MIRAGES - Metabolic Investigation of Red blood cells as a function of Aging, Genetics, Environment and Storage

MIRAGES REDS EXPLORER

Recipient Epidemiology and Donor Evaluation Study REDS-IV-Pediatric

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has launched a seven-year multicenter research program to extend a highly successful program assessing blood banking (blood collection, screening, and processing strategies) and transfusion medicine practices. Research conducted both in the U.S. and Brazil under the Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P) will focus on evaluating and improving the safety and availability of the blood supply as well as the safety and effectiveness of transfusion therapies with attention to not only adults, but also neonates and children who need transfusion.

Improving blood component safety and availability in the United States and internationally through the conduct of epidemiologic, survey, and laboratory studies is the cornerstone of the REDS program which began in 1989.

Reference: Josephson et al. The Recipient Epidemiology and Donor Evaluation Study-IV-Pediatric (REDS-IV-P): A research program striving to improve blood donor safety and optimize transfusion outcomes across the lifespan. Transfusion 2022 May;62(5):982-999. doi: 10.1111/trf.16869 PMID: 35441384 DOI: 10.1111/trf.16869 https://pubmed.ncbi.nlm.nih.gov/35441384

FUNDING: National Heart, Lung and Blood Institutes (NHLBI)
HD/NICHD NIH HHS/United States
75N92019D00032/HL/NHLBI NIH HHS/United States
75N92019D00033/HL/NHLBI NIH HHS/United States
75N92019D00034/HL/NHLBI NIH HHS/United States
75N92019D00035/HL/NHLBI NIH HHS/United States

MIRAGES Sickle Cell Disease

Portal

MIRAGES Sickle Cell Disease Explorer

Metabolic characterization of plasma and red blood cells from the Walk-PHaSST cohort identifies signatures of cardiovascular and renal dysfunction in sickle cell disease

Despite a wealth of relevant exploratory metabolomics studies, no metabolomics study to date has tested enough subjects with biological, genetic and clinical heterogeneity to investigate the impact of factors such as subject's genotype, age, sex or clinical variables (degree of hemolysis, HbS and HbA percentages to disentangle the impact of disease severity and transfusion) on the metabolome of SCD. To bridge this gap, here we leveraged the WALK-PHaSST clinical cohort to perform metabolomics analyses on 587 paired plasma and red blood cell samples from subjects with sickle cell disease. Alterations of red blood cell and plasma pyruvate, sphingosine 1-phosphate, kynurenine and acyl-carnitine metabolism were identified as biomarkers of hemolysis, cardiovascular and renal dysfunction and, ultimately, mortality in SCD patients. The paired testing of plasma and red blood cell identified opposite trends for key markers of disease severity in the two matrices, specfically sphingosine 1-phosphate, suggestive of altered transport of this metabolite in sickle red blood cells. The levels of these metabolites were impacted by biological factors, such as patients' age, sex, body mass index, and iatrogenic factors, such as transfusion, as determined by correlation to HbS and HbA percentages. Treatment with hydroxyurea had a measurable effect on HbF percentages and a moderate effect on plasma and red blood cell metabolism. On the other hand, treatment with the pyruvate kinase activator FT-4202 restored energy reservoirs in human SCD red blood cells in vivo, overcoming the apparent bottleneck in the ATP-generating steps of late glycolysis upstream to pyruvate - one of the top markers of disease severity in this study. Finally, we created an online portal for the sharing and real-time elaboration of all the data generated in this study.

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