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Blood. 2008 Aug 1;112(3):542-50. doi: 10.1182/blood-2007-12-125906. Epub 2008 Jun 3.

Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes.

Author information

1
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Abstract

Human interferon (IFN)-alpha 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-alpha and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN-alpha inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-alpha did not inhibit colony formation of megakaryocytes from human CD34(+) hematopoietic stem cells. IFN-alpha did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN-alpha suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45(NF-E2), MafG. IFN-alpha 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-2R gamma(null) (NOG) mice transplanted with human CD34(+) cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-alpha-induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN-alpha inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-alpha. These results defined the pathogenesis of IFN-alpha-induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.

PMID:
18523149
DOI:
10.1182/blood-2007-12-125906
[Indexed for MEDLINE]
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