Coagulation Gene Expression Profiling in Infants With Necrotizing Enterocolitis

Giuliani, Stefano; Tan, Yew-Wei; Zheng, Deyou; Petropoulou, Evmorfia; Ali, Sohail; Bradley, Sarah; Richards, Justin E.; Kennea, Nigel; Jamshidi, Yalda

doi:10.1097/mpg.0000000000001215

Cited by 17 publications

(10 citation statements)

References 31 publications

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“…Even though the formation of NETs is an innate immune mechanism to combat infection, NETs formation can occur during sterile inflammation, autoimmunity, and ischemia reperfusion injury 9,[18][19][20][21] . Thus, as NEC involves a hyperinflammation reactions, as well as immunothrombosis, an essential role of NETs in NEC development is very likely, especially as neonates diagnosed with severe NEC show intestinal ischemia, thrombocytopenia, disseminated intravascular coagulopathy (DIC), and severe inflammation 22 .…”

mentioning

confidence: 99%

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Klinke

Vincent

Trochimiuk

et al. 2020

Sci Rep

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Various research models to induce necrotizing enterocolitis (NEC) in animals exist, yet significant differences in NEC severity between murine animal models and human patients persist. One possible explanation for the difference in severity may be the variance in neutrophil concentration among newborn humans (50-70%) in comparison to neonatal mice (10-25%). However, neutrophil activity has yet to be evaluated in NEC pathogenesis. Thus, the aim of the study was to evaluate the effects of altered neutrophil concentrations in neonatal mice while simultaneously undergoing a NEC induction. A total of 44 neonatal mice were included in this study and 40 were subjected to an established NEC induction paradigm and 4 were assigned a sham group. Of the 40 mice, 30 received granulocytecolony stimulating factor (G-CSF) on a daily basis, while 10 were used as controls (receiving inactivated G-CSF). Mice undergoing G-CSF treatment were further divided into two subgroups: (1) wildtype and (2) ELANE-knockout (KO). ELANE-KO mice are incapable of producing neutrophil elastase (NE) and were used to evaluate the role of neutrophils in NEC. For each of the groups, the following metrics were evaluated: survival, NEC severity, tissue damage, neutrophil count and activation, and NETs formation. An improved murine model of NEC was developed using (1) Lipopolysaccharides and Neocate gavage feeding, (2) hypoxia, and (3) G-CSF administration. The results suggest that the addition of G-CSF resulted in significantly elevated NEC manifestation rates with consequent tissue damage and intestinal inflammation, without affecting overall mortality. Animals without functioning NE (ELANE-KO) appeared to have been protected from NEC development. This study supports the importance of neutrophils in NEC pathogenesis. The optimized NEC induction paradigm, using G-CSF administration, resulted in elevated neutrophil counts, resembling those of neonatal humans. Elevation of neutrophil levels significantly improved NEC disease manifestation by modeling human physiology more accurately than current NEC models. Thus, in the future, murine NEC experiments should include the elevation of neutrophil levels to improve the transition of research findings from mice to humans.

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mentioning

confidence: 99%

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Klinke

Vincent

Trochimiuk

et al. 2020

Sci Rep

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show abstract

“…A 2.03 of N/L ratio was considered as the cutoff value for the disease with a sensitivity of 0.49 and a specificity of 0.76. Giuliani et al (13) mentioned that neutrophil elastase, CD63, PROS1, HGF, and F12 were upregulated with an overall procoagulant effect, and MFGE8, factor II (thrombin) receptor-like 1 (F2RL1), FGL2, PLAT, PROCR, SERPIND1, and HNF4A were downregulated with a reduction in fibrinolysis and endothelial regeneration in the early period of NEC. As a result, FDP and D-dimer increased and PT and APTT were prolonged.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, X-ray was not chosen as a predictive indicator in the study. Of the mechanism of NEC ( 10 ), changes in inflammation indicators were used at the early diagnosis of infections ( 11 , 12 ); procoagulant status of coagulation function indicators was found at the start of NEC in prematurity ( 13 ); abnormity of blood lactate concentrations in the preoperative period carries a poor prognosis in neonates with NEC ( 14 ). However, whether these can be used as the predictive indicators on the disease (NEC with the presence of PVG) is still uncertain.…”

Section: Introductionmentioning

confidence: 99%

Predictive Indicators for Necrotizing Enterocolitis With the Presence of Portal Venous Gas and Outcomes of Surgical Interventions

et al. 2021

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Objectives: Portal venous gas (PVG) was an important clinical sign in stage II or III necrotizing enterocolitis (NEC) in preterm neonates. Not a proper predictive indicator was found to predict the diseases (NEC with the presence of PVG) up to now. There is a need to put forward predictive indicators and compare the predictive effects among them.Methods: We conducted a retrospective study of preterm neonates with NEC-PVG (n = 61) or NEC-non PVG (n = 62) from 2014 to 2021. Predictive indicators were put forward and determined by receiver operating characteristic curve analysis. An analysis of the surgical interventions and their outcomes was performed.Results: The incidence rate of NEC among preterm neonates was 4.99%; surgical and conservative interventions accounted for 20.47 and 75.07%, and the mortality rate was 0.03%. The composition ratio of shock in the NEC-PVG group increased 13.2% (P = 0.029). C-reactive protein, fibrinogen degradation product, and blood glucose had better predictive effects in the predictive indicators (P < 0.05). Intestinal necrosis and subependymal hemorrhage in the outcomes of surgical interventions had a strong relationship with the presence of PVG in NEC II/III (P < 0.05).Conclusion: Early and reasonable use of antibiotics, improvement of coagulation function, rectification of acidosis, and decreased blood glucose could cut down the occurrence of the disease (NEC with the presence of PVG). Except for subependymal hemorrhage and intestinal necrosis, NEC with the presence of PVG did not increase the occurrence of other outcomes after surgery.

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“…Coagulopathy, a common systemic feature of NEC ( 42 ), is characterized by enhanced coagulation and impaired fibrinolysis ( 43 ). Among the proteins observed in this study, antithrombin III from the liver inactivates thrombin and coagulant factors, while PROS1 inhibits coagulation as a cofactor in the inactivation of Factors Va and VIIIa ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Early Protein Markers of Necrotizing Enterocolitis in Plasma of Preterm Pigs Exposed to Antibiotics

et al. 2020

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Background: Most hospitalized preterm infants receive antibiotics in the first days of life to prevent or treat infections. Short-term, early antibiotic treatment may also prevent the microbiota-dependent gut inflammatory disorder, necrotizing enterocolitis (NEC). It remains a challenge to predict NEC, and a few early blood diagnostic markers exist. Using preterm pigs as model for infants, blood parameters and plasma proteins affected by early progression of NEC were profiled in preterm pigs subjected to oral, systemic, or no antibiotics after preterm birth. Methods: Preterm newborn pigs were treated with saline (CON) or antibiotics (ampicillin, gentamicin, and metronidazole) given enterally (ENT) or parenterally (PAR), and fed formula for 4 days to induce variable microbiome-dependent sensitivities to NEC. The gut was collected for macroscopic scoring of NEC lesions and blood for hematology, blood biochemistry, and LC/MS-based plasma proteomics. Statistical modeling was applied to detect plasma proteins affected by NEC and/or antibiotics. Results: Analyzed across different antibiotic regimens, NEC progression was associated with altered blood parameters and abundance of 89 plasma proteins that were functionally involved in extracellular membrane destruction, lipid metabolism, coagulopathy, and acute phase response. Large NEC-related changes were observed in abundance of RBP4, FGA, AHSG, C5, PTPRG, and A-1-antichymotrypsin 2, indicating potential serving as early markers of NEC. Conversely, antibiotic treatment, independent of NEC, affected only 4 proteins with main differences found between ENT and CON pigs. Conclusion: Early postnatal development of NEC lesions is associated with marked plasma protein changes that may be used for early NEC diagnosis.

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Coagulation Gene Expression Profiling in Infants With Necrotizing Enterocolitis

Cited by 17 publications

References 31 publications

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Development of an improved murine model of necrotizing enterocolitis shows the importance of neutrophils in NEC pathogenesis

Predictive Indicators for Necrotizing Enterocolitis With the Presence of Portal Venous Gas and Outcomes of Surgical Interventions

Early Protein Markers of Necrotizing Enterocolitis in Plasma of Preterm Pigs Exposed to Antibiotics

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