Despite a wealth of exploratory plasma metabolomics studies in
sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of
hemoglobin SS, SC and transfused AA red blood cells (RBCs) in vivo . The current study evaluates the RBC metabolome of 587 subjects with sickle cell
sickle cell disease (SCD) from the WALK-PHaSST clinical cohort. The set includes
hemoglobin SS,
hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events, and HbF related to
hydroxyurea therapy. Here we explore the modulating effects of genotype, age, sex, severity of
hemolysis, and
hydroxyurea and transfusion
therapy on sickle RBC metabolism. Data - collated in an online portal - show that the Hb SS genotype is associated with significant alterations of RBC acylcarnitines,
pyruvate,
sphingosine 1-phosphate,
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-generating
phosphoenolpyruvate to
pyruvate step of glycolysis, which is catalyzed by redox-sensitive
pyruvate kinase. Increasing in vivo concentrations of HbA improved glycolytic flux and normalized the HbS erythrocyte metabolome. An unexpectedly limited metabolic effect of
hydroxyurea and HbF was observed, possibly related to the modest induction of HbF in this cohort. The metabolic signature of HbS RBCs correlated with the degree of steady state
hemolytic anemia, cardiovascular and renal dysfunction and mortality.
Key points: In vivo dysregulation of RBC metabolism by HbS is evaluated by metabolic profiling of 587 patients with variable HbA, HbC and HbF levels;RBC acyl-carnitines,
urate,
pyruvate metabolism, S1P,
kynurenine relate to
hemolysis and cardiorenal dysfunction, respond to transfusion.