Thrombocytopenia is, after anemia, the most common hematological problem among sick neonates, affecting 20-35% of NICU patients. Platelet transfusions (PLTXs) are frequently given to affected neonates, in an effort to reduce the incidence or severity of hemorrhages. Recently, the FDA approved two novel thrombopoietin (TPO) mimetics for the treatment of adults with immune thrombocytopenic purpura. Based on the duration and severity of thrombocytopenia, up to 10% of thrombocytopenic neonates could also benefit from these agents. However, their use in this population has been hampered by a lack of information about differences between neonates and adults with respect to the pharmacokinetics, pharmacodynamics, and toxicities of these agents, and by our inability to predict the duration of neonatal thrombocytopenia. Our long term goal is to improve the treatment of thrombocytopenic neonates through the evidence-based use of PLTXs and TPO mimetics. Toward this goal, we aim to complete the preclinical in vitro and in vivo studies necessary to guide the use of TPO mimetics in newborn infants. Our central hypothesis is that parameters generated through an advanced mathematical model of neonatal thrombopoiesis will enable us to identify neonates who will benefit from TPO mimetics, but that the cellular, molecular, and pharmacodynamic responses of neonates will be different from those of adults. To test this hypothesis, we have formulated the following Specific Aims: 1) To characterize the effects of TPO and two TPO mimetics, romiplostim and eltrombopag, on fetal, neonatal, and adult human megakaryocytes (MKs). 2) To establish the rates of platelet production at baseline and following the administration of romiplostim in newborn mice with thrombocytopenia;3) To determine whether romiplostim and/or eltrombopag cross the blood-brain barrier;and 4) To develop clinically useful parameters to predict the duration of thrombocytopenia in neonates.
These aims will be accomplished using cellular and molecular studies on primary human MKs (S.A. 1), novel murine models of neonatal thrombocytopenia (S.A. 2), serial cerebrospinal fluid studies in newborn lambs (S.A. 3), and mathematical models of neonatal thrombopoiesis (S.A. 4). The first 3 aims will lead to a better understanding of the neonatal responses to TPO mimetics, and of the potential of these agents to cross the blood-brain barrier (this will be critical given the pro-apoptotic effects of TPO on neurons). The studies in S.A. 4 will develop parameters that are predictive of prolonged thrombocytopenia in neonates. Overall, Project 2 is highly synergistic with the other PPG projects in that it applies concepts, methods and mathematical models developed by PPG investigators to evaluate neonatal erythropoiesis and EPO biology to the study of neonatal thrombopoiesis and TPO mimetics, thus allowing the field of neonatal thrombocytopenia to advance exponentially.

Public Health Relevance

The research proposed here has important public health implications because of the frequency of thrombocytopenia among sick neonates and the serious consequences of this condition, including the risk of intracranial hemorrhage and the need for multiple PLTXs, which are associated with the many risks of bloodproduct exposure. Our studies seek to improve the care of thrombocytopenic neonates by potentially decreasing the number of PLTXs they receive, and therefore promote the NIH mission of reducing the burden of illness and improving outcomes.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL046925-18
Application #
8694066
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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
Bastian, Thomas W; Duck, Kari A; Michalopoulos, George C et al. (2016) Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development. J Thromb Haemost :
Witmer, Jordan R; Wetherell, Bailey J; Wagner, Brett A et al. (2016) Direct spectrophotometric measurement of supra-physiological levels of ascorbate in plasma. Redox Biol 8:298-304
Zamora, Tara G; Guiang 3rd, Sixto F; Widness, John A et al. (2016) Iron is prioritized to red blood cells over the brain in phlebotomized anemic newborn lambs. Pediatr Res 79:922-8
Patel, Ravi M; Knezevic, Andrea; Shenvi, Neeta et al. (2016) Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants. JAMA 315:889-97
Patel, Ravi Mangal; Meyer, Erin K; Widness, John A (2016) Research Opportunities to Improve Neonatal Red Blood Cell Transfusion. Transfus Med Rev 30:165-73
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
Weisenhorn, Erin M M; van T Erve, Thomas J; Riley, Nicholas M et al. (2016) Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells. Mol Cell Proteomics 15:3614-3623
Kuruvilla, Denison J; Widness, John A; Nalbant, Demet et al. (2016) A Mass Balance-Based Semiparametric Approach to Evaluate Neonatal Erythropoiesis. AAPS J 18:187-95
Al-Ghananim, Raeda T; Nalbant, Demet; Schmidt, Robert L et al. (2016) Reticulocyte Hemoglobin Content During the First Month of Life in Critically Ill Very Low Birth Weight Neonates Differs From Term Infants, Children, and Adults. J Clin Lab Anal 30:326-34

Showing the most recent 10 out of 179 publications