PREVENTION OF THROMBOCYTOPENIA BY THROMBOPOIETIN IN MYELOSUPPRESSED RHESUS-MONKEYS ACCOMPANIED BY PROMINENT ERYTHROPOIETIC STIMULATION AND IRON DEPLETION

The effectiveness of thrombopoietin (TPO) in alleviating thrombocytope nia was evaluated in a placebo-controlled study involving rhesus monke ys exposed to 5 Gy total-body irradiation (TBI) (300-kV x-rays) to res ult in 3 weeks of pancytopenia. Supraoptimal treatment with human reco mbinant TPO (10 mu g/kg/d subcutaneously, days 1 to 21 after TBI) was highly effective in preventing thrombocytopenia, with nadirs for throm bocytes, on average, far higher than 100 x 10(9)/L, a greatly accelera ted recovery to normal values, and no need for thrombocyte transfusion s. TPO appeared to act selectively in that neutrophil regeneration was not influenced but red blood cell lineage recovery was prominently st imulated, with reticulocyte regeneration being initiated 10 days earli er than in placebo-treated animals. The reticulocytosis was followed b y a normoblastosis that occurred earlier and was more pronounced than in placebo-treated monkeys. The effect of TPO on the red blood cell li neage was also reflected in a less profound nadir for hemoglobin (Hb) and hematocrit values than in placebo controls. However, this effect w as not followed by a rapid recovery to normal values, due to developme nt of a microcytic hypochromic anemia, Iron depletion was demonstrated by measurements of total serum iron and total iron-binding capacity ( TIBC) and could be prevented by prophylactic intramuscular (IM) iron b efore TBI or corrected by IM iron after TPO treatment. Rechallenging w ith TPO in week 8 after TBI demonstrated a homogenous thrombocyte resp onse similar in magnitude to the initial response, but a greatly dimin ished reticulocyte response, This demonstrated that the erythropoietic response to TPO administration depends on the hemopoietic state of th e animal and may reflect multiple TPO target cells. It is postulated t hat the extremely rapid erythropoiesis due to TPO treatment in the ini tial regeneration phase following myelosuppression results in iron dep letion by a mechanism similar to that seen following erythropoietin tr eatment in patients with end-stage renal failure, It is concluded that protracted TPO therapy to counteract thrombocytopenic states may resu lt in iron depletion and that the iron status should be monitored befo re, during, and after TPO treatment, (C) 1997 by The American Society of Hematology.