With its low morbidity and high mortality rates, thrombotic thrombocytopenic purpura (TTP) has imposed a critical physical and economic burden on both society and individuals. Thrombocytopenia commonly occurs in severe liver failure, and a variety of hepatitis viruses are known to induce immune thrombocytopenic purpura. However, TTP is extremely rare in hepatitis E virus infection. We hereby report a case of a 53-year-old male who present with TTP caused by severe hepatitis E, and the patients achieved successful recovery after treatment. Therefore, we propose considering AMAMTS13 testing as an essential and beneficial approach for accurately diagnosing and treating patients with severe hepatitis or infection with notable platelet decline.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12959-023-00507-1.