2/2 Neonatal Platelet Transfusion Threshold Trial (NeoPlaTT) - Abstract Extremely preterm infants born at 23 to 26 weeks gestation have the highest incidence of thrombocytopenia and bleeding and the highest mortality among neonates admitted to the Neonatal Intensive Care Unit (NICU). Approximately 20% of extremely preterm infants develop a severe intracranial hemorrhage, almost always in the first week of life, which is the highest risk period for bleeding. Platelet transfusions are frequently administered to extremely preterm neonates at higher platelet count thresholds than those used in older children and adults to decrease the risk of bleeding. Paradoxically, a recent multicenter randomized trial of infants <34 weeks gestation conducted in Europe (PlaNeT-2) found that neonates randomized to a lower platelet transfusion threshold of 25x10^9/L, compared to 50x10^9/L, had a significantly lower risk of death or serious bleeding. However, 39% of infants received one or more platelet transfusions before enrollment, and the median age at recruitment was 7-8 days, suggesting that a high proportion of thrombocytopenic infants in the first week of life were not randomized before being transfused. This likely contributed to the persistent uncertainty regarding optimal platelet transfusion thresholds, specifically in the most immature preterm infants in the first week of life. In a recent survey, 57% of responding European NICUs continued to use thresholds above 25x10^9/L in infants <28 weeks’ gestation and <7 days old. Another question raised by PlaNeT-2 was whether thresholds lower than 25x10^9/L can be safely applied to extremely preterm infants after the first week of life, when the risk of bleeding is much lower. The Neonatal Platelet Transfusion Threshold (NeoPlaTT) trial was specifically designed to address these critical questions and will test the hypothesis that, among extremely preterm infants born at 23 to 26 weeks gestation, a low platelet transfusion threshold, compared to a high threshold, will improve survival without major or severe bleeding up to 40 weeks postmenstrual age. The Specific Aims will (1) determine the comparative effectiveness of low platelet transfusion thresholds (25x10^9/L in the 1st week of life, 20x10^9/L thereafter), compared to high thresholds (50x10^9/L in the 1st week, 35x10^9/L thereafter), on the risks of death or major/severe bleeding for infants born at 23 to 26 weeks gestation; (2) determine the comparative effectiveness of high vs. low thresholds on mortality as a key secondary outcome, along with serious morbidities and need for platelet transfusion. Importantly, the trial will be conducted in the NICHD Neonatal Research Network, which is a consortium of NICUs with established site research infrastructure and extensive experience conducting multicenter clinical trials with early recruitment of high-risk neonates. If our hypothesis is confirmed, this trial will change the current paradigm regarding the liberal use of platelet transfusions to prevent bleeding towards the avoidance of unnecessary platelet transfusions in this population. Most importantly, knowledge generated from the NeoPlaTT trial may improve outcomes in our most vulnerable patients, while also decreasing costs and conserving resources.