Prediction of Esophageal Variceal Bleeding in Liver Cirrhosis: Is There a Role for Hemostatic Factors?

Abstract

Variceal bleeding is a frequent and ominous complication of liver cirrhosis. Fortunately, primary prophylaxis with β blockers or esophageal band ligation effectively reduces the risk of variceal bleeding and its associated mortality. Periodic endoscopic surveillance of esophageal varices (EV) is currently recommended in every patient with cirrhosis for early detection of EV and initiation of primary variceal bleeding prophylaxis is indicated for high-risk patients. During the last decades several noninvasive tests have emerged, aiming to facilitate access, reduce cost, and avoid unnecessary risk associated with endoscopic EV surveillance. In addition, several hemostatic abnormalities have been described in cirrhosis, and their role in variceal bleeding pathogenesis is yet to be defined. In this article, we review and critically analyze the accuracy of noninvasive EV predictors and utility of hemostatic factors to predict individual variceal bleeding risk. In addition, we summarize available data regarding the therapeutic role of hemostatic factors in primary prevention of variceal bleeding and early recurrence after an initial episode of variceal hemorrhage.

Keywords

variceal bleeding - liver - cirrhosis - hemostasis - blood coagulation - gastrointestinal hemorrhage

• References

• 1 Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362 (9) 823-832
• 2 Turon F, Casu S, Hernández-Gea V, Garcia-Pagán JC. Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol 2013; 27 (5) 649-664
• 3 D'Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999; 19 (4) 475-505
• 4 Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet 2003; 361 (9361) 952-954
• 5 Simonetto DA, Shah VH, Kamath PS. Primary prophylaxis of variceal bleeding. Clin Liver Dis 2014; 18 (2) 335-345
• 6 Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001; 33 (4) 802-807
• 7 de Franchis R ; Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010; 53 (4) 762-768
• 8 Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W ; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46 (3) 922-938
• 9 Moitinho E, Escorsell A, Bandi JC , et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 1999; 117 (3) 626-631
• 10 Bosch J, Abraldes JG, Berzigotti A, García-Pagan JC. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol 2009; 6 (10) 573-582
• 11 Merkel C, Marin R, Angeli P , et al; Gruppo Triveneto per l'Ipertensione Portale. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004; 127 (2) 476-484
• 12 Merli M, Nicolini G, Angeloni S , et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38 (3) 266-272
• 13 Thomopoulos KC, Labropoulou-Karatza C, Mimidis KP, Katsakoulis EC, Iconomou G, Nikolopoulou VN. Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis. Dig Liver Dis 2003; 35 (7) 473-478
• 14 Chalasani N, Imperiale TF, Ismail A , et al. Predictors of large esophageal varices in patients with cirrhosis. Am J Gastroenterol 1999; 94 (11) 3285-3291
• 15 Berzigotti A, Gilabert R, Abraldes JG , et al. Noninvasive prediction of clinically significant portal hypertension and esophageal varices in patients with compensated liver cirrhosis. Am J Gastroenterol 2008; 103 (5) 1159-1167
• 16 Pilette C, Oberti F, Aubé C , et al. Non-invasive diagnosis of esophageal varices in chronic liver diseases. J Hepatol 1999; 31 (5) 867-873
• 17 Schepis F, Cammà C, Niceforo D , et al. Which patients with cirrhosis should undergo endoscopic screening for esophageal varices detection?. Hepatology 2001; 33 (2) 333-338
• 18 Zaman A, Becker T, Lapidus J, Benner K. Risk factors for the presence of varices in cirrhotic patients without a history of variceal hemorrhage. Arch Intern Med 2001; 161 (21) 2564-2570
• 19 Berzigotti A, Seijo S, Arena U , et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013; 144 (1) 102-111.e1
• 20 Sebastiani G, Tempesta D, Fattovich G , et al. Prediction of oesophageal varices in hepatic cirrhosis by simple serum non-invasive markers: results of a multicenter, large-scale study. J Hepatol 2010; 53 (4) 630-638
• 21 Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56 (3) 696-703
• 22 Giannini E, Botta F, Borro P , et al. Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis. Gut 2003; 52 (8) 1200-1205
• 23 Barrera F, Riquelme A, Soza A , et al. Platelet count/spleen diameter ratio for non-invasive prediction of high risk esophageal varices in cirrhotic patients. Ann Hepatol 2009; 8 (4) 325-330
• 24 Agha A, Anwar E, Bashir K, Savarino V, Giannini EG. External validation of the platelet count/spleen diameter ratio for the diagnosis of esophageal varices in hepatitis C virus-related cirrhosis. Dig Dis Sci 2009; 54 (3) 654-660
• 25 Giannini EG, Zaman A, Kreil A , et al. Platelet count/spleen diameter ratio for the noninvasive diagnosis of esophageal varices: results of a multicenter, prospective, validation study. Am J Gastroenterol 2006; 101 (11) 2511-2519
• 26 Ying L, Lin X, Xie ZL, Hu YP, Shi KQ. Performance of platelet count/spleen diameter ratio for diagnosis of esophageal varices in cirrhosis: a meta-analysis. Dig Dis Sci 2012; 57 (6) 1672-1681
• 27 de Mattos AZ, de Mattos AA. Platelet count/spleen diameter ratio: is there sufficient evidence for its use?. Dig Dis Sci 2012; 57 (9) 2473 , author reply 2473–2474
• 28 Schwarzenberger E, Meyer T, Golla V, Sahdala NP, Min AD. Utilization of platelet count spleen diameter ratio in predicting the presence of esophageal varices in patients with cirrhosis. J Clin Gastroenterol 2010; 44 (2) 146-150
• 29 Stefanescu H, Grigorescu M, Lupsor M, Procopet B, Maniu A, Badea R. Spleen stiffness measurement using Fibroscan for the noninvasive assessment of esophageal varices in liver cirrhosis patients. J Gastroenterol Hepatol 2011; 26 (1) 164-170
• 30 Sharma P, Kirnake V, Tyagi P , et al. Spleen stiffness in patients with cirrhosis in predicting esophageal varices. Am J Gastroenterol 2013; 108 (7) 1101-1107
• 31 de Franchis R, Eisen GM, Laine L , et al. Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension. Hepatology 2008; 47 (5) 1595-1603
• 32 de Franchis R. Non-invasive (and minimally invasive) diagnosis of oesophageal varices. J Hepatol 2008; 49 (4) 520-527
• 33 Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48 (5) 835-847
• 34 Vizzutti F, Arena U, Romanelli RG , et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007; 45 (5) 1290-1297
• 35 Bureau C, Metivier S, Peron JM , et al. Transient elastography accurately predicts presence of significant portal hypertension in patients with chronic liver disease. Aliment Pharmacol Ther 2008; 27 (12) 1261-1268
• 36 Lemoine M, Katsahian S, Ziol M , et al. Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis. Aliment Pharmacol Ther 2008; 28 (9) 1102-1110
• 37 Lim JK, Groszmann RJ. Transient elastography for diagnosis of portal hypertension in liver cirrhosis: is there still a role for hepatic venous pressure gradient measurement?. Hepatology 2007; 45 (5) 1087-1090
• 38 Nguyen-Khac E, Saint-Leger P, Tramier B, Coevoet H, Capron D, Dupas JL. Noninvasive diagnosis of large esophageal varices by Fibroscan: strong influence of the cirrhosis etiology. Alcohol Clin Exp Res 2010; 34 (7) 1146-1153
• 39 Colecchia A, Montrone L, Scaioli E , et al. Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis. Gastroenterology 2012; 143 (3) 646-654
• 40 Ruff KC, Sharma VK. Is capsule endoscopy effective for screening and surveillance of esophageal varices in patients with portal hypertension?. Nat Clin Pract Gastroenterol Hepatol 2009; 6 (1) 10-11
• 41 Lu Y, Gao R, Liao Z, Hu LH, Li ZS. Meta-analysis of capsule endoscopy in patients diagnosed or suspected with esophageal varices. World J Gastroenterol 2009; 15 (10) 1254-1258
• 42 Berzigotti A, Bosch J, Boyer TD. Use of noninvasive markers of portal hypertension and timing of screening endoscopy for gastroesophageal varices in patients with chronic liver disease. Hepatology 2014; 59 (2) 729-731
• 43 de Franchis R, Dell'Era A. Invasive and noninvasive methods to diagnose portal hypertension and esophageal varices. Clin Liver Dis 2014; 18 (2) 293-302
• 44 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (6) 878-885
• 45 Weeder PD, Porte RJ, Lisman T. Hemostasis in liver disease: implications of new concepts for perioperative management. Transfus Med Rev 2014; 28 (3) 107-113
• 46 Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?. J Hepatol 2011; 55 (6) 1415-1427
• 47 Pereira J, Accatino L, Alfaro J, Brahm J, Hidalgo P, Mezzano D. Platelet autoantibodies in patients with chronic liver disease. Am J Hematol 1995; 50 (3) 173-178
• 48 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
• 49 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
• 50 Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98 (9) 2730-2735
• 51 Stockschlaeder M, Schneppenheim R, Budde U. Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis. Blood Coagul Fibrinolysis 2014; 25 (3) 206-216
• 52 Giannini EG, Greco A, Marenco S, Andorno E, Valente U, Savarino V. Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol 2010; 8 (10) 899-902 , quiz e109
• 53 Tripodi A, Primignani M, Chantarangkul V , et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology 2006; 44 (2) 440-445
• 54 Violi F, Ferro D. Clotting activation and hyperfibrinolysis in cirrhosis: implication for bleeding and thrombosis. Semin Thromb Hemost 2013; 39 (4) 426-433
• 55 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
• 56 Valla DC, Rautou PE. The coagulation system in patients with end-stage liver disease. Liver Int 2015; 35 (Suppl. 01) 139-144
• 57 Krishnan A, Srinivasan V, Venkataraman J. Variceal recurrence, rebleeding rates and alterations in clinical and laboratory parameters following post-variceal obliteration using endoscopic sclerotherapy. J Dig Dis 2012; 13 (11) 596-600
• 58 Krige JE, Kotze UK, Distiller G, Shaw JM, Bornman PC. Predictive factors for rebleeding and death in alcoholic cirrhotic patients with acute variceal bleeding: a multivariate analysis. World J Surg 2009; 33 (10) 2127-2135
• 59 Chau TN, Chan YW, Patch D, Tokunaga S, Greenslade L, Burroughs AK. Thrombelastographic changes and early rebleeding in cirrhotic patients with variceal bleeding. Gut 1998; 43 (2) 267-271
• 60 Primignani M, Dell'Era A, Bucciarelli P , et al. High-D-dimer plasma levels predict poor outcome in esophageal variceal bleeding. Dig Liver Dis 2008; 40 (11) 874-881
• 61 McKee RF, Hodson S, Dawes J, Garden OJ, Carter DC. Plasma concentrations of endogenous heparinoids in portal hypertension. Gut 1992; 33 (11) 1549-1552
• 62 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 (4) 463-470
• 63 Goulis J, Patch D, Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet 1999; 353 (9147) 139-142
• 64 Basili S, Ferro D, Violi F. Endotoxaemia, hyperfibrinolysis, and bleeding in cirrhosis. Lancet 1999; 353 (9158) 1102
• 65 Hou MC, Lin HC, Liu TT , et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004; 39 (3) 746-753
• 66 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 (2) 531-539
• 67 Basili S, Raparelli V, Violi F. The coagulopathy of chronic liver disease: is there a causal relationship with bleeding? Yes. Eur J Intern Med 2010; 21 (2) 62-64
• 68 Tripodi A, Primignani M, Chantarangkul V , et al. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int 2013; 33 (3) 362-367
• 69 Tripodi A, Chantarangkul V, Primignani M , et al. Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med 2012; 7 (2) 139-144
• 70 Martí-Carvajal AJ, Karakitsiou DE, Salanti G. Human recombinant activated factor VII for upper gastrointestinal bleeding in patients with liver diseases. Cochrane Database of Systematic Reviews 2012; (3) No.: CD004887
• 71 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 (8) 716-724
• 72 Afdhal NH, Dusheiko GM, Giannini EG , et al. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy. Gastroenterology 2014; 146 (2) 442-52.e1
• 73 de Franchis R, Arcidiacono PG, Carpinelli L , et al. Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian Endoscopic Club. Hepatology 1993; 18 (5) 1102-1107
• 74 Ozal E, Kuralay E, Bingöl H, Cingöz F, Ceylan S, Tatar H. Does tranexamic acid reduce desmopressin-induced hyperfibrinolysis?. J Thorac Cardiovasc Surg 2002; 123 (3) 539-543
• 75 Calvaruso V, Maimone S, Gatt A , et al. Coagulation and fibrosis in chronic liver disease. Gut 2008; 57 (12) 1722-1727
• 76 Thachil J. The contribution of megakaryocytes to liver fibrosis. Gut 2009; 58 (11) 1565