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Semin Thromb Hemost 2015; 41(05): 481-487
DOI: 10.1055/s-0035-1550438
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Francisco Barrera
1   Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
,
Pamela Zúñiga
2   Departamento de Oncología-Hematología, Escuela de Medicina, Pontificia Universidad Católica, Santiago, Chile
,
Marco Arrese
1   Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
› Author Affiliations
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Publication History

Publication Date:
06 June 2015 (online)

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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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet 2003; 361 (9361) 952-954
    CrossrefPubMedGoogle Scholar
  • 5 Simonetto DA, Shah VH, Kamath PS. Primary prophylaxis of variceal bleeding. Clin Liver Dis 2014; 18 (2) 335-345
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 21 Castera L, Pinzani M, Bosch J. Non invasive evaluation of portal hypertension using transient elastography. J Hepatol 2012; 56 (3) 696-703
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 32 de Franchis R. Non-invasive (and minimally invasive) diagnosis of oesophageal varices. J Hepatol 2008; 49 (4) 520-527
    CrossrefPubMedGoogle Scholar
  • 33 Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 2008; 48 (5) 835-847
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 44 Lisman T, Porte RJ. Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116 (6) 878-885
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 54 Violi F, Ferro D. Clotting activation and hyperfibrinolysis in cirrhosis: implication for bleeding and thrombosis. Semin Thromb Hemost 2013; 39 (4) 426-433
    Article in Thieme ConnectPubMedGoogle Scholar
  • 55 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
    CrossrefPubMedGoogle Scholar
  • 56 Valla DC, Rautou PE. The coagulation system in patients with end-stage liver disease. Liver Int 2015; 35 (Suppl. 01) 139-144
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 63 Goulis J, Patch D, Burroughs AK. Bacterial infection in the pathogenesis of variceal bleeding. Lancet 1999; 353 (9147) 139-142
    CrossrefPubMedGoogle Scholar
  • 64 Basili S, Ferro D, Violi F. Endotoxaemia, hyperfibrinolysis, and bleeding in cirrhosis. Lancet 1999; 353 (9158) 1102
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 75 Calvaruso V, Maimone S, Gatt A , et al. Coagulation and fibrosis in chronic liver disease. Gut 2008; 57 (12) 1722-1727
    CrossrefPubMedGoogle Scholar
  • 76 Thachil J. The contribution of megakaryocytes to liver fibrosis. Gut 2009; 58 (11) 1565
    PubMedGoogle Scholar