Neonatal thrombocytopenia and megakaryocytopoiesis

Abstract

Thrombocytopenia is common among sick neonates, affecting 20% to 35% of all patients admitted to the neonatal intensive care unit (NICU). While most cases of neonatal thrombocytopenia are mild or moderate and resolve within 7 to 14 days with appropriate therapy, 2.5% to 5% of NICU patients develop severe thrombocytopenia, sometimes lasting for several weeks and requiring >20 platelet transfusions. The availability of thrombopoietic agents offers the possibility of decreasing the number of platelet transfusions and potentially improving the outcomes of these infants. However, adding thrombopoietin (TPO) mimetics to the therapeutic armamentarium of neonatologists will require careful attention to the substantial developmental differences between neonates and adults in the process of megakaryocytopoiesis and in their responses to TPO. Taken together, the available data suggest that TPO mimetics will stimulate platelet production in neonates, but might do so through different mechanisms and at different doses than those established for adults. In addition, the specific groups of thrombocytopenic neonates most likely to benefit from therapy with TPO mimetics need to be defined, and the potential nonhematological effects of these agents on the developing organism need to be considered. This review summarizes our current understanding of neonatal megakaryocytopoiesis, and examines in detail the developmental factors relevant to the potential use of TPO mimetics in neonates.

Figure 1. Effect of postnatal age on the mean platelet counts of premature infants

Mean platelet counts were plotted according to gestational age at birth, and data were grouped according to weeks of gestation completed at birth, as follows: 22–24 weeks, 25 to 26 weeks, 27 to 28 weeks, 29 to 30 weeks, 31 to 32 weeks, and 33 to 34 weeks. As can be seen, mean platelet counts increased with post-natal age in all groups, but the most premature infants (22–24 weeks, blue line) had mean platelet counts persistently lower than those of the more mature infants. Reprinted from: Christensen RD, et al. The CBC: reference ranges for neonates. Semin Perinatol 2009;33:3–11, with permission.

Figure 2. In vitro relationship of maximal megakaryocyte colony count and recombinant (r) human TPO concentration

Bone marrow from thrombocytopenic (T) and non-thrombocytopenic (NT) neonates and adults was cultured in the presence of increasing concentrations of rTPO and the number of megakaryocyte colonies counted. Neonatal progenitors reached a plateau at 10 ng/ml and had a larger area under the curve than did adult progenitors, which reached a plateau at 50 ng/ml. Reprinted from: Sola MC, et al. Dose-response relationship of megakaryocyte progenitors from the bone marrow of thrombocytopenic and non-thrombocytopenic neonates to recombinant thrombopoietin. Br J Haematol 2000; 110:449-53, with permission.

Figure 3. The percentage of megakaryocytes ≥ 8N in peripheral blood (PB) and cord blood (CB) cultures differed depending on media source and rTPO concentration

PB- and CB-CD34⁺ cells were cultured for 14 days in serum-free unconditioned medium (UCM) and bone marrow stromal conditioned medium (CM), with varying rTPO concentrations. PB-derived megakaryocytes (solid lines) cultured in UCM (A) exhibited a rTPO dose-dependent increase in ploidy levels, an effect not observed in the presence of CM (B). CB-derived megakaryocytes (dashed lines) reached highest ploidy levels when cultured in CM with no rTPO, and effect that was reversed by increasing rTPO concentrations ≥1 ng/ml (B). Data shown represent the means and standard error of the mean (SEM) of four separate experiments. Reprinted from: Pastos K, et al. Differential effects of recombinant thrombopoietin and bone marrow stromal-conditioned media on neonatal versus adult megakaryocytes. Blood 2006; 108: 3360-2, with permission.