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Semin Thromb Hemost 2020; 46(06): 682-692
DOI: 10.1055/s-0040-1715451
Review Article

Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease

Saro Khemichian
1   Division of Gastrointestinal and Liver Diseases, Keck Medicine of University of Southern California, Los Angeles, California
,
Norah A. Terrault
1   Division of Gastrointestinal and Liver Diseases, Keck Medicine of University of Southern California, Los Angeles, California
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Abstract

Thrombocytopenia is one of the most common hematologic complications in cirrhosis. Despite limited data linking platelet count and bleeding risk in patients with cirrhosis, the use of platelets transfusions for invasive procedures has been a common practice. Recently, thrombopoietin (TPO) receptor agonists have been approved for use in patients with chronic liver disease (CLD) undergoing invasive procedures. The aim of this study was to review current literature on bleeding risk in patients with cirrhosis and the use of platelet transfusions and TPO receptor agonists in the context of invasive procedures. PubMed search was conducted to find articles relating to cirrhosis, thrombocytopenia, and new novel treatments for this condition. Search terms included CLD, cirrhosis, thrombocytopenia, bleeding, thrombosis, coagulopathy, hemostasis, and TPO receptor agonists. Romiplostim, eltrombopag, avatrombopag, and lusutrombopag are approved TPO receptor agonists, with avatrombopag and lusutrombopag specifically approved for use in patients with CLD undergoing invasive procedures. In patients with platelet counts < 50,000/mm3, avatrombopag and lusutrombopag increased the platelet counts above this threshold in the majority of treated patients and reduced the frequency of platelet transfusions. At the approved doses, incidence of thrombosis was not increased and therapies were well tolerated. Studies were not powered to assess whether risk of bleeding complications was reduced and the fundamental question of whether correction of thrombocytopenia is warranted in patients undergoing invasive procedures remains unanswered. The use of TPO receptor agonists has resulted in less requirement for platelet transfusions. In patients with cirrhosis undergoing invasive procedures for whom platelet transfusion is planned, TPO receptor agonists are an alternative and avoid the risks associated with transfusions. However, there is need for a thoughtful approach to manage bleeding risk in patients with cirrhosis undergoing procedures, with the consideration of a comprehensive hemostatic profile, the severity of portal hypertension, and the complexity of the invasive procedure to guide decisions regarding transfusions or use of TPO receptor agonists.

Keywords

cirrhosis - avatrombopag - lusutrombopag - hemostasis - bleeding - thromboelastography - portal vein thrombosis


Publication History

Article published online:
20 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
    CrossrefPubMedGoogle Scholar
  • 2 Leonardi F, Maria N, Villa E. Anticoagulation in cirrhosis: a new paradigm?. Clin Mol Hepatol 2017; 23 (01) 13-21
    CrossrefPubMedGoogle Scholar
  • 3 Intagliata NM, Caldwell SH, Tripodi A. Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis. Gastroenterology 2019; 156 (06) 1582-1599.e1
    CrossrefPubMedGoogle Scholar
  • 4 O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA clinical practice update: coagulation in cirrhosis. Gastroenterology 2019; 157 (01) 34-43.e1
    CrossrefPubMedGoogle Scholar
  • 5 Afdhal N, McHutchison J, Brown R. , et al. Thrombocytopenia associated with chronic liver disease. J Hepatol 2008; 48 (06) 1000-1007
    CrossrefPubMedGoogle Scholar
  • 6 Bashour FN, Teran JC, Mullen KD. Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease. Am J Gastroenterol 2000; 95 (10) 2936-2939
    CrossrefPubMedGoogle Scholar
  • 7 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 (03) 173-178
    CrossrefPubMedGoogle Scholar
  • 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 (01) 53-61
    CrossrefPubMedGoogle Scholar
  • 9 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
    CrossrefPubMedGoogle Scholar
  • 10 Li J, Han B, Li H. , et al. Association of coagulopathy with the risk of bleeding after invasive procedures in liver cirrhosis. Saudi J Gastroenterol 2018; 24 (04) 220-227
    CrossrefPubMedGoogle Scholar
  • 11 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
  • 12 Cocero N, Bezzi M, Martini S, Carossa S. Oral surgical treatment of patients with chronic liver disease: assessments of bleeding and its relationship with thrombocytopenia and blood coagulation parameters. J Oral Maxillofac Surg 2017; 75 (01) 28-34
    CrossrefPubMedGoogle Scholar
  • 13 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
    CrossrefPubMedGoogle Scholar
  • 14 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
  • 15 Cerini F, Gonzalez JM, Torres F. , et al. Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study. Hepatology 2015; 62 (02) 575-583
    CrossrefPubMedGoogle Scholar
  • 16 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
  • 17 Shiha G, Ibrahim A, Helmy A. , et al. Asian-Pacific Association for the Study of the Liver (APASL) consensus guidelines on invasive and non-invasive assessment of hepatic fibrosis: a 2016 update. Hepatol Int 2017; 11 (01) 1-30
    CrossrefPubMedGoogle Scholar
  • 18 Brown Jr RS. Current management of thrombocytopenia in chronic liver disease. Gastroenterol Hepatol (N Y) 2019; 15 (03) 155-157
    PubMedGoogle Scholar
  • 19 Northup P, Reutemann B. Management of coagulation and anticoagulation in liver transplantation candidates. Liver Transpl 2018; 24 (08) 1119-1132
    CrossrefPubMedGoogle Scholar
  • 20 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
  • 21 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 2019
    Google Scholar
  • 22 Rocha LL, Neto AS, Pessoa CMS. , et al. Comparison of three transfusion protocols prior to central venous catheterization in patients with cirrhosis: a randomized controlled trial. J Thromb Haemost 2019
    Google Scholar
  • 23 Davis JPE, Northup PG, Caldwell SH, Intagliata NM. Viscoelastic testing in liver disease. Ann Hepatol 2018; 17 (02) 205-213
    CrossrefPubMedGoogle Scholar
  • 24 Aubron C, Flint AW, Bailey M. , et al. Is platelet transfusion associated with hospital-acquired infections in critically ill patients?. Crit Care 2017; 21 (01) 2
    CrossrefPubMedGoogle Scholar
  • 25 Tinegate H, Birchall J, Gray A. , et al; BCSH Blood Transfusion Task Force. Guideline on the investigation and management of acute transfusion reactions. Prepared by the BCSH Blood Transfusion Task Force. Br J Haematol 2012; 159 (02) 143-153
    CrossrefPubMedGoogle Scholar
  • 26 Pereboom IT, de Boer MT, Haagsma EB, Hendriks HG, Lisman T, Porte RJ. Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury. Anesth Analg 2009; 108 (04) 1083-1091
    CrossrefPubMedGoogle Scholar
  • 27 Brown Jr RS. Review article: a pharmacoeconomic analysis of thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther 2007; 26 (Suppl. 01) 41-48
    PubMedGoogle Scholar
  • 28 Elsaid MI, Rustgi VK, Loo N. , et al. The burden associated with thrombocytopenia and platelet transfusions among patients with chronic liver disease. J Med Econ 2020; 23 (04) 378-385
    CrossrefPubMedGoogle Scholar
  • 29 Gordon SC, Pockros PJ, Terrault NA. , et al. Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection. Hepatology 2012; 56 (05) 1651-1660
    CrossrefPubMedGoogle Scholar
  • 30 Nplate (Package Insert). Thousand Oaks, CA: Amgen Inc; 2018
    Google Scholar
  • 31 Casanovas Taltavull T, Peña-Cala MC. Romiplostim therapy as a second-line treatment before splenectomy for refractory immune thrombocytopenia in a cirrhotic patient with iatrogenic Cushing syndrome secondary to corticosteroids. Clin Case Rep 2017; 5 (02) 159-163
    CrossrefPubMedGoogle Scholar
  • 32 Buccoliero G, Urbano T, Massa P, Resta F, Pisconti S. Romiplostim for severe thrombocytopenia in the treatment of chronic hepatitis C virus infection: a new option for clinicians?. New Microbiol 2014; 37 (01) 97-101
    PubMedGoogle Scholar
  • 33 Voican CS, Naveau S, Perlemuter G. Successful antiviral therapy for hepatitis C virus-induced cirrhosis after an increase in the platelet count with romiplostim: two case reports. Eur J Gastroenterol Hepatol 2012; 24 (12) 1455-1458
    CrossrefPubMedGoogle Scholar
  • 34 Castellote J, Girbau A, Arajol C, Xiol X. Romiplostim in chronic liver disease with severe thrombocytopenia undergoing an elective invasive procedure. Rev Esp Enferm Dig 2011; 103 (10) 556
    CrossrefPubMedGoogle Scholar
  • 35 Moussa MM, Mowafy N. Preoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis. J Gastroenterol Hepatol 2013; 28 (02) 335-341
    CrossrefPubMedGoogle Scholar
  • 36 Promacta (Package Insert). East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018
    Google Scholar
  • 37 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 (02) 442-52.e1
    CrossrefPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Kuter DJ, Allen LF. Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled phase 1 studies. Br J Haematol 2018; 183 (03) 466-478
    CrossrefPubMedGoogle Scholar
  • 40 Abdela J. Current advance in thrombopoietin receptor agonists in the management of thrombocytopenia associated with chronic liver disease: focus on avatrombopag. Clin Med Insights Blood Disord 2019; 12: X19875105
    CrossrefPubMedGoogle Scholar
  • 41 Doptelet (Package Insert). Durham, NC: Dova Pharmaceuticals Inc; 2018
    Google Scholar
  • 42 Terrault N, Chen YC, 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
    CrossrefPubMedGoogle Scholar
  • 43 Mulpleta (Package Insert). Florham Park, NJ: Shionogi Inc.; 2018
    Google Scholar
  • 44 Kim ES. Lusutrombopag: First Global Approval. Drugs 2016; 76 (01) 155-158
    CrossrefPubMedGoogle Scholar
  • 45 Hidaka H, Kurosaki M, Tanaka H. , et al. Lusutrombopag reduces need for platelet transfusion in patients with thrombocytopenia undergoing invasive procedures. Clin Gastroenterol Hepatol 2019; 17 (06) 1192-1200
    CrossrefPubMedGoogle Scholar
  • 46 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
    CrossrefPubMedGoogle Scholar
  • 47 Hassanein T, Gogineni R, Ochai T, Kano T. Lusutrombopag for the Managment of Thrombocytopenia in Chronic Liver Disease Patients with Comorbid Obesity or Diabetes. Hepatology 2019; 70 (Suppl. 01) 1093A
    PubMedGoogle Scholar
  • 48 Takada H, Kurosaki M, Nakanishi H. , et al. Real-life experience of lusutrombopag for cirrhotic patients with low platelet counts being prepared for invasive procedures. PLoS One 2019; 14 (02) e0211122
    CrossrefPubMedGoogle Scholar
  • 49 Taniki N, Nakamoto N. , K Y. Effectiveness and Safety of Thrombopoietin-Receptor Agonist Lusutrombopag for Chronic Liver Disease Patients Who Undergo Elective Invasive Procedures: Results from a Real-World, Multicenter Study. Hepatology 2019; 70 (Suppl. 01) 265A
    PubMedGoogle Scholar
  • 50 Uojima H, Arase Y, Itokawa N. , et al. Relationship between response to lusutrombopag and splenic volume. World J Gastroenterol 2018; 24 (46) 5271-5279
    CrossrefPubMedGoogle Scholar
  • 51 Loffredo L, Violi F. Thrombopoietin receptor agonists and risk of portal vein thrombosis in patients with liver disease and thrombocytopenia: a meta-analysis. Dig Liver Dis 2019; 51 (01) 24-27
    CrossrefPubMedGoogle Scholar
  • 52 LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012
    Google Scholar
  • 53 Jurczak W, Chojnowski K, Mayer J. , et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol 2018; 183 (03) 479-490
    CrossrefPubMedGoogle Scholar
  • 54 Sato S, Miyake T, Kataoka M. , et al. Efficacy of repeated lusutrombopag administration for thrombocytopenia in a patient scheduled for invasive hepatocellular carcinoma treatment. Intern Med 2017; 56 (21) 2887-2890
    CrossrefPubMedGoogle Scholar
  • 55 Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel J B. Thrombopoietin receptor agonists: ten years later. Haematologica 2019; 104 (06) 1112-1123
    CrossrefPubMedGoogle Scholar