Thrombocytopenia in Chronic Liver Disease
The Epidemiology and Pathophysiology of Thrombocytopenia in Chronic Liver Disease
Chronic liver disease affects approximately 7.4 million people in the US.1–4 Among patients with liver disease, the incidence of thrombocytopenia is approximately 6% in those without cirrhosis and approximately 70% among those with cirrhosis.1–4 Mild to moderate thrombocytopenia, defined as a platelet count of 50-150 x 109/L, rarely causes spontaneous bleeding during invasive procedures.1–4 However, severe thrombocytopenia, defined as less than 50 x 1099/L, significantly increases the bleeding risk and may even lead to the cancellation of invasive procedures.1–4
Thrombocytopenia is associated with a significant disease burden.5 Direct costs of thrombocytopenia are caused by the need for blood monitoring, periprocedure hospital stays, therapy required to raise the platelet count, complications of therapy, and inadequate therapy for low platelet counts.5 Indirect costs of thrombocytopenia include costs for disability, increased time away from work, decreased quality of life, increased procedures as a result of inadequate therapy, morbidity from untreated acute problems, or postponed therapy for chronic conditions.5 Thrombopoietin, the hormone that regulates the production of platelets, is primarily produced by hepatocytes, including both parenchymal and endothelial cells, and is secreted into the bloodstream at a constant rate.6–9
Normal thrombopoiesis is regulated via a feedback mechanism, by which low platelet counts lead to higher thrombopoietin levels due to decreased platelet degradation.2,9,10 The resulting increased platelet mass binds increasing amounts of thrombopoietin, thereby reducing the amount of free thrombopoietin.2,9,10 Thrombocytopenia in cirrhosis develops as the result of a multifactorial process that comprises reduced hepatic production of thrombopoietin as well as reduced bone marrow production.2,9,10 The decreased production of thrombopoietin can also be mediated by viruses, chronic alcohol abuse, nutritional deficiencies, medication, bone marrow failure, and marrow neoplastic infiltration.10 The prevalence and severity of thrombocytopenia correlate with and parallel the severity of underlying liver disease—particularly, the extent of fibrosis.2,9,10
The Bleeding Risks in Thrombocytopenia Associated with Chronic Liver Disease
While the bleeding risk is much higher in patients with severe thrombocytopenia, the relative bleeding risk is low for thoracentesis, paracentesis, endoscopy, upper GI endoscopy, and colonoscopy.11 A medium risk of bleeding exists in patients with chronic liver disease for liver biopsy, bronchoscopy, ethanol ablation, and chemoembolization for hepatocellular carcinoma.11 Finally, biliary interventions, dental procedures, transjugular intrahepatic portosystemic shunt, laparoscopic interventions, nephrostomy tube placement, radiofrequency ablation, renal biopsy, and vascular catheterization are associated with a high bleeding risk in patients with chronic liver disease.11
Unfortunately, conventional coagulation tests do not fully reflect the derangement in hemostasis and do not accurately predict the risk of bleeding.12 The limitations of laboratory tests in patients with liver disease include a lack of defined thresholds for bleeding risk, variation between laboratories, a lack of validation in chronic liver disease, variation between laboratories, and limited availability.12
The Clinical Management of Thrombocytopenia
Currently, there are no consensus values for prophylactic platelet transfusions in chronic liver disease, and the cutoff values vary considerably depending on the clinical setting and the procedure planned.12,16–21 According to the guidelines by the American Association for the Study of Liver Diseases, platelet transfusion prior to liver biopsy should be considered when platelet counts are below 50-60 x 109/L.12,16–21 The dose of the transfusion should be based on the degree of correction desired; one apheresis pack is expected to increase the platelet count by ~30 x 109/L.12,16–21 However, a single transfusion does not ensure a hemostatic platelet level, and multiple transfusions are often needed.12,16–21 The complications associated with repeated prophylactic platelet transfusions in patients with cirrhosis prior to invasive procedures are well-documented and include febrile nonhemolytic and allergic reactions, need for hospitalization, potential iron overload, risk of infection, platelet refractoriness due to HLA alloimmunization, and cost.16,18,22–24
Partial splenic artery embolization is an effective procedure in cirrhotic patients.25,26It decreases rates of ascites and esophageal variceal bleeding, lowers morbidity rates compared with laparoscopic splenectomy, and gives persistent improvements in leukocyte and platelet counts, which decline in the months following the procedure.25,26 Limitations and concerns associated with partial splenic artery embolization include numerous associated morbidities and post-embolization syndrome with pain, fever, nausea, and vomiting.25,26 The most common serious complications are pleural effusion and/or ascites, portal vein thrombosis, splenic abscess, and the mortality rate is 0-6%.25,26
Eltrombopag and romiplostim are first-generation thrombopoietin-receptor agonists. Neither are approved for the management of thrombocytopenia due to chronic liver disease. Eltrombopag acts with the transmembrane domain of the thrombopoietin receptor on megakaryocyte precursors and megakaryocytes and promotes the proliferation and differentiation of megakaryocytes.27,28 In the US, eltrombopag is approved for the treatment of immune thrombocytopenia and thrombocytopenia due to hepatitis C.29,30 Eltrombopag carries a boxed warning for thrombotic events, including portal vein thrombosis, following the results of the ELEVATE trial indicating an increased risk in the group receiving eltrombopag.28 Romiplostim has no sequential homology to endogenous thrombopoietin, and it acts by activating the signal transduction pathways promoting the proliferation and differentiation of bone marrow cells into megakaryocytes.27,31,32 It is FDA approved for the treatment of chronic immune thrombocytopenia.27,31,32
As second-generation agonists, lusutrombopag and avatrombopag act selectively on the thrombopoietin receptor to activate signal transduction pathways promoting the proliferation and differentiation of bone marrow cells into megakaryocytes.33 Both lusutrombopag and avatrombopag are approved in the US in for the treatment of thrombocytopenia in chronic liver disease in patients scheduled to undergo a procedure.34,35
L-PLUS 1 and L-PLUS 2 trials were double-blind, placebo-controlled phase 3 studies evaluating the use of lusutrombopag in treating thrombocytopenia in patients with chronic liver disease undergoing scheduled invasive procedures.36,37 Randomized patients received either lusutrombopag or placebo for 7 days. A scheduled invasive procedure was performed 2 to 7 days after the last dose of drug or placebo. Follow-up continued another 15 days after the procedure was completed.36 The primary endpoint was the proportion of patients not requiring platelet transfusion prior to the first invasive procedure.36 In L-PLUS 1, lusutrombopag significantly reduced the need for platelet transfusion prior to undergoing invasive procedure compared with placebo (79% versus 12%; P<0.0001).36 In addition, significantly more patients in the lusutrombopag arm achieved a platelet count ≥50 x 109/L compared with placebo. (P<0.0001).36 The median increase in platelets without transfusion in the lusutrombopag arm was 87 x 109/L.36 Lusutrombopag was safe and well tolerated with no deaths or discontinuations due to adverse events. The most common adverse events (>20%) included postoperative fever and pain, procedural hypertension, and increased AST.36 Lusutrombopag-treated patients had a lower incidence of bleeding-related adverse events versus placebo (15% versus 27%).36 A total of 2 thrombotic events were recorded, 1 in each arm and not related to platelet count change. 36 The efficacy results of lusutrombopag in the L-PLUS 2 trial are shown in figure 1.37
Avatrombopag was FDA approved for the treatment of thrombocytopenia in adults with chronic liver disease scheduled to undergo a procedure.36 Avatrombopag was studied in the ADAPT-1 and ADAPT-2 trials, which were identical double-blind, placebo-controlled, phase 3 studies evaluating the use of avatrombopag in treating thrombocytopenia in patients with chronic liver disease undergoing scheduled invasive procedures.38 Randomized patients received either avatrombopag or placebo for 5 days. A scheduled invasive procedure was performed 5 to 8 days after the last dose of drug or placebo. Follow-up continued another 7 days after the procedure was completed.38 The primary endpoint was the proportion of patients not requiring platelet transfusion prior to the first invasive procedure and no need for rescue therapy for bleeding up to 7-days post-procedure.38 Significantly more avatrombopag-treated patients did not require platelet rescue therapy compared with placebo (66%-69% versus 23%-35%). In addition, significantly more patients in the avatrombopag arm achieved a platelet count ≥50 x 109/L compared with placebo.38 The efficacy results of the ADAPT-1 and ADAPT-2 trials are shown in figure 2.
Peak platelet counts without transfusion in the avatrombopag arm occurred on day 10 (procedure day) and decreased to baseline values by day 35.38 Avatrombopag was safe and well tolerated with no deaths or treatment-related discontinuations due to adverse events.38 Both arms had similar incidences of adverse events.38 The most common adverse events (>5%) included pyrexia, abdominal pain, nausea, and headache.38
Clinical Considerations and Conclusions
Coagulation disorders in patients with chronic liver disease are complex and carry an increased risk of bleeding as well as an increased risk of clotting. Lusutrombopag and avatrombopag provide an addition to the armamentarium to reduce bleeding risks in patients scheduled to undergo procedures. Before considering prescribing thrombopoietin receptor agonists for thrombocytopenia, an extensive evaluation of a patient’s risk of thrombotic events should be performed and the presence of patent hepatic vessels and flow in the portal vein should be assessed.10 Doppler sonography should be closely monitored during and after the use of thrombopoietin receptor agonists, especially if the patient reports abdominal complaints.10 The optimal target platelet count to achieve after initiation of a thrombopoietin receptor agonists is currently unclear.10 However, results from the ELEVATE study suggested an association between platelet count ≥200 x 109/L and the occurrence of portal venous thrombotic events.10 Until further data are available, clinicians should consider stopping thrombopoietin receptor agonists therapy once this threshold has been reached.10
- Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008;48(6):1000-1007. doi:10.1016/j.jhep.2008.03.009
- Peck‐Radosavljevic M. Thrombocytopenia in chronic liver disease. Liver Int. 2017;37(6):778-793. doi:10.1111/liv.13317
- Poordad F. Review article: thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther. 2007;26 Suppl 1:5-11. doi:10.1111/j.1365-2036.2007.03510.x
- Qureshi K, Patel S, Meillier A. The Use of Thrombopoietin Receptor Agonists for Correction of Thrombocytopenia prior to Elective Procedures in Chronic Liver Diseases: Review of Current Evidence. Int J Hepatol. 2016;2016. doi:10.1155/2016/1802932
- Brown RS. Review article: a pharmacoeconomic analysis of thrombocytopenia in chronic liver disease. Aliment Pharmacol Ther. 2007;26 Suppl 1:41-48. doi:10.1111/j.1365-2036.2007.03505.x
- Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339(11):746-754. doi:10.1056/NEJM199809103391107
- Kaushansky K. Lineage-Specific Hematopoietic Growth Factors. N Engl J Med. 2006;354(19):2034-2045. doi:10.1056/NEJMra052706
- Kuter DJ. New thrombopoietic growth factors. Blood. 2007;109(11):4607-4616. doi:10.1182/blood-2006-10-019315
- Varghese LN, Defour J-P, Pecquet C, Constantinescu SN. The Thrombopoietin Receptor: Structural Basis of Traffic and Activation by Ligand, Mutations, Agonists, and Mutated Calreticulin. Front Endocrinol. 2017;8. doi:10.3389/fendo.2017.00059
- Mitchell O, Feldman DM, Diakow M, Sigal SH. The pathophysiology of thrombocytopenia in chronic liver disease. Hepatic Med Evid Res. 2016;8:39-50. doi:10.2147/HMER.S74612
- Terrault N, Bibbiani F, Chen Y-C. Superiority of avatrombopag (AVA) to placebo (PBO) for the treatment of chronic liver disease (CLD)-associated thrombocytopenia (TCP) in patients undergoing scheduled procedures: results of 2 randomized, PBO-controlled phase 3 studies. Hepatology. Hepatology;(2017;66(suppl S1):):124A-125A. Abstract 217.
- Kujovich JL. Coagulopathy in liver disease: a balancing act. ASH Educ Program Book. 2015;2015(1):243-249. doi:10.1182/asheducation-2015.1.243
- Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies. mAbs. 2010;2(3):256-265.
- Kumar A, Sharma P, Arora A. Review article: portal vein obstruction – epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther. 2015;41(3):276-292. doi:10.1111/apt.13019
- Rajesh S, Mukund A, Arora A. Imaging Diagnosis of Splanchnic Venous Thrombosis. Gastroenterology Research and Practice. doi:10.1155/2015/101029
- Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Management of thrombocytopenia due to liver cirrhosis: A review. World J Gastroenterol WJG. 2014;20(10):2595-2605. doi:10.3748/wjg.v20.i10.2595
- Kurokawa T, Ohkohchi N. Platelets in liver disease, cancer and regeneration. World J Gastroenterol. 2017;23(18):3228-3239. doi:10.3748/wjg.v23.i18.3228
- Patel IJ, Davidson JC, Nikolic B, et al. Consensus guidelines for periprocedural management of coagulation status and hemostasis risk in percutaneous image-guided interventions. J Vasc Interv Radiol JVIR. 2012;23(6):727-736. doi:10.1016/j.jvir.2012.02.012
- Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, American Association for the Study of Liver Diseases. Liver biopsy. Hepatol Baltim Md. 2009;49(3):1017-1044. doi:10.1002/hep.22742
- Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19(5):1519-1538. doi:10.1200/JCO.2001.19.5.1519
- Wiltrout C, Kondo KL. Correction of Coagulopathy for Percutaneous Interventions. Semin Interv Radiol. 2010;27(4):338-347. doi:10.1055/s-0030-1267857
- DeAngelis GA, Khot R, Haskal ZJ, et al. Bleeding Risk and Management in Interventional Procedures in Chronic Liver Disease. J Vasc Interv Radiol. 2016;27(11):1665-1674. doi:10.1016/j.jvir.2016.05.039
- Stroncek DF, Rebulla P. Platelet transfusions. Lancet Lond Engl. 2007;370(9585):427-438. doi:10.1016/S0140-6736(07)61198-2
- 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. doi:10.1111/liv.12038
- Gangireddy VGR, Kanneganti PC, Sridhar S, Talla S, Coleman T. Management of Thrombocytopenia in Advanced Liver Disease. Canadian Journal of Gastroenterology and Hepatology. doi:10.1155/2014/532191
- Hadduck TA, McWilliams JP. Partial splenic artery embolization in cirrhotic patients. World J Radiol. 2014;6(5):160-168. doi:10.4329/wjr.v6.i5.160
- Maan R, de Knegt RJ, Veldt BJ. Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies. Drugs. 2015;75(17):1981-1992. doi:10.1007/s40265-015-0480-0
- Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before Procedures in Patients with Cirrhosis and Thrombocytopenia. N Engl J Med. 2012;367(8):716-724. doi:10.1056/NEJMoa1110709
- FDA Approves Promacta (eltrombopag), the First Oral Medication to Increase Platelet Production for People With Serious Blood Disorder. Drugs.com. https://www.drugs.com/newdrugs/fda-approves-promacta-eltrombopag-first-oral-increase-platelet-production-serious-blood-disorder-1188.html. Accessed August 13, 2018.
- PROMACTA® Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022291s020,207027s005lbl.pdf. Accessed November 19, 2018.
- Basu PP, Nair T, Farhat S, Shah NJ, Jafri M, Foustin S. 87 SINGLE USE OF ROMIPLOSTIM THROMBOPOIETIN ANALOGUE IN SEVERE THROMBOCYTOPENIA FOR OUTPATIENT PERCUTANEOUS LIVER BIOPSY IN PATIENTS WITH CHRONIC LIVER DISEASE-A RANDOMIZED DOUBLE BLINDED PROSPECTIVE TRIAL. J Hepatol. 2012;56:S38. doi:10.1016/S0168-8278(12)60101-9
- Moussa MM, Mowafy N. Preoperative use of romiplostim in thrombocytopenic patients with chronic hepatitis C and liver cirrhosis. J Gastroenterol Hepatol. 2013;28(2):335-341. doi:10.1111/j.1440-1746.2012.07246.x
- Kim ES. Lusutrombopag: First Global Approval. Drugs. 2016;76(1):155-158. doi:10.1007/s40265-015-0525-4
- Research C for DE and. Approved Drugs - FDA approves avatrombopag for thrombocytopenia in adults with chronic liver disease. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm608323.htm. Accessed November 16, 2018.
- Research C for DE and. Approved Drugs - FDA approves lusutrombopag for thrombocytopenia in adults with chronic liver disease. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm615348.htm. Accessed August 9, 2018.
- Izumi N, Osaki Y, Yamamoto K, et al. a Phase 3, Randomized, Double-blind, Placebo-controlled Study of Lusutrombopag for Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Elective Invasive Procedures in Japan (l-plus 1): lb-30. Hepatology. 2015;62(6). https://insights.ovid.com/hepatology/hepa/2015/12/000/phase-randomized-double-blind-placebo-controlled/72/01515467. Accessed November 14, 2018.
- Afdhal N, Duggal A, Ociai T. Lusutrombopag for Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Who Are Undergoing Non-Emergency Invasive Procedures: Results from An International Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (L-PLUS 2). Hepatology. 2017;66(suppl S1):1254A. Abstract LB-1.
- 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. May 2018. doi:10.1053/j.gastro.2018.05.025