Correcting thrombocytopenia in patients with liver diseases: A difficult hurdle



Dr Chun-Tao Wai, Desmond Wai Liver and Gastrointestinal Diseases Centre, Gleneagles Medical Centre #03-17/18, 6 Napier Road, Singapore 258499, Singapore. Email:

Platelet count reflects liver function

Platelets have a very close relationship with the liver, the source of thrombopoietin. Thrombocytopenia is common in patients with acute liver injuries such as acute liver failure, acute exacerbation of chronic hepatitis B, and acute-on-chronic liver failure.[1-3] And patients' platelet count often improves once the acute liver injury is resolved.

The degree of thrombocytopenia also parallels the extent of chronic hepatic injury. Many studies have shown that platelet count is one of the factors that reflect the degree of liver fibrosis or the severity of liver cirrhosis.[4, 5] Among the patients with decompensated cirrhosis, the post-transplant platelet count starts to exceed the baseline level about three weeks after liver transplantation.[6]

The several mechanisms of thrombocytopenia among patients with liver diseases have been well reviewed elsewhere.[7] Platelets are produced in the bone marrow in response to thrombopoietin, a glycoprotein produced mainly in the liver. Production of thrombopoietin is reduced in both acute and chronic liver injuries. Hypersplenism, a result of portal hypertension, leads to increased splenic platelet sequestration. In addition, hepatitis C virus may directly cause bone marrow suppression and immune-mediated platelet destruction.

Platelet count affects treatment of chronic hepatitis C

Standard treatment for chronic hepatitis C (CHC) consists of pegylated interferon plus ribavirin, with or without a protease inhibitor such as boceprevir or telaprevir. Sustained virological response (SVR) can be expected in about 50–80% of patients, depending on viral genotype, triple versus combination therapy, and presence of cirrhosis.[8] However, thrombocytopenia is one of the major complications of interferon treatment, as interferon may lead to direct inhibition of megakaryocytes and autoimmune destruction of platelets. Severe thrombocytopenia, platelets < 50 000/microL, occurring during antiviral treatment of CHC may lead to bleeding.[9] Though uncommon, life-threatening and even fatal bleeding complications have been reported. The dose of pegylated interferon ought to be reduced when platelets drop below 80 000/microL, and pegylated interferon should be stopped if platelets drop below 50 000/microL. Yet dose reduction of pegylated interferon may adversely affect chance of SVR.[10]

Strategies to boost platelet count in hepatitis C patients

Several strategies have been suggested to increase platelet count prior to, or during antiviral treatment in CHC patients with thrombocytopenia. Hypersplenism can be corrected by laparoscopic splenectomy or partial splenic embolization.[11] But these procedures are associated with morbidity such as portal vein thrombosis, infection, or worsening of liver function. Besides, the rise of platelets after partial splenic embolization may only be shortlived. Elthrombopag, an oral thrombopoietin receptor agonist, brought much excitement to the hepatology community when its pioneer trials showed it being beneficial in raising platelet count prior to and during antiviral treatment for CHC patients.[12] However, the use of elthrombopag in cirrhotic patients is limited when subsequent studies showed it being associated with portal vein thrombosis and myelofibrosis and only a very limited SVR in those who complete subsequent antiviral treatment. To date, elthrombopag has not been approved for use in CHC patients or patients with advanced liver dysfunction. New strategies are urgently needed to meet this need.

New strategy for correcting thrombocytopenia in CHC patients

Against this background, the study by Moussa and Mowafy reported in this issue of Journal of Gastroenterology and Hepatology is both interesting and significant.[13] In their well-designed, single-arm prospective study, the Egyptian authors administered romiplostim, a thrombopoietin-mimetic peptide that stimulates the thrombopoietin receptor to 35 patients with CHC, liver cirrhosis, and thrombocytopenia, prior to elective surgery. Mean platelet count increased from 31 000/microL at baseline to a peak of 73 000/microL between days 18 and 39. Surgical interventions were performed with no perioperative bleeding. Platelet transfusion was not required in any of the patients. Bone marrow examination, performed at baseline and at the end of the study, showed none developed myelofibrosis, while no thrombotic complication was seen throughout the study.

The strength of the study was the close follow-up and well-documented clinical data, which included laboratory monitoring every three days and paired bone marrow examination. The weaknesses are the short follow-up (90 days from time of first injection), lack of a control group, that is, patients given preoperative platelet transfusion instead of romiplostim. Further, the majority of surgical procedures were minor (11/35 cataract and 11/35 hernia surgery), rarely requiring need for platelet transfusion. One may argue that administration of one unit of cell separated platelets prior to a hernia repair is a simpler option than administering romiplostim subcutaneously, monitoring the platelet count regularly (every three days in this study), and only operating when platelets rise above 70 000/microL. Further, controlled clinical trials and cost analysis are needed to compare romiplostim administration versus platelet transfusion prior to a relatively minor elective operation.

However, looking at the overall picture, this study suggests that use of romiplostim is safe and effective as it raised platelet count in 33/35 of the patients, with the majority peaking platelet count between two to three weeks since the first peptide injection. This may help raise platelet counts in CHC patients undergoing antiviral treatment. Currently, most of adverse effects of antiviral therapy with pegylated interferon, ribavirin, and protease inhibitors, such as anemia, leucopenia, fever, body ache, etc can be managed with supportive treatment such as erythropoietin, G-CSF injection, paracetamol, and nonsteroidal anti-inflammatory drugs. Yet no good treatment exists for thrombcyopenia. This study brings hope for CHC patients with thrombocytopenia who are in need of antiviral treatment.

Understandingly, this is a phase II study, and the authors rightly caution in the concluding paragraph that further studies in larger group of patients over a longer period of time are warranted in defining the optimal treatment schedule and dosage of romiplostim. Nevertheless, studies on romiplostim will be closely watched by hepatologists like me, as this may bring hope to many patients with advanced fibrosis or cirrhosis from CHC who are excluded from current antiviral treatment due to pre-existing thrombocytopenia.