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The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK\u2010PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and transfusion therapy on sickle RBC metabolism. Results show that RBCs from patients with Hb SS genotypes\u2014compared to AA RBCs from recent transfusion events or SC RBCs\u2014are characterized by significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1\u2010phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP\u2010generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox\u2010sensitive pyruvate kinase. Metabolomics, clinical and hematological data were collated in a novel online portal. In conclusion, we identified metabolic signatures of HbS RBCs that correlate with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality.<\/jats:p>","DOI":"10.1002\/ajh.26923","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:54:40Z","timestamp":1679925280000},"page":"1017-1028","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":false,"given":"Angelo","family":"D'Alessandro","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics University of Colorado Denver \u2013 Anschutz Medical Campus  Aurora Colorado USA"},{"name":"Department of Medicine \u2013 Division of Hematology University of Colorado Denver \u2013 Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7465-0581","authenticated-orcid":false,"given":"S. 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