Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies.

Thrombocytopenia (platelets <150 x 10[9]/L) is common in the early newborn period. Recent evidence suggests this is due mainly to impaired fetal megakaryocytopoiesis/platelet production. The cause remains unknown. Thrombopoietin (Tpo) is now recognized as the major regulator of platelet production in adults. However, nothing is known about Tpo levels, or the role of Tpo in megakaryocytopoiesis/platelet production, in the fetus/newborn. To answer these questions we: 1) measured plasma Tpo levels by ELISA at birth in healthy term (n = 17) and preterm (gestational age, 24-34 wk) babies (n = 16), and in thrombocytopenic preterm babies (n = 13); and 2) assessed the in vitro Tpo dose response characteristics of circulating megakaryocyte precursor cells (MKp) from all three groups. The median Tpo levels were similar in term babies 145 pg/mL (range 52-237 pg/mL) compared with preterm babies 132 pg/mL (32-318 pg/mL). In the thrombocytopenic preterm babies the median Tpo level of 185 (46-264) was not significantly higher than in healthy babies, despite the fact that their median platelet counts were significantly lower--82 x 10(9)/L (range 21-135), compared with the healthy preterm babies 252 x 109/L (152-320)--p < 0.0001. Tpo levels in the thrombocytopenic preterm babies were also much lower than levels measured in three thrombocytopenic children (905, 2138, and 2700 pg/mL). MKp from all three groups showed dose-dependent proliferation in response to Tpo (p < 0.01 at 100 ng/mL Tpo). Increases in MKp were greater in healthy and thrombocytopenic preterm babies when compared with term babies: 48.2-, 24.6-, and 9.8-fold, respectively (p < 0.05 for both comparisons). These results strongly suggest that: 1) Tpo is a major regulator of megakaryocytopoiesis/platelet production in the fetus/newborn, 2) impaired fetal Tpo production may be a factor in early thrombocytopenia in preterm babies, and 3) recombinant human Tpo is likely to be effective in the treatment of early neonatal thrombocytopenia.