Interferon-α2b–induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes

Abstract

AbstractHuman interferon (IFN)–α is the standard therapy for chronic hepatitis C to prevent its progression to liver cirrhosis and hepatocellular carcinoma. Thrombocytopenia is one of the major adverse effects of IFN-α and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN-α inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-α did not inhibit colony formation of megakaryocytes from human CD34+ hematopoietic stem cells. IFN-α did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN-α suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45NF-E2, MafG. IFN-α also significantly reduced the number of human platelets but not megakaryocytes, and did not inhibit endomitosis of human megakaryocytes in immunodeficient NOD/Shi-scid/IL-2Rγnull (NOG) mice transplanted with human CD34+ cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-α–induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN-α inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-α. These results defined the pathogenesis of IFN-α–induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.