Thrombopoietin (TPO), acting by way of its specific receptor (c-mpl), is a physiologic stimulator of platelet production. It is not known, however, whether TPO has this role in the human fetus or neonate, or whether TPO or c-mpl are expressed in the fetus, and if so in which organs and at what gestations. It is also unknown whether serum TPO concentrations change in predictable ways during various neonatal thrombocytopenias, whether measuring TPO would be useful clinically, and whether, for certain neonates, recombinant(r)TPO might be an alternative to platelet transfusions. We devised studies for the systematic evaluation of these issues. First, we sought TPO and c-mpl transcripts (RT-PCR) in various organs of 12 human fetuses of 6-24 wks gestation. At all gestational ages, expression of TPO and c-mpl was highest in liver. At 8 wks TPO expression was not detected in brain, eye, heart, or lung, but at 16 wks these organs contained TPO transcripts. TPO and c-mpl expression in liver and kidney remained constant through out the gestational period tested. We next compared TPO concentrations (ELISA) in umbilical cord blood of preterm (n=18) and term neonates (n=32), vs venous blood of adults (n=89). TPO was below the limit of delectability (20 pg/mL) in all but one adult, but was measured in 41 of 50 cord bloods (59±6 pg/mL, X±SEM). TPO was not different in term (47±7 pg/mL) vs preterm infants (60±9), and was not different in 8 born after pregnancy induced hypertension(63±14) vs 42 without hypertension (49±6). In neonates with normal platelet counts, TPO did not correlate with platelet count. However, in 3 thrombocytopenic neonates, studied serially, an inverse relationship between TPO and platelets was observed. In each case the suspected mechanism was increased platelet consumption, however all had low marrow megakaryocytes and high serum TPO (314±34) which decreased as the platelet counts normalized. We conclude that; 1) TPO and c-mpl transcripts are detected in the human fetus as early as 6 wks gestation, 2) serum TPO is higher in cord blood than in adult blood, 3) elevated TPO occurs in some cases of neonatal thrombocytopenia and falls as the condition remits. We speculate that TPO and c-mpl are regulators of platelet production in the human fetus and neonate, and that studies to assess treatment of certain thrombocytopenic neonates using rTPO are warranted.