Thrombocytopenia in Cirrhosis: a Review of Pathophysiology and Management Options Andrew H

Review

Thrombocytopenia in Cirrhosis: A Review of Pathophysiology and Management Options Andrew H. Moore, M.D.

BACKGROUND procedures and correction of platelet abnormalities for these procedures can increase hospitalization time and in- Thrombocytopenia is one of the most common hemato- crease overall health care costs.4 logical abnormalities and is often the first abnormality seen in patients with chronic liver disease. Thrombocytopenia The pathophysiology of thrombocytopenia in chronic affects approximately 6% of patients without cirrho- liver disease is a rapidly evolving field. Previously, thrombosis and 70% of patients with cirrhosis. It is defined as a cytopenia was thought to be solely a result of splenic se- platelet count of less than 150,000/μL, with 100,000 to questration caused by congestive splenomegaly as a result 150,000/μL considered as mild thrombocytopenia, 50,000 of portal hypertension. Now, however, there are several to 100,000/μL labeled as moderate thrombocytopenia, other proposed mechanisms regarding platelet production and less than 50,000/μL defined as severe thrombocyto- and destruction in cirrhosis (Fig. 1). penia.1 Thrombocytopenia can often be used as a marker of advanced liver disease, and some studies have shown Platelet production is largely associated with throm- moderate-to-severe thrombocytopenia to be a strong in- bopoietin (TPO). TPO is predominantly synthesized in dependent predictor of mortality.2,3 Mild-to-moderate the liver in parenchymal and sinusoidal endothelial cells thrombocytopenia rarely has any clinical significance be- and in the kidneys. Small amounts are also made in bone cause spontaneous bleeding is unlikely to occur at these marrow stromal cells. TPO binds to the c-mpl receptor on levels. However, moderate-to-severe thrombocytopenia megakaryocytes, which, in turn, regulates the differenti- can prevent patients from receiving vital interventions ation into platelets.5 There appears to be a direct correla- such as medications and invasive procedures. Delayed tion with stages of cirrhosis, levels of circulating TPO, and

Abbreviations: FDA, US Food and Drug Administration; HCV, hepatitis C virus; ITP, idiopathic thrombocytopenic purpura; TIPS, transjugular intrahepatic portosystemic shunt; TPO, thrombopoietin. From the Department of Internal Medicine, Rush University Medical Center, Chicago, IL. Potential conflict of interest: Nothing to report. Received June 4, 2019; accepted July 14, 2019.

183 | Clinical Liver Disease, VOL 14, NO 5, NOVEMBER 2019 An Official Learning Resource of AASLD Review Thrombocytopenia in Cirrhosis Moore

FIG 1 Common mechanisms of thrombocytopenia in cirrhosis.

degree of thrombocytopenia. Increasing stages of fibrosis ethylene diamine tetraacetic acid. It is always important have been shown to lead to decreasing levels of circulating to exclude pseudothrombocytopenia by reviewing the pe- TPO, and thus a worsening degree of thrombocytopenia.6 ripheral smear for clumping or by repeating the complete In a study by Koruk et al.,7 comparing serum TPO levels in blood count using a heparin or sodium citrate anticoagu- patients with chronic hepatitis and liver cirrhosis, TPO lev- lant. Pulmonary hypertension and pulmonary emboli are els were normal in control and chronic hepatitis groups. also associated with platelet consumption and can often However, TPO levels decreased as the degree of cirrhosis be seen in patients with cirrhosis. increased. Another cause of decreased platelet production includes reduced bone marrow production that can MANAGEMENT OF THROMBOCYTOPENIA be a result of numerous causative factors but is commonly IN CIRRHOSIS seen with alcohol abuse and with viral infections. Thrombocytopenia plays an important role in the Mechanisms of platelet destruction can also contribute management of liver cirrhosis because a number of pro- to thrombocytopenia in patients with cirrhosis. Immune- cedures have significant bleeding risks associated with mediated destruction plays a large role in platelet destruc- them. Bedside and routine procedures such as paracen- tion, specifically in patients with autoimmune liver diseases tesis and esophagogastroduodenoscopy are generally and chronic hepatitis C virus (HCV), both of which have considered a lower bleeding risk; however, liver biopsies, been shown to have an increased association with auto- chemoembolizations, transjugular intrahepatic portosys- immune thrombocytopenia purpura. Sepsis is another im- temic shunts (TIPSs), and biliary procedures are considered portant contributor to platelet destruction. Patients with higher risk, and thus could be deferred or could place the cirrhosis are at an increased risk for sepsis compared with patient at significant risk for bleeding.8 In an analysis of the general population, and multiple mechanisms such as bleeding complications after liver biopsy in patients with tumor necrosis factor-α release during inflammatory states HCV with cirrhosis, 11% of biopsies were missed at the have been shown to contribute to platelet destruction.6 24-month mark because of thrombocytopenia, and there was a significantly increased risk for bleeding in patients Another cause of thrombocytopenia, which is associ- 9 with a platelet count of less than 60,000/μL. ated with platelet sequestration but not directly related to the mechanisms listed earlier, is pseudothrombocytopenia. There have been several advances in the management This is a falsely low platelet count because of platelet clump- of thrombocytopenia in chronic liver disease over the past ing after some samples are exposed to the anticoagulant decade. Standard treatments of thrombocytopenia include

184 | Clinical Liver Disease, VOL 14, NO 5, NOVEMBER 2019 An Official Learning Resource of AASLD Review Thrombocytopenia in Cirrhosis Moore transfusions, splenectomy, or splenic artery embolization. the development of thrombocytopenia, and a number of Aside from an inability to correct platelet function, there management options are available for its treatment, with are several problems associated with platelet transfusions. early promising results noted among the newly approved First, no clear cutoffs exist to guide platelet transfusions, TPO receptor agonists. Further studies are needed to in- specifically with regard to safe thresholds for different pro- vestigate the association of morbidity and mortality with cedures. Second, platelet transfusions carry an increased thrombocytopenia and the role that TPO receptor agonists risk for infection in all patients with cirrhosis and an in- play in increasing survival in patients with chronic liver dis- creased risk for graft-versus-host disease in transplant pa- ease and cirrhosis. tients. Lastly, multiple platelet transfusions can lead to CORRESPONDENCE platelet refractoriness, an inability to achieve the desired platelet count after a transfusion.10 Laparoscopic splenec- Andrew H. Moore, M.D., Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612. E-mail: tomy and splenic artery embolization have been extensively [email protected] studied and have been shown to have effective improve- ment in thrombocytopenia. However, both are associated REFERENCES with significant morbidity and mortality rates. TIPS has 1) Peck-Radosavljevic M. 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185 | Clinical Liver Disease, VOL 14, NO 5, NOVEMBER 2019 An Official Learning Resource of AASLD Review Thrombocytopenia in Cirrhosis Moore

12) Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before proce- 14) Tateishi R, Seike M, Kudo M, et al. A randomized controlled trial dures in patients with cirrhosis and thrombocytopenia. N Engl J Med of lusutrombopag in Japanese patients with chronic liver disease 2012;367:716-724. undergoing radiofrequency ablation. J Gastroenterol 2019;54: 171-181. 13) Hidaka H, Kurosaki M, Tanaka H, et al. Lusutrombopag reduces need for platelet transfusion in patients with thrombocytope- 15) Moussa MM, Mowafy N. Preoperative use of romiplostim in throm- nia undergoing invasive procedures. Clin Gastroenterol Hepatol bocytopenic patients with chronic hepatitis C and liver cirrhosis. 2019;17:1192-1200. J Gastroenterol Hepatol 2013;28:335-341.

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