In vivoevaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction

Abstract

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 were collated in an online portal and 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.

Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine

“…Post-HS elevation in circulating levels of amino acids are consistent with proteolytic events (eg, collagen breakdown, proline), altered hepatic function (eg, transamination, alanine—as reported with in vivo tracing of stable isotope-labeled glutamine in rodents 48 ), and kidney dysfunction (eg, creatinine 49 ) at 30 minutes after the EOS. Of note, creatinine accumulation and elevated hemolysis have been previously associated with dysregulated carnitine metabolism, as a function of impaired reuptake by SLC22A5 in the kidney in response to acute or chronic hypoxia, 50,51 and following osmotic stress-induced alterations of the Lands cycle, which participates in damaged lipid repair in the mature red blood cell 52,53 . Of note, elevation in circulating levels of acyl-carnitines was here associated with viscoelastic measurements of reduced clot strength, consistent with a previously described role of acyl-carnitines as anticoagulants via inhibition of factor Xa 54 …”

Complete absence of GLUT1 does not impair human terminal erythroid differentiation

“…Interestingly, these metabolic alterations were accompanied by elevation in acyl-carnitine pools, lysophospholipids, and odd-chain fatty acids derived from alpha-oxidation of longer chain polyunsaturated fatty acids, despite decreases in several classes of lipids. These lipidomics data are suggestive of increased oxidant stress to the RBC membrane fraction, consistent with the activation of the Lands cycle and an increased susceptibility to osmotic fragility, similar to that observed for RBCs from patients suffering from chronic 46 or acute kidney disease 47,48 , sickle cell disease and hypoxia 49 .…”

A novel composition of endogenous metabolic modulators improves red blood cell properties in sickle cell disease

“…For example, all glycolytic intermediates (except pyruvate) are significantly increased in SCA but not in HbSC disease [9]. The metabolic profile of patients with SCD could also differ over time [9, 10]. Several plasma and RBC metabolites alter on the occurrence of VOEs compared to the steady‐state condition [10].…”

“…Increased knowledge on the pathophysiology of SCD has provided new therapeutic targets. SCD RBCs show alterations in various metabolites compared to healthy RBCs [9]. In addition, RBC metabolism in patients with HbSC disease differs from patients with SCA.…”

“…In addition, RBC metabolism in patients with HbSC disease differs from patients with SCA. For example, all glycolytic intermediates (except pyruvate) are significantly increased in SCA but not in HbSC disease [9]. The metabolic profile of patients with SCD could also differ over time [9, 10].…”