Semin Thromb Hemost 2020; 46(06): 656-664
DOI: 10.1055/s-0040-1714205
Review Article

Incidence of Bleeding and Thrombosis in Patients with Liver Disease

Lara N. Roberts
1   Department of Haematological Medicine, King's Thrombosis Centre, London, United Kingdom
,
William Bernal
2   Liver Intensive Therapy Unit, Institute of Liver Studies, King’s College Hospital, London, United Kingdom
› Author Affiliations

Abstract

Historically, liver disease has been associated with a bleeding tendency. Global hemostatic assays have demonstrated that hemostasis is overall rebalanced, in both acute liver failure and chronic liver disease. It is now recognized that many bleeding events in chronic liver disease are mediated by portal hypertension rather than an underlying hemostatic defect. This is acknowledged in recent guidelines, which recommend against coagulation testing prior to low risk procedures in this patient group, with avoidance also of attempts at correction of prolonged coagulation times. Over time, the incidence of bleeding events has decreased in both chronic liver disease and acute liver failure, with improved supportive care, targeted treatments for underlying cause of liver disease, and the advent of liver transplantation. Concurrently, there has been increased recognition of the risk of thrombosis in chronic liver disease, with a predilection for the splanchnic vasculature. This review describes the incidence of bleeding and thrombosis in chronic liver disease and acute liver failure, including the periprocedural and liver transplantation setting.



Publication History

Article published online:
05 August 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1 (02) 150-161
  • 2 O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology 2019; 157 (01) 34-43.e1
  • 3 Basili S, Raparelli V, Napoleone L. , et al. PRO-LIVER Collaborators. Platelet count does not predict bleeding in cirrhotic patients: results from the PRO-LIVER study. Am J Gastroenterol 2018; 113 (03) 368-375
  • 4 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
  • 5 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
  • 6 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
  • 7 Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362 (09) 823-832
  • 8 Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004; 40 (03) 652-659
  • 9 Merli M, Nicolini G, Angeloni S. , et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38 (03) 266-272
  • 10 Zoli M, Merkel C, Magalotti D. , et al. Natural history of cirrhotic patients with small esophageal varices: a prospective study. Am J Gastroenterol 2000; 95 (02) 503-508
  • 11 de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis 2001; 5 (03) 645-663
  • 12 Kalafateli M, Triantos CK, Nikolopoulou V, Burroughs A. Non-variceal gastrointestinal bleeding in patients with liver cirrhosis: a review. Dig Dis Sci 2012; 57 (11) 2743-2754
  • 13 Rodríguez-Castro KI, Antonello A, Ferrarese A. Spontaneous bleeding or thrombosis in cirrhosis: what should be feared the most?. World J Hepatol 2015; 7 (14) 1818-1827
  • 14 Schepis F, Turco L, Bianchini M, Villa E. Prevention and management of bleeding risk related to invasive procedures in cirrhosis. Semin Liver Dis 2018; 38 (03) 215-229
  • 15 Spyropoulos AC, Brohi K, Caprini J. , et al. SSC Subcommittee on Perioperative and Critical Care Thrombosis and Haemostasis of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient-specific thromboembolic risk. J Thromb Haemost 2019; 17 (11) 1966-1972
  • 16 Patel IJ, Rahim S, Davidson JC. , et al. Society of Interventional Radiology Consensus Guidelines for the Periprocedural Management of Thrombotic and Bleeding Risk in Patients Undergoing Percutaneous Image-Guided Interventions-Part II: recommendations: endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol 2019; 30 (08) 1168-1184.e1
  • 17 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
  • 18 Vuyyuru SK, Singh AD, Gamanagatti SR, Rout G, Gunjan D. , Shalimar. A randomized control trial of thromboelastography-guided transfusion in cirrhosis for high-risk invasive liver-related procedures. Dig Dis Sci 2020; 65 (07) 2104-2111
  • 19 Pache I, Bilodeau M. Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease. Aliment Pharmacol Ther 2005; 21 (05) 525-529
  • 20 McVay PA, Toy PT. Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities. Transfusion 1991; 31 (02) 164-171
  • 21 Patel MD, Joshi SD. Abnormal preprocedural international normalized ratio and platelet counts are not associated with increased bleeding complications after ultrasound-guided thoracentesis. AJR Am J Roentgenol 2011; 197 (01) W164-8
  • 22 Hibbert RM, Atwell TD, Lekah A. , et al. Safety of ultrasound-guided thoracentesis in patients with abnormal preprocedural coagulation parameters. Chest 2013; 144 (02) 456-463
  • 23 Fisher NC, Mutimer DJ. Central venous cannulation in patients with liver disease and coagulopathy—a prospective audit. Intensive Care Med 1999; 25 (05) 481-485
  • 24 Mumtaz H, Williams V, Hauer-Jensen M. , et al. Central venous catheter placement in patients with disorders of hemostasis. Am J Surg 2000; 180 (06) 503-505 , discussion 506
  • 25 Tercan F, Ozkan U, Oguzkurt L. US-guided placement of central vein catheters in patients with disorders of hemostasis. Eur J Radiol 2008; 65 (02) 253-256
  • 26 McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Gastroenterology 1990; 99 (05) 1396-1400
  • 27 Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986; 2 (02) 165-173
  • 28 Seeff LB, Everson GT, Morgan TR. , et al. HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8 (10) 877-883
  • 29 Zakaria N, Knisely A, Portmann B. , et al. Acute sickle cell hepatopathy represents a potential contraindication for percutaneous liver biopsy. Blood 2003; 101 (01) 101-103
  • 30 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
  • 31 Vieira da Rocha EC, D'Amico EA, Caldwell SH. , et al. A prospective study of conventional and expanded coagulation indices in predicting ulcer bleeding after variceal band ligation. Clin Gastroenterol Hepatol 2009; 7 (09) 988-993
  • 32 Lim EJ, Gow PJ, Angus PW. Endoscopic variceal ligation for primary prophylaxis of esophageal variceal hemorrhage in pre-liver transplant patients. Liver Transpl 2009; 15 (11) 1508-1513
  • 33 Medina JB, Andrade NS, de Paula Eduardo F. , et al. Bleeding during and after dental extractions in patients with liver cirrhosis. Int J Oral Maxillofac Surg 2018; 47 (12) 1543-1549
  • 34 Bismuth H, Castaing D, Ericzon BG. , et al. Hepatic transplantation in Europe: first report of the European Liver Transplant Registry. Lancet 1987; 2 (8560): 674-676
  • 35 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
  • 36 Massicotte L, Thibeault L, Roy A. Classical notions of coagulation revisited in relation with blood losses, transfusion rate for 700 consecutive liver transplantations. Semin Thromb Hemost 2015; 41 (05) 538-546
  • 37 Parikh A, Washburn KW, Matsuoka L. , et al. A multicenter study of 30 days complications after deceased donor liver transplantation in the model for end-stage liver disease score era. Liver Transpl 2015; 21 (09) 1160-1168
  • 38 Bhutiani N, Jones CM, Cannon RM. , et al. Assessing relative cost of complications following orthotopic liver transplant. Clin Transplant 2018; 32 (04) e13209
  • 39 Cywinski JB, Alster JM, Miller C, Vogt DP, Parker BM. Prediction of intraoperative transfusion requirements during orthotopic liver transplantation and the influence on postoperative patient survival. Anesth Analg 2014; 118 (02) 428-437
  • 40 Pustavoitau A, Lesley M, Ariyo P. , et al. Predictive modeling of massive transfusion requirements during liver transplantation and its potential to reduce utilization of blood bank resources. Anesth Analg 2017; 124 (05) 1644-1652
  • 41 Schrem H, Klußmann A, Focken M. , et al. Post-operative hemorrhage after liver transplantation: risk factors and long-term outcome. Ann Transplant 2016; 21: 46-55
  • 42 Afdhal NH, Giannini EG, Tayyab G. , et al. ELEVATE Study Group. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med 2012; 367 (08) 716-724
  • 43 Peck-Radosavljevic M, Simon K, Iacobellis A. , et al. Lusutrombopag for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures (L-PLUS 2). Hepatology 2019; 70 (04) 1336-1348
  • 44 Terrault N, Chen Y-C, Izumi N. , et al. Avatrombopag before procedures reduces need for platelet transfusion in patients with chronic liver disease and thrombocytopenia. Gastroenterology 2018; 155 (03) 705-718
  • 45 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
  • 46 Habib M, Roberts LN, Patel RK, Wendon J, Bernal W, Arya R. Evidence of rebalanced coagulation in acute liver injury and acute liver failure as measured by thrombin generation. Liver Int 2014; 34 (05) 672-678
  • 47 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
  • 48 Stravitz RT, Ellerbe C, Durkalski V. , et al. Acute Liver Failure Study Group. Bleeding complications in acute liver failure. Hepatology 2018; 67 (05) 1931-1942
  • 49 Gazzard BG, Portmann B, Murray-Lyon IM, Williams R. Causes of death in fulminant hepatic failure and relationship to quantitative histological assessment of parenchymal damage. Q J Med 1975; 44 (176) 615-626
  • 50 Ollivier-Hourmand I, Allaire M, Goutte N. , et al. French Network for Vascular Disorders of the Liver. The epidemiology of Budd-Chiari syndrome in France. Dig Liver Dis 2018; 50 (09) 931-937
  • 51 Ageno W, Dentali F, Pomero F. , et al. Incidence rates and case fatality rates of portal vein thrombosis and Budd-Chiari syndrome. Thromb Haemost 2017; 117 (04) 794-800
  • 52 Ki M, Choi HY, Kim K-A, Kim BH, Jang ES, Jeong SH. Incidence, prevalence and complications of Budd-Chiari syndrome in South Korea: a nationwide, population-based study. Liver Int 2016; 36 (07) 1067-1073
  • 53 Rajani R, Björnsson E, Bergquist A. , et al. The epidemiology and clinical features of portal vein thrombosis: a multicentre study. Aliment Pharmacol Ther 2010; 32 (09) 1154-1162
  • 54 Montenovo M, Rahnemai-Azar A, Reyes J, Perkins J. Clinical impact and risk factors for portal vein thrombosis for patients on wait list for liver transplant. Exp Clin Transplant 2018; 16 (02) 166-171
  • 55 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
  • 56 Violi F, Corazza GR, Caldwell SH. , et al. PRO-LIVER Collaborative Group. Incidence and recurrence of portal vein thrombosis in cirrhotic patients. Thromb Haemost 2019; 119 (03) 496-499
  • 57 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
  • 58 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
  • 59 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
  • 60 Ali M, Ananthakrishnan AN, McGinley EL, Saeian K. Deep vein thrombosis and pulmonary embolism in hospitalized patients with cirrhosis: a nationwide analysis. Dig Dis Sci 2011; 56 (07) 2152-2159
  • 61 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
  • 62 Ocak G, Vossen CY, Verduijn M. , et al. Risk of venous thrombosis in patients with major illnesses: results from the MEGA study. J Thromb Haemost 2013; 11 (01) 116-123
  • 63 Bezinover D, Iskandarani K, Chinchilli V. , et al. Autoimmune conditions are associated with perioperative thrombotic complications in liver transplant recipients: a UNOS database analysis. BMC Anesthesiol 2016; 16 (01) 26
  • 64 Bekker J, Ploem S, de Jong KP. Early hepatic artery thrombosis after liver transplantation: a systematic review of the incidence, outcome and risk factors. Am J Transplant 2009; 9 (04) 746-757
  • 65 Zahr Eldeen F, Roll GR, Derosas C. , et al. Preoperative thromboelastography as a sensitive tool predicting those at risk of developing early hepatic artery thrombosis after adult liver transplantation. Transplantation 2016; 100 (11) 2382-2390
  • 66 Capelli R, Allard MA, Ciacio O. , et al. Late hepatic artery thrombosis after liver transplantation: which strategy? A single-center retrospective study. Transpl Int 2019; 32 (05) 473-480
  • 67 Mourad MM, Liossis C, Gunson BK. , et al. Etiology and management of hepatic artery thrombosis after adult liver transplantation. Liver Transpl 2014; 20 (06) 713-723
  • 68 Settmacher U, Nüssler NC, Glanemann M. , et al. Venous complications after orthotopic liver transplantation. Clin Transplant 2000; 14 (03) 235-241
  • 69 Blasi A, Hernandez V, Fernandez J. , et al. Venous thrombotic events after liver transplantation. Clin Appl Thromb Hemost 2018; 24 (02) 317-322
  • 70 Jia YP, Lu Q, Gong S. , et al. Postoperative complications in patients with portal vein thrombosis after liver transplantation: evaluation with Doppler ultrasonography. World J Gastroenterol 2007; 13 (34) 4636-4640
  • 71 Ishitani M, Angle J, Bickston S, Caldwell S, Isaacs R, Pruett T. Liver transplantation: incidence and management of deep venous thrombosis and pulmonary emboli. Transplant Proc 1997; 29 (07) 2861-2863
  • 72 Cherian TP, Chiu K, Gunson B. , et al. Pulmonary thromboembolism in liver transplantation: a retrospective review of the first 25 years. Transpl Int 2010; 23 (11) 1113-1119
  • 73 Annamalai A, Kim I, Sundaram V, Klein A. Incidence and risk factors of deep vein thrombosis after liver transplantation. Transplant Proc 2014; 46 (10) 3564-3569
  • 74 Salami A, Qureshi W, Kuriakose P, Moonka D, Yoshida A, Abouljoud M. Frequency and predictors of venous thromboembolism in orthotopic liver transplant recipients: a single-center retrospective review. Transplant Proc 2013; 45 (01) 315-319
  • 75 Gould MK, Garcia DA, Wren SM. , et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e227S-e277S
  • 76 North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319 (15) 983-989