Study identifies hemoglobin C oxidative damage as key driver of HbSC sickle cell disease severity
A new preprint study demonstrates that hemoglobin C (HbC) is highly prone to oxidative denaturation, causing red blood cell membrane damage in HbSC sickle cell disease. Researchers compared mouse models of HbCC, HbSC, and HbSS disease and found that oxidative damage and reduced red blood cell deformability were most severe in HbCC, followed by HbSC, then HbSS, despite HbSS having higher overall reactive oxygen species. The findings suggest that targeting oxidative membrane injury — not just sickling — could be a valuable therapeutic strategy for HbSC disease.
Researchers studying sickle cell disease variants found that hemoglobin C (HbC) is particularly susceptible to oxidative denaturation, leading to hemichrome (Heinz body) formation and red blood cell (RBC) membrane damage in HbSC disease. Using mouse models, the team showed that oxidized ferryl hemoglobin and Heinz body formation were most pronounced in HbCC, followed by HbSC and then HbSS, even though HbSS RBCs had significantly higher reactive oxygen species — indicating HbC has a greater intrinsic propensity for denaturation than HbS. RBC deformability, measured by elongation index, followed the same pattern, with HbCC cells being the least deformable. The study also found that hydroxyurea treatment in HbSC patients reduced Heinz body formation and improved RBC deformability even when fetal hemoglobin induction was minimal, suggesting a mechanism beyond antisickling. Notably, the antioxidant quercetin produced similar improvements in Heinz body burden and RBC deformability without affecting hemoglobin levels, fetal hemoglobin, reticulocyte count, or RBC dehydration. These results highlight HbC-driven oxidative membrane injury as a distinct and important contributor to RBC dysfunction in HbSC disease, opening potential new avenues for antioxidant-based therapies.
What's missing
As a preprint, this study has not yet undergone formal peer review. The mouse model findings may not fully translate to human disease, and the clinical data on hydroxyurea were observational rather than from a controlled trial. The study does not report long-term outcomes of quercetin treatment or address its bioavailability and safety profile in sickle cell patients. The mechanisms by which hydroxyurea reduces Heinz body formation independently of fetal hemoglobin induction remain unexplained.
What different sources said
- bioRxivCenter
Hemoglobin C is prone to oxidative denaturation, resulting in red blood cell membrane damage in HbSC disease
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