INFLAMMATORY EFFECTS OF PLATELET TRANSFUSIONS IN NEONATAL MODELS OF DISEASE

Abstract

Background and Objective: Preterm neonates have a high incidence of thrombocytopenia and of intracranial bleeding, and are often transfused at higher platelet counts than adults. However, observational and randomized studies have found a higher incidence of bleeding, mortality and bronchopulmonary dysplasia (BPD, a lung disease of prematurity) in neonates receiving more platelet transfusions. The mechanisms underlying these findings are unknown, but neonatal and adult platelets are functionally different, and we have hypothesized that transfusing adult platelets into a neonate may result in a “developmental mismatch”, with potential negative consequences. Since it is now clear that platelets are important regulators of immune responses and inflammation, we designed this study to investigate the inflammatory effects and cellular immune interactions of transfused adult platelets in neonatal murine models of disease.

Methods: We are studying the effects of platelet transfusions (from adult murine donors) in healthy newborn pups, pups with three different etiologies of thrombocytopenia, and in a model of hyperoxia-induced BPD. The models of thrombocytopenia include neonatal LPS and E. coli sepsis models, and transgenic mice lacking the thrombopoietin receptor (c-mpl-/-), which have congenital thrombocytopenia.

Results & Discussion: Platelet transfusions can trigger a systemic inflammatory response in pups without underlying inflammation, prolong the inflammatory response in those with pre-existing sterile inflammation, and increase sepsis-induced morality in septic pups infected with E. coli. The majority of systemic cytokines increased with transfusion are specific to monocytes/macrophages, suggesting that at least some of these inflammatory effects could be mediated through interactions between the transfused platelets and the neonatal monocytes/macrophages. Platelets are well known to interact with and alter the monocyte inflammatory response through interactions with platelet surface receptors (P-selectin) and the platelet releasate (TGFB, B2M, and RANTES). P-selectin surface expression is known to be developmentally different between neonatal and adult platelets, further supporting our hypothesis that adult platelets are potentially more immune-active and could interact more readily with neonatal leukocytes, leading to inflammation and worse outcomes. Studies are ongoing to further explore the mechanisms underlying these findings and how developmental differences between the transfused adult platelets and the endogenous neonatal platelets contribute to these responses.