This proposal brings together the expertise of the Palis and Morrell labs in developmental hematopoiesis and platelet biology, respectively, in order to gain a mechanistic understanding of the complications associated with platelet transfusions into neonates. Thrombocytopenia is common in newborns, particularly in premature infants. Platelet transfusions are prophylactically used to prevent bleeding, but recent clinical studies have shown that the transfusion of platelets to neonates, while perhaps reducing bleeding risk, can increase serious and sometimes long-term complications including retinopathies, necrotizing enterocolitis and sepsis. We therefore seek to better understand the mechanisms that contribute to these platelet-mediated adverse outcomes. Our long-term aim is to mitigate their adverse effects of platelet transfusions and ultimately develop ex vivo modified platelets, including platelets derived from induced pluripotent stem (iPS) cells, to increase the safety of transfusion therapy for neonates. We have discovered that, compared to adult platelets, neonatal platelets differentially express several immune-related molecules. These data lead to our overall hypothesis that the transfusion of adult platelets into neonates drives an inflammatory phenotype in monocyte leading to adverse complications. This hypothesis is further supported by our preliminary data utilizing a novel murine neonatal transfusion model, where monocyte inflammatory responses were enhanced by adult, but not neonatal, platelet transfusions. We will utilize this in vivo model to define platelet-driven immune responses, focusing on the causative role of platelet-derived immune mediators in the activation of monocytes both in vitro and in vivo. Finally, to obtain a deeper understanding of the developmental program of adult versus neonatal platelets, we will initiate comparative studies of murine and human platelet transcriptomes and proteomes, focusing on the differential expression of immune-related molecules. Completion of this project will establish fundamental insights regarding the developmental biology of platelets and their ability to interact with the immune system of neonates. This knowledge will lay the groundwork for future studies in re-programming platelet immune functions to improve safety and efficacy of platelet transfusions both for neonates and adults.
Thrombocytopenia is common in newborns, particularly in premature infants. Platelet transfusions are prophylactically used to prevent bleeding, but recent clinical studies have shown that the transfusion of platelets to neonates, while perhaps reducing bleeding risk, can increase serious and sometimes long-term complications including retinopathies, necrotizing enterocolitis and sepsis. We therefore seek to better understand the platelet-mediated mechanisms that contribute to these adverse outcomes with the long-term goal of improving the safety of platelet transfusions for newborn infants.
