Coagulation Pathways, Hemostasis, and Thrombosis in Liver Failure

 

 Buy Article Permissions and Reprints

Abstract

Achieving hemostasis, preventing and treating thrombosis, and laboratory measurement of the hemostatic pathways constitute the core elements of managing the critically ill patient with liver failure. Uncontrolled bleeding in acutely decompensated cirrhosis and acute-on-chronic liver failure is probably the most familiar clinical challenge to intensivists. Bleeding in these patients can be broadly divided into pressure-driven (portal hypertension-related) bleeding with only limited dependence on hemostatic pathways and intractable mucosal/wound bleeding, which is much more directly related to a severely disturbed hemostatic system with imbalances in the coagulation cascade and the fibrinolytic system. Both types of bleeding can occur simultaneously and may even coexist with inappropriate thrombosis such as portal vein thrombosis or venous thromboembolism. Due to the fundamental role of the liver in coagulation factor synthesis and its direct and indirect regulation of nearly all aspects of the hemostatic system, laboratory measurements of coagulation pathways also constitute key aspects of all prognostic scores that guide clinical decisions and forecast optimal interventions in both acute and chronic forms of liver failure.

• References

• 1 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
  CrossrefPubMedGoogle Scholar
• 2 Lisman T, Stravitz RT. Rebalanced hemostasis in patients with acute liver failure. Semin Thromb Hemost 2015; 41 (05) 468-473
  Article in Thieme ConnectPubMedGoogle Scholar
• 3 Intagliata NM, Argo CK, Stine JG, Lisman T, Caldwell SH, Violi F. ; Faculty of the 7th International Coagulation in Liver Disease. Concepts and controversies in haemostasis and thrombosis associated with liver disease: Proceedings of the 7th International Coagulation in Liver Disease Conference. Thromb Haemost 2018; 118 (08) 1491-1506
  Article in Thieme ConnectPubMedGoogle Scholar
• 4 Intagliata NM, Caldwell SH. Changes in hemostasis in liver disease. J Hepatol 2017; 67 (06) 1332-1333
  CrossrefPubMedGoogle Scholar
• 5 Intagliata NM, Caldwell SH. The hemostatic and hematopoietic system in liver disease. In: Sanyal AJ, Boyer T, Terrault N, Lindor KD. , eds. Zakim and Boyer's Hepatology: A Textbook of Liver Disease. 7th ed. Philadelphia, PA: Elsevier; 2018: 293-300
  Google Scholar
• 6 Tripodi A, Salerno F, Chantarangkul V. , et al. Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41 (03) 553-558
  CrossrefPubMedGoogle Scholar
• 7 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 (02) 265-270
  CrossrefPubMedGoogle Scholar
• 8 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 (06) 2105-2111
  CrossrefPubMedGoogle Scholar
• 9 Sinegre T, Duron C, Lecompte T. , et al. Increased factor VIII plays a significant role in plasma hypercoagulability phenotype of patients with cirrhosis. J Thromb Haemost 2018; 16 (06) 1132-1140
  CrossrefPubMedGoogle Scholar
• 10 Lisman T, Bos S, Intagliata NM. Mechanisms of enhanced thrombin-generating capacity in patients with cirrhosis. J Thromb Haemost 2018; 16 (06) 1128-1131
  CrossrefPubMedGoogle Scholar
• 11 Tripodi A, Primignani M, Chantarangkul V. , et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology 2006; 44 (02) 440-445
  CrossrefPubMedGoogle Scholar
• 12 Fisher C, Patel VC, Stoy SH. , et al. Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure. J Crit Care 2018; 43: 54-60
  CrossrefPubMedGoogle Scholar
• 13 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 (01) 53-61
  CrossrefPubMedGoogle Scholar
• 14 Lisman T, Leebeek FW, Mosnier LO. , et al. Thrombin-activatable fibrinolysis inhibitor deficiency in cirrhosis is not associated with increased plasma fibrinolysis. Gastroenterology 2001; 121 (01) 131-139
  CrossrefPubMedGoogle Scholar
• 15 Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost 2012; 10 (07) 1312-1319
  CrossrefPubMedGoogle Scholar
• 16 Rijken DC, Kock EL, Guimarães AH. , et al. Evidence for an enhanced fibrinolytic capacity in cirrhosis as measured with two different global fibrinolysis tests. J Thromb Haemost 2012; 10 (10) 2116-2122
  CrossrefPubMedGoogle Scholar
• 17 Maddrey WC, Boitnott JK, Bedine MS, Weber Jr FL, Mezey E, White Jr RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978; 75 (02) 193-199
  CrossrefPubMedGoogle Scholar
• 18 Kamath PS, Wiesner RH, Malinchoc M. , et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33 (02) 464-470
  CrossrefPubMedGoogle Scholar
• 19 Moreau R, Jalan R, Gines P. , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
  CrossrefPubMedGoogle Scholar
• 20 O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97 (02) 439-445
  CrossrefPubMedGoogle Scholar
• 21 Davis JPE, Northup PG, Caldwell SH, Intagliata NM. Viscoelastic testing in liver disease. Ann Hepatol 2018; 17 (02) 205-213
  CrossrefPubMedGoogle Scholar
• 22 Northup PG, Caldwell SH. Coagulation in liver disease: a guide for the clinician. Clin Gastroenterol Hepatol 2013; 11 (09) 1064-1074
  CrossrefPubMedGoogle Scholar
• 23 Stravitz RT, Ellerbe C, Durkalski V. , et al; and the Acute Liver Failure Study Group. Bleeding complications in acute liver failure. Hepatology 2018; 67 (05) 1931-1942
  CrossrefPubMedGoogle Scholar
• 24 Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol 2002; 37 (04) 463-470
  CrossrefPubMedGoogle Scholar
• 25 Papatheodoridis GV, Patch D, Webster GJ, Brooker J, Barnes E, Burroughs AK. Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography. Hepatology 1999; 29 (04) 1085-1090
  CrossrefPubMedGoogle Scholar
• 26 Hung A, Garcia-Tsao G. Acute kidney injury, but not sepsis, is associated with higher procedure-related bleeding in patients with decompensated cirrhosis. Liver Int 2018; 38 (08) 1437-1441
  CrossrefPubMedGoogle Scholar
• 27 De Robertis E, Kozek-Langenecker SA, Tufano R, Romano GM, Piazza O, Zito Marinosci G. Coagulopathy induced by acidosis, hypothermia and hypocalcaemia in severe bleeding. Minerva Anestesiol 2015; 81 (01) 65-75
  PubMedGoogle Scholar
• 28 Scheiner B, Lindner G, Reiberger T. , et al. Acid-base disorders in liver disease. J Hepatol 2017; 67 (05) 1062-1073
  CrossrefPubMedGoogle Scholar
• 29 Basili S, Raparelli V, Napoleone L. , et al. Platelet count does not predict bleeding in cirrhotic patients: results from the PRO-LIVER study. Am J Gastroenterol 2018; 113 (03) 368-375
  CrossrefPubMedGoogle Scholar
• 30 Drolz A, Horvatits T, Roedl K. , et al. Coagulation parameters and major bleeding in critically ill patients with cirrhosis. Hepatology 2016; 64 (02) 556-568
  CrossrefPubMedGoogle Scholar
• 31 Li J, Qi X, Deng H. , et al. Association of conventional haemostasis and coagulation tests with the risk of acute upper gastrointestinal bleeding in liver cirrhosis: a retrospective study. Gastroenterol Rep (Oxf) 2016; 4 (04) 315-319
  PubMedGoogle Scholar
• 32 Napolitano G, Iacobellis A, Merla A. , et al. Bleeding after invasive procedures is rare and unpredicted by platelet counts in cirrhotic patients with thrombocytopenia. Eur J Intern Med 2017; 38: 79-82
  CrossrefPubMedGoogle Scholar
• 33 Nadim MK, Durand F, Kellum JA. , et al. Management of the critically ill patient with cirrhosis: a multidisciplinary perspective. J Hepatol 2016; 64 (03) 717-735
  CrossrefPubMedGoogle Scholar
• 34 Sabate A, Dalmau A. Fibrinogen: a clinical update on liver transplantation. Transplant Proc 2015; 47 (10) 2925-2928
  CrossrefPubMedGoogle Scholar
• 35 Intagliata NM, Caldwell SH, Porte RJ, Lisman T. Prediction of bleeding in cirrhosis patients: is the forecast any clearer?. Hepatology 2016; 64 (03) 989-990
  CrossrefPubMedGoogle Scholar
• 36 Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017; 65 (01) 310-335
  CrossrefPubMedGoogle Scholar
• 37 Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5 (03) 419-424
  CrossrefPubMedGoogle Scholar
• 38 Villanueva C, Colomo A, Bosch A. , et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368 (01) 11-21
  CrossrefPubMedGoogle Scholar
• 39 Zimmon DS, Kessler RE. The portal pressure-blood volume relationship in cirrhosis. Gut 1974; 15 (02) 99-101
  CrossrefPubMedGoogle Scholar
• 40 Ewe K. Bleeding after liver biopsy does not correlate with indices of peripheral coagulation. Dig Dis Sci 1981; 26 (05) 388-393
  CrossrefPubMedGoogle Scholar
• 41 Tripodi A, Primignani M, Mannucci PM, Caldwell SH. Changing concepts of cirrhotic coagulopathy. Am J Gastroenterol 2017; 112 (02) 274-281
  CrossrefPubMedGoogle Scholar
• 42 Goodpasture EW. Fibrinolysis and chronic hepatic insufficiency. Bull Johns Hopkins Hosp 1914; 25: 330-336
  PubMedGoogle Scholar
• 43 Brodsky I, Dennis LH. Evaluation of fibrinolysis in hepatic cirrhosis. Relation of serial thrombin time and euglobulin lysis time. Am J Clin Pathol 1966; 45 (01) 61-69
  CrossrefPubMedGoogle Scholar
• 44 Violi F, Ferro D, Basili S. , et al. Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. Gastroenterology 1995; 109 (02) 531-539
  CrossrefPubMedGoogle Scholar
• 45 Ferro D, Celestini A, Violi F. Hyperfibrinolysis in liver disease. Clin Liver Dis 2009; 13 (01) 21-31
  CrossrefPubMedGoogle Scholar
• 46 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 (01) 78-83
  CrossrefPubMedGoogle Scholar
• 47 Colucci M, Binetti BM, Branca MG. , et al. Deficiency of thrombin activatable fibrinolysis inhibitor in cirrhosis is associated with increased plasma fibrinolysis. Hepatology 2003; 38 (01) 230-237
  PubMedGoogle Scholar
• 48 Joist JH. AICF and DIC in liver cirrhosis: expressions of a hypercoagulable state. Am J Gastroenterol 1999; 94 (10) 2801-2803
  PubMedGoogle Scholar
• 49 Kujovich JL. Hemostatic defects in end stage liver disease. Crit Care Clin 2005; 21 (03) 563-587
  CrossrefPubMedGoogle Scholar
• 50 Bezinover D, Dirkmann D, Findlay J. , et al. Perioperative coagulation management in liver transplant recipients. Transplantation 2018; 102 (04) 578-592
  CrossrefPubMedGoogle Scholar
• 51 Ramsay MA, Randall HB, Burton EC. Intravascular thrombosis and thromboembolism during liver transplantation: antifibrinolytic therapy implicated?. Liver Transpl 2004; 10 (02) 310-314
  CrossrefPubMedGoogle Scholar
• 52 Molenaar IQ, Warnaar N, Groen H, Tenvergert EM, Slooff MJ, Porte RJ. Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007; 7 (01) 185-194
  CrossrefPubMedGoogle Scholar
• 53 Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014; (11) CD006640
  PubMedGoogle Scholar
• 54 Pabinger I, Fries D, Schöchl H, Streif W, Toller W. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr 2017; 129 (9-10): 303-316
  CrossrefPubMedGoogle Scholar
• 55 De Gottardi A, Thévenot T, Spahr L. , et al. Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study. Clin Gastroenterol Hepatol 2009; 7 (08) 906-909
  CrossrefPubMedGoogle Scholar
• 56 Puchalski JT, Argento AC, Murphy TE, Araujo KL, Pisani MA. The safety of thoracentesis in patients with uncorrected bleeding risk. Ann Am Thorac Soc 2013; 10 (04) 336-341
  CrossrefPubMedGoogle Scholar
• 57 Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. ; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology 2009; 49 (03) 1017-1044
  CrossrefPubMedGoogle Scholar
• 58 Karvellas CJ, Fix OK, Battenhouse H, Durkalski V, Sanders C, Lee WM. ; U S Acute Liver Failure Study Group. Outcomes and complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study. Crit Care Med 2014; 42 (05) 1157-1167
  CrossrefPubMedGoogle Scholar
• 59 Shah NL, Northup PG, Caldwell SH. A clinical survey of bleeding, thrombosis, and blood product use in decompensated cirrhosis patients. Ann Hepatol 2012; 11 (05) 686-690
  CrossrefPubMedGoogle Scholar
• 60 De Pietri L, Bianchini M, Montalti R. , et al. Thrombelastography-guided blood product use before invasive procedures in cirrhosis with severe coagulopathy: a randomized, controlled trial. Hepatology 2016; 63 (02) 566-573
  CrossrefPubMedGoogle Scholar
• 61 Vaquero J, Fontana RJ, Larson AM. , et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005; 11 (12) 1581-1589
  CrossrefPubMedGoogle Scholar
• 62 Munoz SJ, 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 (01) 103-107
  CrossrefPubMedGoogle Scholar
• 63 Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ, Macik BG. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 2003; 9 (02) 138-143
  CrossrefPubMedGoogle Scholar
• 64 Stravitz RT, Lisman T, Luketic VA. , et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol 2012; 56 (01) 129-136
  CrossrefPubMedGoogle Scholar
• 65 Krisl JC, Meadows HE, Greenberg CS, Mazur JE. Clinical usefulness of recombinant activated factor VII in patients with liver failure undergoing invasive procedures. Ann Pharmacother 2011; 45 (11) 1433-1438
  CrossrefPubMedGoogle Scholar
• 66 Le TV, Rumbak MJ, Liu SS, Alsina AE, van Loveren H, Agazzi S. Insertion of intracranial pressure monitors in fulminant hepatic failure patients: early experience using recombinant factor VII. Neurosurgery 2010; 66 (03) 455-458 , discussion 458
  CrossrefPubMedGoogle Scholar
• 67 Thabut D, Rudler M, Rousseau G, Poynard T. Recombinant activated factor VII in chronic liver diseases: should we be afraid of thromboembolic events?. J Hepatol 2011; 55 (02) 483-485
  CrossrefPubMedGoogle Scholar
• 68 Shah NL, Intagliata NM, Northup PG, Argo CK, Caldwell SH. Procoagulant therapeutics in liver disease: a critique and clinical rationale. Nat Rev Gastroenterol Hepatol 2014; 11 (11) 675-682
  PubMedGoogle Scholar
• 69 Arshad F, Ickx B, van Beem RT. , et al. Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial. BMC Surg 2013; 13: 22
  CrossrefPubMedGoogle Scholar
• 70 Wei AC, Tung-Ping Poon R, Fan ST, Wong J. Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma. Br J Surg 2003; 90 (01) 33-41
  PubMedGoogle Scholar
• 71 Massicotte L, Denault AY, Beaulieu D. , et al. Transfusion rate for 500 consecutive liver transplantations: experience of one liver transplantation center. Transplantation 2012; 93 (12) 1276-1281
  CrossrefPubMedGoogle Scholar
• 72 Kahn SR, Lim W, Dunn AS. , et al. 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: e195S-226S
  CrossrefPubMedGoogle Scholar
• 73 Cook D, Crowther M, Meade M. , et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005; 33 (07) 1565-1571
  CrossrefPubMedGoogle Scholar
• 74 Lim W, Meade M, Lauzier F. , et al; PROphylaxis for ThromboEmbolism in Critical Care Trial Investigators. Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*. Crit Care Med 2015; 43 (02) 401-410
  CrossrefPubMedGoogle Scholar
• 75 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 (07) 1524-1528 , quiz 1680
  CrossrefPubMedGoogle Scholar
• 76 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
  CrossrefPubMedGoogle Scholar
• 77 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 (01) 96-101
  CrossrefPubMedGoogle Scholar
• 78 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8 (09) 800-805
  CrossrefPubMedGoogle Scholar
• 79 Ng KJ, Lee YK, Huang MY, Hsu CY, Su YC. Risks of venous thromboembolism in patients with liver cirrhosis: a nationwide cohort study in Taiwan. J Thromb Haemost 2015; 13 (02) 206-213
  CrossrefPubMedGoogle Scholar
• 80 Stine JG, Niccum BA, Zimmet AN. , et al. Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatitis. Clin Transl Gastroenterol 2018; 9 (03) 140
  CrossrefPubMedGoogle Scholar
• 81 Ambrosino P, Tarantino L, Di Minno G. , et al. The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis. Thromb Haemost 2017; 117 (01) 139-148
  Article in Thieme ConnectPubMedGoogle Scholar
• 82 Søgaard KK, Horváth-Puhó E, Montomoli J, Vilstrup H, Sørensen HT. Cirrhosis is associated with an increased 30-day mortality after venous thromboembolism. Clin Transl Gastroenterol 2015; 6: e97
  CrossrefPubMedGoogle Scholar
• 83 Barbar S, Noventa F, Rossetto V. , et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8 (11) 2450-2457
  CrossrefPubMedGoogle Scholar
• 84 Bogari H, Patanwala AE, Cosgrove R, Katz M. Risk-assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease. Thromb Res 2014; 134 (06) 1220-1223
  CrossrefPubMedGoogle Scholar
• 85 Spyropoulos AC, Anderson Jr FA, FitzGerald G. , et al; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
  CrossrefPubMedGoogle Scholar
• 86 Decousus H, Tapson VF, Bergmann JF. , et al; IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139 (01) 69-79
  CrossrefPubMedGoogle Scholar
• 87 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 (01) 26-32
  CrossrefPubMedGoogle Scholar
• 88 Shatzel J, Dulai PS, Harbin D. , et al. Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis: a single-center retrospective cohort study. J Thromb Haemost 2015; 13 (07) 1245-1253
  CrossrefPubMedGoogle Scholar
• 89 Villa E, Cammà C, Marietta M. , et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260.e4
  CrossrefPubMedGoogle Scholar
• 90 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 (01) 75-82
  CrossrefPubMedGoogle Scholar
• 91 Qi X, De Stefano V, Li H, Dai J, Guo X, Fan D. Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Eur J Intern Med 2015; 26 (01) 23-29
  CrossrefPubMedGoogle Scholar
• 92 Intagliata NM, Henry ZH, Maitland H. , et al. Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when compared to traditional anticoagulation. Dig Dis Sci 2016; 61 (06) 1721-1727
  CrossrefPubMedGoogle Scholar
• 93 Hum J, Shatzel JJ, Jou JH, Deloughery TG. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol 2017; 98 (04) 393-397
  CrossrefPubMedGoogle Scholar
• 94 Intagliata NM, Maitland H, Caldwell SH. Direct oral anticoagulants in cirrhosis. Curr Treat Options Gastroenterol 2016; 14 (02) 247-256
  CrossrefPubMedGoogle Scholar
• 95 Potze W, Lisman T. Issues with monitoring of unfractionated heparin in cirrhosis. Ther Drug Monit 2015; 37 (02) 279-280
  CrossrefPubMedGoogle Scholar
• 96 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 (06) 919-927
  CrossrefPubMedGoogle Scholar
• 97 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 (09) 1823-1829
  CrossrefPubMedGoogle Scholar
• 98 Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis. Hepatology 2015; 61 (04) 1435-1436
  CrossrefPubMedGoogle Scholar
• 99 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 (02) e88390
  CrossrefPubMedGoogle Scholar
• 100 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 (05) 666-673
  CrossrefPubMedGoogle Scholar
• 101 Intagliata NM, Maitland H, Pellitier S, Caldwell SH. Reversal of direct oral anticoagulants for liver transplantation in cirrhosis: a step forward. Liver Transpl 2017; 23 (03) 396-397
  CrossrefPubMedGoogle Scholar
• 102 Siegal DM, Curnutte JT, Connolly SJ. , et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373 (25) 2413-2424
  CrossrefPubMedGoogle Scholar
• 103 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 (02) 660-667
  CrossrefPubMedGoogle Scholar
• 104 Qi X, De Stefano V, Senzolo M, Xu H, Mancuso A. Splanchnic vein thrombosis: etiology, diagnosis, and treatment. Gastroenterol Res Pract 2015; 2015: 506136
  PubMedGoogle Scholar
• 105 Berzigotti A, García-Criado A, Darnell A, García-Pagán JC. Imaging in clinical decision-making for portal vein thrombosis. Nat Rev Gastroenterol Hepatol 2014; 11 (05) 308-316
  CrossrefPubMedGoogle Scholar
• 106 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu EASL Clinical Practice Guidelines: vascular diseases of the liver. J Hepatol 2016; 64 (01) 179-202
  CrossrefPubMedGoogle Scholar
• 107 de Franchis R. ; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63 (03) 743-752
  CrossrefPubMedGoogle Scholar
• 108 Dhar A, Mullish BH, Thursz MR. Anticoagulation in chronic liver disease. J Hepatol 2017; 66 (06) 1313-1326
  CrossrefPubMedGoogle Scholar
• 109 Potze W, Siddiqui MS, Boyett SL. , et al. Preserved hemostatic status in patients with non-alcoholic fatty liver disease. J Hepatol 2016; 65 (05) 980-987
  CrossrefPubMedGoogle Scholar
• 110 Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011; 9 (09) 1713-1723
  CrossrefPubMedGoogle Scholar
• 111 Lin SY, Lin CL, Lin CC, Wang IK, Hsu WH, Kao CH. Risk of acute coronary syndrome and peripheral arterial disease in chronic liver disease and cirrhosis: a nationwide population-based study. Atherosclerosis 2018; 270: 154-159
  CrossrefPubMedGoogle Scholar
• 112 Patel SS, Nabi E, Guzman L. , et al. Coronary artery disease in decompensated patients undergoing liver transplantation evaluation. Liver Transpl 2018; 24 (03) 333-342
  CrossrefPubMedGoogle Scholar
• 113 Patel SS, Guzman L, Lin FP. , et al. Utilization of aspirin and statin in management of coronary artery disease in patients with cirrhosis undergoing liver transplant evaluation. Liver Transpl 2018; 24 (07) 872-880
  CrossrefPubMedGoogle Scholar
• 114 Arshad F, Lisman T, Porte RJ. Hypercoagulability as a contributor to thrombotic complications in the liver transplant recipient. Liver Int 2013; 33 (06) 820-827
  CrossrefPubMedGoogle Scholar