The non-haemostatic roles of platelet activation in neonatal transition and inflammation

The neonatal period is associated with substantial physiological and biochemical transition. With these changes exists a substantial degree of risk both from delayed transition and infection. These risks are both increased by prematurity, with lower gestational ages at birth conferring greater risks. Recent work has noted substantial differences between neonatal and adult platelets. Neonatal platelets have been shown to be “hyporeactive” in comparison to their adult equivalents, and are not as important in clot formation in early life. Using EV enriched platelet poor samples, I examined the role of platelet activation in neonatal transition building on work previously completed as part of the Extracellular Vesicles in Early preterm Neonates and Thrombin generation (EVENT) study. Here I identified modest proteomic changes between day of life 1 and day of life 3 in very preterm neonates. To examine if this was likely reflective of the true biology of transition, we employed a mouse model examining platelets isolated from neonatal mice on day of life 1, day of life 3 and adulthood. A distinct proteome emerged between preterm and term neonates with high expression of extracellular matrix proteins and reduced immune proteins in the preterm cohort. The markers of Platelet Activation foR identification of late onset sEpsis in infaNTs (PARENT) study was a pre-registered multi-site observational study which sought to explore if platelet and endothelial activation markers (in EVs and EV enriched plasma) could prospectively identify late onset sepsis in a preterm neonatal population. Clinical data from the PARENT cohort (n=323) demonstrated that the majority of antibiotic days for late onset sepsis were for children who had no proven infection and the diagnosis of culture proven sepsis remains difficult clinically. Experimentally EV enriched plasma from neonates in PARENT (n=109) was examine using bottom-up proteomics and flow cytometry. Bottom-up proteomics demonstrated a small number of highly upregulated proteins related to leucocyte biology and acute phase reactants which were found in neonates with sepsis. No statistically significant difference was demonstrated between numbers of unlabelled EVs, platelet EVs and endothelial EVs.