Effects of Platelet Transfusions on Neonatal Chronic Lung Disease and Sepsis-Induced Mortality

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SUMMARY This K99/R00 proposal describes a five-year mentored research and training plan that will facilitate the transition of Dr. Patricia Davenport to an independent academic researcher in neonatal hematology. Dr. Davenport is a productive and dedicated young physician-scientist working in a clinically relevant and understudied field. PLTs are active participants in both hemostasis and inflammation, yet clinical awareness of these dual roles has lagged behind research discoveries, particularly in neonatology. Preterm infants are at high risk of spontaneous bleeding (particularly intracranial) and thus are typically transfused at higher PLT counts than children or adults, in the hope of preventing bleeding. However, a recent large randomized trial in preterm neonates found that liberal PLT transfusions increased mortality and risk of chronic lung disease, without decreasing bleeding. The mechanisms mediating these findings are unknown, but we hypothesize that they are at least partly related to the developmental differences between neonatal and adult PLTs. The overarching aim of this proposal is to improve the management of neonatal thrombocytopenia through a better understanding of the consequences of PLT transfusions in neonates with various underlying pathologies. Our overall hypothesis is that the effects of PLT transfusions increasing neonatal mortality and severity of chronic lung disease are mediated by an amplification of the neonatal inflammatory responses. To test this hypothesis, we designed the following Specific Aims: 1. Determine the effects of PLT transfusions on newborn mice with and without endotoxemia; 2. Determine the effects of PLT transfusions on mortality in a neonatal model of sepsis; and 3. Characterize the effects of PLT transfusions in a neonatal murine model of chronic lung disease. This research is highly significant, as knowledge gained from it will inform clinical practice and research. Dr. Davenport will receive mentorship from her co- mentors, Dr. Martha Sola-Visner, an NIH-funded researcher in the field of neonatal PLT biology, and Dr. Stella Kourembanas, a world-renowned investigator in neonatal pulmonary physiology and chronic lung disease. In addition, Dr. Davenport will have the guidance of her Scientific Advisory Committee, composed of distinguished scientists with expertise in transfusion medicine and immunology, neonatal sepsis and inflammation, infectious diseases, and study design/statistics. The training opportunities and resources at Boston Children’s Hospital (BCH) and Harvard Medical School provide an ideal environment for the candidate’s career development. The Division of Newborn Medicine at BCH is committed to Dr. Davenport’s success and has assured at least 75% protected time to devote to the activities described in this proposal. A detailed career development and training plan is presented, including mentored research, didactic coursework, seminars and presentations at scientific meetings, and a plan for manuscript writing and R00 submission. The expertise and knowledge gained from this Award will enable Dr. Davenport to obtain future R01 funding and transition to an independent research career focusing on neonatal PLT biology, and particularly the interactions of PLTs with the neonatal lung.