Recombinant Human Thrombopoietin Increases Platelet Numbers and Reduces the Risk of Bleeding Events in Thrombocytopenic Patients with Chronic Hepatitis B Virus Infection: A Multicenter Observational Study
Authors: Zhai Wan-Yi , Feng Ru , Zhu Xiao-Lu , He Yun , Fu Hai-Xia , Liu Yi , Shen Jian-Liang , Jiang Qian , Jiang Hao , Lu Jin , Wang Qian-Ming , Wang Jing-Wen , Liu Hui , Wang Hao , Ma Hui , Xie Yan-Di , Xu Lan-Ping , Liu Kai-Yan , Huang Xiao-Jun , Zhang Xiaohui 
Published: October 2019

Abstract
Introduction Hepatitis B virus (HBV) is a widespread virus that severely affects people's health, especially in China. HBV has infected over 400 million people worldwide (Liaw YF et al, Lancet, 2009), of which 93 million are Chinese (Hou J.L. et al, 2015). People infected with hepatitis B virus may develop chronic HBV infection, leading to a high risk of liver cirrhosis or hepatocellular carcinoma. Thrombocytopenia can be observed in patients with chronic HBV infection, especially in patients with liver cirrhosis. Thrombocytopenia plays a key role in thrombin generation and possibly bleeding tendencies in patients with chronic HBV infection. Those patients are at a higher risk of bleeding comparing to the patients without thrombocytopenia, which may lead to a higher mortality. However, its pathogenesis is considered to be complicated and remains poorly understood. Currently, there are not many effective treatments for chronic HBV infection patients with concomitant thrombocytopenia. Moreover, due to the invasiveness of procedures or inadequate effectiveness, the current treatments still have limited applications. Recombinant human thrombopoietin (rh-TPO) can promote megakaryocyte development and platelet production, resulting in an elevation in platelet counts both in vitro and in vivo, though there is still no information available for its effect in chronic HBV infection patients with concomitant thrombocytopenia.
Methods The aim of the study is to explore the effectiveness and safety of rh-TPO in the treatment of thrombocytopenia in patients with chronic HBV infection. This was a multicenter, observational study conducted in China between January 2003 and May 2018. Patients with chronic HBV infection (defined as seropositive for HBV surface antigen (HBsAg) for more than 6 months and/or had serum HBV DNA levels greater than 500 copies/ml) accompanied with thrombocytopenia (defined as a platelet count of <100 000 per cubic millimeter) were enrolled and divided into 2 groups by the occurrence of liver cirrhosis. Each patient received nucleoside analog (NA) alone treatment, or NA plus prednisone or NA plus rh-TPO treatment. Platelet counts, occurrence of bleeding events and adverse events were evaluated before and after treatment.
Results Through our research, we have noticed that among patients with chronic HBV infection associated thrombocytopenia, patients with liver cirrhosis had significantly lower platelet counts compared to those without liver cirrhosis, especially in cirrhotic patients with splenomegaly. After treatment, patients treated with NA plus prednisone and patients treated with NA plus rh-TPO had significantly higher platelet count elevations than those treated with NA alone, respectively. Chronic HBV infection patients with liver cirrhosis reacted superior to both prednisone and rh-TPO treatment compared to patients without liver cirrhosis, especially in those without splenomegaly. During the observations before and after treatment, fewer bleeding events were observed in patients treated with rh-TPO or prednisone, compared to the NA alone group. No severe bleeding events occurred during the treatment. 22 variables considered relevant to the presence of bleeding events were tested using univariate analysis. The platelet counts, prothrombin time (PT), prothrombin activity (PTA) and methods of treatment were significantly associated with bleeding events. The platelet counts, and methods of treatment were risk factors associated with bleeding events in multivariate analysis. The adverse events among patients receiving different methods of treatment were mild and balanced. Liver function and HBV replication were not worsened after treatment. No severe adverse events were observed during the treatment with rh-TPO, and no patients stopped treatment due to adverse events during the observation.
Conclusion Treatment with rh-TPO could elevate the platelet counts and reduce the risk of bleeding events in chronic HBV infection patients with thrombocytopenia. The treatment with rh-TPO was more effective in patients with liver cirrhosis, especially in those without splenomegaly. No severe adverse events were observed during rh-TPO treatment, proving the safety of rh-TPO in the use of treatment in chronic HBV infection associated thrombocytopenia.

Disclosures
No relevant conflicts of interest to declare.