an impaired ability to leave the circulation and enter the tissues.120–122 Secondly, neonatal neutrophils have an overall reduced ability to generate neutrophil extracellular traps (NETs), which are an important component of the innate immune response that limits the dissemination of a variety of pathogens.123–125 NETs are extracellular, web‐like structures composed of a variety of antimicrobial molecules, such as elastase, myeloperoxidase, lactoferrin and defensins, and are key for protection against infection in neonates, trapping, neutralising and killing bacteria, fungi, viruses and parasites.126 Thirdly, neonatal neutrophils have lower levels of various antimicrobial granule proteins, such as lactoferrin and bactericidal/permeability‐increasing protein (BPI), particularly in preterm neonates.95 Recent data suggest that lactoferrin may be particularly important for converting neonatal neutrophils and monocytes to myeloid‐derived suppressor cells (MDSC), which are now recognised as being critical in controlling diseases associated with deregulated inflammation in neonates, including NEC.127,128 Finally, although term neonates are able to phagocytose both Gram‐positive and Gram‐negative bacteria normally, in preterm neonates phagocytosis of bacteria and of Candida albicans is less efficient.102,129
Platelets and megakaryocytes in the fetus and neonate
Platelets appear in the circulation at 5–6 weeks’ gestation and reach values of 150 × 109/l by the end of the first trimester110,118 and 175–250 × 109/l during the second and third trimesters.93,130,131 Although some studies have suggested that there is a linear increase in the platelet count with increasing gestational age, a large study of more than 5000 fetal blood samples showed that there was no further significant increase in fetal platelet count through the second and third trimesters.131 Thus, a platelet count of less than 150 × 109/l can be considered abnormal, even in the most preterm neonate.
Developmental megakaryopoiesis and thrombopoiesis
As for most of the other types of blood cell, there are many differences between neonates and adults in the processes that regulate megakaryocyte production (megakaryopoiesis) and platelet production (thrombopoiesis).132,133 These differences are particularly marked in preterm neonates and likely to contribute to the frequent occurrence of thrombocytopenia in sick neonates; they are important to consider in the investigation and treatment of neonatal thrombocytopenia (see Chapter 4).
The principal cytokine regulating platelet production in the fetus and newborn, as in adults, is thrombopoietin (TPO).34 Circulating levels of TPO, which is produced in the liver from early in fetal life,134,135 are higher in healthy term and preterm neonates than in adults.136,137 This does not seem to be a compensatory mechanism since TPO‐induced signalling is upregulated in cord blood megakaryocytes compared with adult megakaryocytes.133 Fetal megakaryocytes are also smaller and of lower ploidy than their adult counterparts, which may be the reason that they not infrequently circulate in the peripheral blood in preterm neonates (Fig. 1.17) and that cord blood‐derived megakaryocytes produce approximately 50% fewer platelets per cell138 (reviewed in references 139 and 140). Furthermore, unlike adults, thrombocytopenic neonates can only increase their megakaryocyte number, and not size, in response to consumptive thrombocytopenia.141 Nevertheless, fetal megakaryocytes appear to be cytoplasmically mature and express increased amounts of messenger RNA for the transcription factor GATA1 and increased surface glycoprotein 1b compared with adult megakaryocytes.133 These functional differences in fetal and neonatal megakaryocytes are now known to be accompanied by increased expression of genes associated with a number of signalling pathways, including those mediated by transforming growth factor β (TGFβ), insulin‐like growth factor (IGF) and Janus kinase 2 (JAK2), in fetal compared with adult megakaryocytes.142
Fig. 1.17 Blood film of a preterm neonate born at 24 weeks’ gestation showing a circulating megakaryocyte and giant platelet. MGG, ×100.
There are also developmental differences in megakaryocyte progenitor cells. The numbers of these cells are high early in fetal life and fall towards term and are higher in healthy preterm than term babies.132,143,144 Additionally, fetal megakaryocyte progenitors have more proliferative potential in vitro than those derived from adults, perhaps related to stronger activation of the JAK2 and mTOR pathways in response to TPO stimulation as found in cord blood megakaryocytes.133 These properties may explain how fetal and neonatal platelet counts are maintained at levels similar to those of adults, at least in the healthy fetus and neonate. The observation of increased numbers of reticulated (young) platelets in fetal compared with adult peripheral blood is consistent with this hypothesis.145
Platelet numbers in the neonate and fetus – normal values
Since platelet counts in fetal blood reach normal adult values by the end of the second trimester, it is reasonable to consider that platelet counts of less than 150 × 109/l represent thrombocytopenia in a healthy neonate regardless of gestation at birth. This conclusion has been challenged by a large retrospective analysis of 47 000 neonates, in which a reference range of platelet counts at different gestational ages was determined by excluding the highest and lowest 5th percentile of all observed counts. By this method, the lowest limit of platelet counts was found to be 104 × 109/l for infants of less than 32 weeks’ gestation, compared with 123 × 109/l for neonates of greater than 32 weeks’ gestation.146 However, as the study included all neonates, regardless of clinical status, these counts may simply reflect the high frequency of thrombocytopenia in neonatal units, where sepsis and placental insufficiency are common causes for admission, rather than representing a new physiological definition of normal platelet counts in the newborn. Indeed, the mean platelet count was above 200 × 109/l regardless of gestation at birth, consistent with accepted normal ranges for the platelet count in neonates.143
Several studies have investigated the clinical relevance of newer automated platelet parameters in neonatal medicine, particularly the immature platelet fraction (IPF). Overall, these studies support the conclusion that in neonates, as in adults, the IPF% provides a measure of the proportion of immature platelets and a surrogate measure of platelet production although the results are variable.147 MacQueen and colleagues established reference ranges for the IPF% in their hospitals based on more than 20 000 automated results from nearly 9000 neonates.148 They reported a higher IPF% in the most premature infants (less than 32 weeks’ gestation). Consistent with this, they also found that IPF% values were higher in neonates who developed consumptive thrombocytopenia compared with those were considered to have reduced platelet production, suggesting that further clinical studies of the value of the IPF% in neonates might be useful, given the practical difficulties of bone marrow aspiration in the newborn.
Neonatal platelet function
Studies of neonatal platelet function in vitro have consistently shown hyporeactivity of neonatal compared with adult platelets to a wide range of platelet agonists, including adenosine diphosphate (ADP), thrombin and thromboxane and especially so to collagen and adrenaline (epinephrine).132,149 In keeping with this, the number of α‐adrenergic receptors on neonatal platelets has been found to be 50% lower than on adult platelets.150,151 By contrast, expression of the main platelet adhesion receptors appears to be similar
