Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants, and a leading cause of mortality in neonates born prior to 32 weeks' gestation. Clinical studies show that >90% of patients with confirmed NEC develop thrombocytopenia, but the underlying mechanisms remain unclear due to limited investigative attention so far. Because premature infants who develop NEC are also at risk of serious bleeding complications such as intraventricular hemorrhage, thrombocytopenia in a critically-ill infant with NEC is usually treated prophylactically with platelet transfusions (to correct the platelet count, not actual bleeding). There is some evidence to link platelet transfusions with adverse outcomes in NEC, but platelet transfusions continue to be used widely in these patients because the question remains whether the inferior outcomes of infants treated with platelet transfusions reflect the adverse effects of the transfused platelets or merely the confounding effect of the higher severity of illness of these infants. Understanding the pathophysiological role of platelets in NEC is critical for rational transfusion practices. To investigate these questions, the investigators have developed murine models of NEC-related thrombocytopenia and generated preliminary data on the pathophysiological role of platelets and the mechanisms of thrombocytopenia during NEC.
Three specific aims are proposed: (1) Elucidate the mechanisms underlying the development of thrombocytopenia during NEC, and establish major sites of platelet consumption during NEC; (2) Determine the effect of thrombocytopenia on intestinal injury during NEC; and (3) Determine the effect of platelet transfusions on intestinal injury during NEC. In the third aim, the investigators will also compare fresh vs. stored platelets for their inflammatory effects. Accomplishment of the proposed aims will generate novel insights into the effects of platelet transfusions on neonatal intestinal injury. Important information on the immunomodulatory effects of platelet transfusions in neonates will also be obtained. These studies will also provide important reference points for clinical evaluation of transfusion practices in premature infants and during intestinal injury.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. Most infants with confirmed NEC experience a drop in their platelet counts with 24-28 hours of onset of NEC. In this application, the investigators seek to investigate the mechanisms and effects of reduced platelet counts, and the effects of platelet transfusions in these patients.
| Ho, Thao T B; Groer, Maureen W; Kane, Bradley et al. (2018) Dichotomous development of the gut microbiome in preterm infants. Microbiome 6:157 |
| Patel, Ravi M; Josephson, Cassandra D; Shenvi, Neeta et al. (2018) Platelet transfusions and mortality in necrotizing enterocolitis. Transfusion : |
