EBNEO commentary: Platelet transfusions in neonates and brain development: The new frontier.

Preterm neonates have a high incidence of thrombocytopenia and intraventricular haemorrhage (IVH). Because of this, they are traditionally transfused at higher platelet count (PC) thresholds compared to older children and adults, under the premise that higher PCs decrease bleeding risk.1 Paradoxically, the largest randomised platelet transfusion threshold trial in preterm neonates (PlaNeT-2), found a higher incidence of death or major bleeding within 28 days of randomisation (primary outcome) and a higher incidence of bronchopulmonary dysplasia (BPD) among neonates randomised to a higher platelet transfusion threshold (<50 × 109/L), compared to those randomised to a lower threshold (<25 × 109/L).2 Neonates with a high baseline risk of bleeding and/or death benefited from the lower platelet transfusion threshold as much as low-risk neonates.3 In this manuscript, Moore and collaborators provide evidence that high platelet transfusion thresholds are associated with increased mortality and neurodevelopmental impairment (NDI) at 2 years of corrected age.4 The study had a high follow-up rate (92%), combining results from formal neurodevelopmental (ND) assessment tools (41% of participants), review of medical records, practitioners' notes and early intervention services. Participants were dichotomised as having a favourable or unfavourable outcome (death or severe CP, developmental delay or visual or hearing loss). The combination of different methods to assess ND outcomes is a limitation of the study and restricted the ability of investigators to evaluate subtle deficits or specific neurologic domains. Future trials should include standardised ND assessments at 2 years and be powered for this outcome. Nevertheless, the fact that only severe deficits were included made the findings even more concerning. Given the initial finding that neonates randomised to a higher platelet transfusion threshold had a higher incidence of BPD, the authors performed a post hoc analysis that found a higher need for respiratory support at 2 years among children randomised to the high threshold group. While BPD is common among preterm infants, oxygen dependence or need for respiratory support at 2 years of age is not. Thus, the higher incidence of this outcome among children randomised to the higher threshold suggests platelet transfusions given to high-risk preterm neonates might trigger or enhance pathways leading to severe lung disease. The mechanisms underlying increased morbidity and mortality associated with platelet transfusions are likely related to non-hemostatic effects of platelets. Platelets are critical regulators of immune and inflammatory responses, and it has been hypothesised that adult (transfused) platelets are more pro-inflammatory than neonatal platelets.5-8 In support of this hypothesis, pre-clinical studies suggest platelet transfusions trigger inflammation or dysregulated immune responses in neonates, in a context-dependent manner.9 Whether NDI results from the direct effects of transfused platelets on the developing brain or is mediated by higher rates of IVH and BPD observed in infants randomised to the high threshold group (both of which are associated with NDI), is unknown. Additional studies are needed to define the mechanisms underlying the deleterious and beneficial effects of platelet transfusions, which remain lifesaving in neonates with bleeding or severe thrombocytopenia. In the meantime, this study further supports the use of a restrictive, evidence-based approach to neonatal platelet transfusions. URL LINK: https://ebneo.org/ebneo-commentary-platelet-transfusions-in-neonates-and-brain-development-the-new-frontier/. The authors are supported by grants PO1 HL046925 (MSV), K99 HL156051 (PD) and P01HL152961 (CD). None.