation in Liver Disease Study Group. The International Normalized Ratio (INR) in the MELD score: problems and solutions. Am J Transplant 2010; 10 (6) 1349-1353
  • 33 Kamath PS, Wiesner RH, Malinchoc M , et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33 (2) 464-470
  • 34 Tripodi A, Chantarangkul V, Primignani M , et al. The international normalized ratio calibrated for cirrhosis (INR(liver)) normalizes prothrombin time results for model for end-stage liver disease calculation. Hepatology 2007; 46 (2) 520-527
  • 35 Gatt A, Chen D, Pruthi RK , et al. From vitamin K antagonists to liver international normalized ratio: a historical journey and critical perspective. Semin Thromb Hemost 2014; 40 (8) 845-851
  • 36 Stangier J, Stähle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol 2008; 48 (12) 1411-1419
  • 37 Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet 2013; 52 (4) 243-254
  • 38 Kubitza D, Roth A, Becka M , et al. Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2013; 76 (1) 89-98
  • 39 Russmann S, Niedrig DF, Budmiger M , et al. Rivaroxaban postmarketing risk of liver injury. J Hepatol 2014; 61 (2) 293-300
  • 40 Caldeira D, Barra M, Santos AT , et al. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart 2014; 100 (7) 550-556
  • 41 Prins MH, Bamber L, Cano SJ , et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of pulmonary embolism; results from the EINSTEIN PE trial. Thromb Res 2015; 135 (2) 281-288
  • 42 Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis. Hepatology 2014;
  • 43 Dabbagh O, Oza A, Prakash S, Sunna R, Saettele TM. Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest 2010; 137 (5) 1145-1149
  • 44 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8 (9) 800-805
  • 45 Aldawood A, Arabi Y, Aljumah A , et al. The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients. Thromb J 2011; 9 (1) 1
  • 46 Caldwell S, Intagliata N. Dismantling the myth of “autoanticoagulation” in cirrhosis: an old dogma dies hard. Hepatology 2012; 55 (5) 1634-1637
  • 47 Reichert JA, Hlavinka PF, Stolzfus JC. Risk of hemorrhage in patients with chronic liver disease and coagulopathy receiving pharmacologic venous thromboembolism prophylaxis. Pharmacotherapy 2014; 34 (10) 1043-1049
  • 48 Gómez Cuervo C, Bisbal Pardo O, Pérez-Jacoiste Asín MA. Efficacy and safety of the use of heparin as thromboprophylaxis in patients with liver cirrhosis: a systematic review and meta-analysis. Thromb Res 2013; 132 (4) 414-419
  • 49 Kahn SR, Lim W, Dunn AS , et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e195S-e226S
  • 50 Senzolo M, Sartori MT, Lisman T. Should we give thromboprophylaxis to patients with liver cirrhosis and coagulopathy?. HPB (Oxford) 2009; 11 (6) 459-464
  • 51 Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol 2013; 11 (9) 1064-1074
  • 52 Holbrook A, Schulman S, Witt DM , et al; American College of Chest Physicians. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e152S-e184S
  • 53 Werner KT, Sando S, Carey EJ , et al. Portal vein thrombosis in patients with end stage liver disease awaiting liver transplantation: outcome of anticoagulation. Dig Dis Sci 2013; 58 (6) 1776-1780
  • 54 Yerdel MA, Gunson B, Mirza D , et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000; 69 (9) 1873-1881
  • 55 Qi X, Han G, Fan D. Management of portal vein thrombosis in liver cirrhosis. Nature reviews. Gastroenterol Hepatol 2014; 11: 435-446
  • 56 Englesbe MJ, Schaubel DE, Cai S, Guidinger MK, Merion RM. Portal vein thrombosis and liver transplant survival benefit. Liver Transpl 2010; 16 (8) 999-1005
  • 57 Nery F, Chevret S, Condat B , et al. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: Results of a longitudinal study. Hepatology 2015; 61 (2) 660-667
  • 58 Wanless IR, Liu JJ, Butany J. Role of thrombosis in the pathogenesis of congestive hepatic fibrosis (cardiac cirrhosis). Hepatology 1995; 21 (5) 1232-1237
  • 59 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
  • 60 Shimamatsu K, Wanless IR. Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver. Hepatology 1997; 26 (2) 343-350
  • 61 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9) 526-533
  • 62 Amitrano L, Brancaccio V, Guardascione MA , et al. Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis. Hepatology 2000; 31 (2) 345-348
  • 63 Poujol-Robert A, Boëlle PY, Poupon R, Robert A. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology 2004; 39 (4) 1174-1175
  • 64 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
  • 65 Marra F, Grandaliano G, Valente AJ, Abboud HE. Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 1995; 22 (3) 780-787
  • 66 Duplantier JG, Dubuisson L, Senant N , et al. A role for thrombin in liver fibrosis. Gut 2004; 53 (11) 1682-1687
  • 67 Kopec AK, Joshi N, Towery KL , et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther 2014; 351 (2) 288-297
  • 68 Borensztajn K, Stiekema J, Nijmeijer S, Reitsma PH, Peppelenbosch MP, Spek CA. Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via protease-activated receptor-2 activation. Am J Pathol 2008; 172 (2) 309-320
  • 69 Abe W, Ikejima K, Lang T , et al. Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol 2007; 46 (2) 286-294
  • 70 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
  • 71 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
  • 72 Shen H, Shahzad G, Jawairia M, Bostick RM, Mustacchia P. Association between aspirin use and the prevalence of nonalcoholic fatty liver disease: a cross-sectional study from the Third National Health and Nutrition Examination Survey. Aliment Pharmacol Ther 2014; 40 (9) 1066-1073