The unifying theme of this PPG renewal is understanding the pathophysiology, and thereby establishing the optimal management of two of the most frequently encountered hematologic conditions among critically ill, premature infants: anemia and thrombocytopenia. Current treatment for these conditions relies largely on transfusion of red blood cells and platelets, therapies that remain empiric, controversial and incompletely investigated in this population. Prior studies by our PPG group and others have established that many aspects of the pathophysiology of anemia and thrombocytopenia in premature infants are unique to this population. However, our understanding of the consequences of this unique physiology in informing various treatment strategies is incomplete. Importantly, studies from our group suggest that treatment approaches substantially influence short- and long-term outcomes. Hence, the goals of our renewal are to define the unique hematological features of preterm infants as they mature, the novel roles of red blood cells and platelets on neonatal inflammation and immune regulation, and the consequences of neonatal anemia and its two commonly utilized treatment strategies on neurodevelopment. Our 4 interrelated projects, whose objectives are directly relevant to our unifying theme, include: Project 1 ?Impact of thrombocytopenia and platelet transfusions on neonatal inflammation and host defense,? PL Martha Sola-Visner; Project 2 ?Impact of anemia on gut injury and immune function in preterm infants,? PL Cassandra Josephson (and Sean Stowell); Project 3 ?The effect of neonatal anemia and its treatment on brain development,? PL Michael Georgieff; and Project 4 ?The effect of anemia and its treatment on neurodevelopmental outcomes of premature infants,? PL Peg Nopoulos. Core A (?Administrative and data management core?) and Core B (?Biostatistical analysis and mathematical modeling core,?) will provide support for all projects. Our goals will be achieved through a combination of human clinical/translational studies and closely-matched animal models, in order to incorporate clinical and mechanistic insights to better understand the developmental stage-specific effects of cytopenias and transfusions in neonates. At our last renewal, and again in this submission, our PPG broke geographical barriers to pursue the best possible combination of multidisciplinary scientists to achieve our goals. Our history of success conducting multisite research will be invaluable in coordinating studies across the various performance sites. Over the past 24 years, our PPG has made a substantial impact on clinical practice and research in neonatal hematology and transfusion medicine. With this renewal, we are poised to continue to challenge paradigms and advance knowledge, with the ultimate goal of improving the outcomes of our most vulnerable patients.

Public Health Relevance

The proposed studies will enhance our understanding of the effects of the two most important, common and costly hematological conditions encountered in the NICU: anemia and thrombocytopenia. Specifically, our research will determine the impact of different treatment strategies, particularly red cell and platelet transfusions, on critically important neonatal short- and long-term outcomes. Thus, these studies support the NIH's mission of reducing the burdens of illness and disability in our most vulnerable patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046925-23
Application #
9968329
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Mondoro, Traci
Project Start
1992-07-01
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
23
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Cakir, Bertan; Liegl, Raffael; Hellgren, Gunnel et al. (2018) Thrombocytopenia is associated with severe retinopathy of prematurity. JCI Insight 3:
Nalbant, Demet; Cancelas, José A; Mock, Donald M et al. (2018) In premature infants there is no decrease in 24-hour posttransfusion allogeneic red blood cell recovery after 42 days of storage. Transfusion 58:352-358
Benavides, Amanda; Metzger, Andrew; Tereshchenko, Alexander et al. (2018) Sex-specific alterations in preterm brain. Pediatr Res :
Mock, Donald M; Nalbant, Demet; Kyosseva, Svetlana V et al. (2018) Development, validation, and potential applications of biotinylated red blood cells for posttransfusion kinetics and other physiological studies: evidenced-based analysis and recommendations. Transfusion 58:2068-2081
Sparger, Katherine A; Ramsey, Haley; Lorenz, Viola et al. (2018) Developmental differences between newborn and adult mice in response to romiplostim. Platelets 29:365-372
Patel, Ravi M; Josephson, Cassandra D; Shenvi, Neeta et al. (2018) Platelet transfusions and mortality in necrotizing enterocolitis. Transfusion :
Teramo, Kari A; Klemetti, Miira M; Widness, John A (2018) Robust increases in erythropoietin production by the hypoxic fetus is a response to protect the brain and other vital organs. Pediatr Res :
MacQueen, B C; Christensen, R D; Henry, E et al. (2017) The immature platelet fraction: creating neonatal reference intervals and using these to categorize neonatal thrombocytopenias. J Perinatol 37:834-838
Schmidt, Robert L; Mock, Donald M; Franco, Robert S et al. (2017) Antibodies to biotinylated red blood cells in adults and infants: improved detection, partial characterization, and dependence on red blood cell-biotin dose. Transfusion 57:1488-1496
Wallin, Diana J; Zamora, Tara G; Alexander, Michelle et al. (2017) Neonatal mouse hippocampus: phlebotomy-induced anemia diminishes and treatment with erythropoietin partially rescues mammalian target of rapamycin signaling. Pediatr Res 82:501-508

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