Thrombocytopenia is frequent among sick neonates, but little is known about its underlying mechanisms. It is known, however, that neonatal megakaryocytes are smaller and of lower ploidy than their adult counterparts and that smaller megakaryocytes produce fewer platelets than larger, more polyploid, megakaryocytes. We hypothesized that neonatal megakaryocytes would not increase their size in response to thrombocytopenia, thus limiting the ability of neonates to mount a response. To test this, we obtained marrow specimens from thrombocytopenic and nonthrombocytopenic neonates and adults. Megakaryocytes were immunohistochemically stained, quantified using an eyepiece reticle, and measured using an image analysis system with incorporated electronic micrometer. We found that, after adjusting for differences in cellularity, neonates and adults had similar megakaryocyte concentrations. When samples from the same sources were compared (tibial clot and vertebral body sections in neonates, iliac crest biopsies in adults), there were also no differences in megakaryocyte concentration between thrombocytopenic and nonthrombocytopenic subjects. The megakaryocyte diameter, however, was greater in adults than in neonates (19.4 Ϯ 3.0 versus 15.3 Ϯ 1.7 m, p Ͻ 0.0001). Thrombocytopenic adults also had a higher proportion of large megakaryocytes than nonthrombocytopenic adults (p Ͻ 0.001). This was not observed among thrombocytopenic neonates, suggesting a developmental limitation in their ability to increase megakaryocyte size. T hrombocytopenia is a common problem among sick neonates, affecting 20% to 35% of neonates admitted to neonatal intensive care units (NICUs) (1,2). In approximately 50% of cases, the thrombocytopenia is thought to be secondary to increased platelet consumption, mainly associated with sepsis, necrotizing enterocolitis (NEC), or alloantibodies. In the remainder of cases, the mechanism underlying the thrombocytopenia is frequently unclear, although a mounting body of evidence suggests that decreased platelet production causes or complicates many such cases (3-5).In adults with thrombocytopenia due to increased platelet consumption, the marrow attempts to compensate by increasing megakaryocyte number, size, and ploidy (6 -8). It is unknown whether thrombocytopenic neonates can compensate in a similar manner, particularly since megakaryocytes from normal fetuses and neonates are smaller and of lower ploidy than megakaryocytes from adults (9 -12). Indeed, the number and size of megakaryocytes in thrombocytopenic neonates have never been systematically evaluated, and it is not known whether neonates are capable of increasing their megakaryocyte size and number in response to platelet consumption.This study was designed to answer this question by quantifying the megakaryocyte number and size in bone marrow samples from thrombocytopenic and nonthrombocytopenic neonates. Because small megakaryocytes with low DNA content cannot be reliably differentiated from other cell types using hematoxylin and eosin-st...