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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3241-3248
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Thrombocytopenia caused by the development of antibodies to
thrombopoietin
Junzhi Li,
Chun Yang,
Yuping Xia,
Amy Bertino,
John Glaspy,
Michael Roberts, and
David J. Kuter
From the Hematology Unit, Massachusetts General
Hospital, Boston, MA; UCLA Cancer Center, Los Angeles, CA; and
Hematology & Oncology Associates, Phoenix, AZ.
Thrombocytopenia developed in some individuals treated with a
recombinant thrombopoietin (TPO), pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). Three of the
subjects who developed severe thrombocytopenia were analyzed in detail
to determine the cause of their thrombocytopenia. Except for easy
bruising and heavy menses, none of these subjects had major bleeding
episodes; none responded to intravenous immunoglobulin or prednisone.
Bone marrow examination revealed a marked reduction in megakaryocytes.
All 3 thrombocytopenic subjects had antibody to PEG-rHuMGDF that
cross-reacted with endogenous TPO and neutralized its biological
activity. All anti-TPO antibodies were immunoglobulin G (IgG), with
increased amounts of IgG4; no IgM antibodies to TPO were detected at
any time. A quantitative assay for IgG antibody to TPO was developed
and showed that the antibody concentration varied inversely with the
platelet count. Anti-TPO antibody recognized epitopes located in the
first 163 amino acids of TPO and prevented TPO from binding to its
receptor. In 2 subjects, endogenous TPO levels were elevated, but the
TPO circulated as a biologically inactive immune complex with anti-TPO
IgG; the endogenous TPO in these complexes had an apparent molecular
weight of 95 000, slightly larger than the full-length recombinant
TPO. None of the subjects had atypical HLA or platelet antigens, and
the TPO cDNA was normal in both that were sequenced. Treatment of one subject with cyclosporine eliminated the antibody and normalized the
platelet count. These data demonstrate a new mechanism for thrombocytopenia in which antibody develops to TPO; because endogenous TPO is produced constitutively, thrombocytopenia ensues.
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