Probing Red Blood Cell Deformability in Sickle Cell Disease, Sickle Cell Trait, and Healthy Controls by Ektacytometry

ABSTRACT Introduction Red blood cell (RBC) deformability is a key determinant of sickle cell disease (SCD) pathophysiology. We evaluated RBC deformability across HbSS, HbAS, and HbAA genotypes and investigated its associations with hemolysis, fetal hemoglobin (HbF), coinherited α‐thalassemia, hydroxyurea treatment, and the PIEZO1 E756del variant. Methods We used Lorrca ektacytometry to compare RBC deformability across 174 participants with HbSS, HbAS, and HbAA genotypes. Deformability was evaluated across a range of shear stresses, osmotic pressures, and oxygen tensions. Associations between deformability and hemolysis markers, HbF levels, α‐thalassemia status, hydroxyurea use, and the PIEZO1 E756del variant were assessed. Results HbSS RBCs showed markedly reduced deformability across all shear stresses, osmotic pressures, and oxygen tensions compared to HbAS and HbAA RBCs. Reduced deformability correlated with elevated markers of hemolysis, including lactate dehydrogenase (LDH) and bilirubin. Higher HbF levels were independently associated with improved RBC deformability, whereas coinherited α‐thalassemia was not associated with improved deformability. Hydroxyurea use was associated with significantly improved deformability. The PIEZO1 E756del variant was associated with reduced deformability among participants with HbSS. Conclusion RBC deformability is substantially impaired in HbSS and is associated with markers of hemolysis and several genetic and treatment‐related factors. These findings support Lorrca ektacytometry as a robust biomarker platform for assessing RBC health and treatment response in SCD. Trial Registration ClinicalTrials.gov identifier: NCT03685721