Neonatal anemia is the most commonly encountered hematologic problem among all neonates cared for in the neonatal intensive care unit (NICU). Project 1 seeks to better understand the pathophysiology and treatment of this challenging and important condition, especially as it affects premature, critically ill very low birth weight (VLBW) infants who require intensive laboratory blood monitoring leading to the need for multiple red blood cell (RBC) transfusions (RBCTX). In the revised research strategy proposed in Aims 1, 2 and 3, recombinant human erythropoietin (Epo) will first be administered to 1.0 to 1.5 kg VLBW infants;then comprehensive pharmacokinetics (PK) and pharmacodynamics (PD) data will be systematically gathered and analyzed to identify clinical and laboratory covariate parameters differentiating the infants based on their level of Epo responsiveness. Finally the Epo responsiveness predictors thus determined will be applied prospectively in the Aim 4 Study, a 2 x 2 design in which VLBW infants will be identified as good or poor EPO responders, based on the predictors, and then randomly assigned to receive Epo treatment or no treatment. This will test the central hvpothesis of Project 1: RBCTX can be eliminated in the majority of good Epo responders by optimal administration of Epo, but only marginal reductions in RBCTx will occur in the poor Epo responders. Project 1 challenges the prevailing thinking that the efficacy of Epo dosing in stimulating erythropoiesis is insufficient to eliminate the need for RBC transfusions in VLBW infants. Based on extensive preclinical and clinical PK/PD studies by our PPG team, we contend that previous Epo treatment studies in VLBW infants were not able to realize the full potential of Epo to eliminate RBCTX (in contrast to the very successful use of Epo in adult renal failure patients) because previous VLBW studies were conducted 1) without Epo dosing individualized for the complexities of neonatal erythropoiesis and PK/PD of Epo and 2) without consistent criteria for RBC transfusion, Epo dosing, and patient enrollment. The overall impact of Project 1 will be significant and potentially transformative: the development of a personalized, mechanism-driven approach built on sound principles will improve understanding of neonatal anemia and will be applicable to the care of premature, anemic infants. Project 1 synergizes with other PPG groups by expanding knowledge: 1) of erythropoiesis and Epo's PD (Projects 3 and 4);and 2) of PK and PD modeling (thromobopoiesis in Project 2).

Public Health Relevance

Project 1 results confirming our hypothesis that PK/PD optimized Epo treatment is effective in eliminating RBC transfusions administered to a select sub-group of NICU infants will provide fundamental knowledge about neonatal anemia that will reduce the burden of illness and disability caused by this condition. In addition, our results will stimulate researchers to extend our findings to other sub-groups with neonatal anemia, ie, smaller and sicker infants, and will stimulate novel treatments with similar, new biotechnology-produced protein drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046925-17
Application #
8491918
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
17
Fiscal Year
2013
Total Cost
$336,054
Indirect Cost
$114,959
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Sparger, Katherine A; Ramsey, Haley; Lorenz, Viola et al. (2017) Developmental differences between newborn and adult mice in response to romiplostim. Platelets :1-8
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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Bastian, T W; Duck, K A; Michalopoulos, G C et al. (2017) Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost 15:565-574
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
Peters, Anna L; Beuger, Boukje; Mock, Donald M et al. (2016) Clearance of stored red blood cells is not increased compared with fresh red blood cells in a human endotoxemia model. Transfusion 56:1362-9
Ekhaguere, Osayame A; Morriss Jr, Frank H; Bell, Edward F et al. (2016) Predictive factors and practice trends in red blood cell transfusions for very-low-birth-weight infants. Pediatr Res 79:736-41
Brumbaugh, Jane E; Conrad, Amy L; Lee, Jessica K et al. (2016) Altered brain function, structure, and developmental trajectory in children born late preterm. Pediatr Res 80:197-203

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