Lower efficacy of transfusion of red blood cells from donors with sickle cell trait.

Sickle cell trait (SCT), the heterozygous state for the hemoglobin S (HbS) mutation, affects roughly 1 in 13 African American individuals and is common among blood donors recruited for antigen-matched transfusions in sickle cell disease (SCD). While individuals with SCT are typically asymptomatic, it is unclear whether red blood cells (RBCs) from SCT donors have impaired storage quality and transfusion efficacy. Here, we integrate multi-omics to characterize RBCs from donors SCT and evaluate their performance post-transfusion. We first profiled RBCs from 174 HbAS and 248 HbAA volunteers, identifying elevated levels of metabolic markers of the storage lesion in SCT RBCs at baseline. We then interrogated the REDS RBC Omics dataset (>13,000 donors), identifying blood donors carrying the HbS E6V variants. SCT RBCs exhibited accelerated metabolic aging, oxidative stress, and proteostatic activation-phenotypes further exacerbated by storage duration and co-inheritance of G6PD deficiency. Functional assays confirmed decreased osmotic fragility and increased oxidative hemolysis in SCT RBCs by storage Day 42. Pre-clinically, stored RBCs from Townes mice carrying one allele of human sickle hemoglobin were characterized by a drop in post-transfusion recovery compared to mice expressing canonical human hemoglobin. Clinically, analysis of 6828 transfusion events revealed that SCT RBCs were associated with lower hemoglobin increments 24 h post-transfusion. These findings provide mechanistic and clinical evidence that SCT influences RBC quality and transfusion outcomes. Given the overrepresentation of SCT in donor pools serving patients with SCD, our study supports a more personalized approach to inventory management and transfusion strategies in high-risk populations.