Thrombocytopenia caused by the development of antibodies to thrombopoietin

Thrombocytopenia developed in some individuals treated with a recombinant t hrombopoletin (TPO), pegylated recombinant human megakaryocyte growth and d evelopment factor (PEG-rHuMGDF). Three of the subjects who developed severe thrombocytopenia were analyzed in detail to determine the cause of their t hrombocytopenia. Except for easy bruising and heavy menses, none of these s ubjects had major bleeding episodes; none responded to intravenous immunogl obulin or prednisone. Bone marrow examination revealed a marked reduction i n megakaryocytes. All 3 thrombocytopenic subjects had antibody to PEG-rHuMG DF that cross-reacted with endogenous TPO and neutralized its biological ac tivity. All anti-TPO antibodies were immunoglobulin G (IgG), with increased amounts of IgG4; no IgM antibodies to TPO were detected at any time. A qua ntitative assay for IgG antibody to TPO was developed and showed that the a ntibody concentration varied inversely with the platelet count. Anti-TPO an tibody recognized epitopes located in the first 163 amino acids of TPO and prevented TPO from binding to its receptor. In 2 subjects, endogenous TPO l evels were elevated, but the TPO circulated as a biologically inactive immu ne 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 r ecombinant 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 platel et count. These data demonstrate a new mechanism for thrombocytopenia in wh ich antibody develops to TPO; because endogenous TPO is produced constituti vely, thrombocytopenia ensues. (Blood. 2001;98:3241-3248) (C) 2001 by The A merican Society of Hematology.