Background: Sickle cell disease (SCD) is a severe hemoglobin disorder characterized by recurrent vaso-occlusive events, chronic hemolytic anemia, and a pro-inflammatory state associated with early mortality. In recent years, free hemoglobin S (HbS) and heme released by intravascular hemolysis have been shown in vitro to activate innate immune cells, leading to the production of pro-inflammatory cytokines, especially IL-6 and IL-18. However, the link between hemolysis and chronic inflammation, which persists despite transfusion programs, has been little investigated to date in patients with SCD.

Methods: In 2024, we conducted a prospective single-center study in 69 SCD patients and 10 beta-thalassemia controls, aged 1 to 18 years, followed in a French university hospital reference center (GR-Ex/CPP-DC2016-2618/CNIL-MR01). Hemolysis and inflammatory markers, including aspartate aminotransferase (AST), free bilirubin, lactate dehydrogenase (LDH), C-reactive protein (CRP), IL-6 and IL-18, were compared between controls and SCD patients at steady state (n=58, including 30 under regular transfusion program) and during vaso-occlusive crisis (VOC) (n=11). Correlations between hemolysis and inflammatory markers were assessed, notably within the group of patients on a transfusion program, and the impact of hydroxyurea (HU) was also investigated.

Results: Increased levels of hemolysis and inflammatory markers, including CRP, IL-6 and IL-18, were observed in SCD patients at steady state compared to controls, with a further increase during VOC. Patients receiving regular transfusions had similar levels of hemolysis and inflammatory markers as other SCD patients at steady state. A positive correlation was found between hemolysis and inflammatory markers in SCD patients, unlike in beta-thalassemia controls, which persisted in the subgroup of patients under regular transfusion program. Thus, IL-6 was correlated with LDH (r = 0.43, p = 0.02) and AST (r = 0.56, p = 0.002), while IL-18 was correlated with LDH (r = 0.50, p = 0.005), AST (r = 0.56, p = 0.002), and free bilirubin (r = 0.41, p = 0.03). Patients treated with HU showed a trend toward decreased levels of hemolysis and inflammatory markers, although this reduction was modest and not statistically significant. Besides, in a subgroup of 18 steady-state patients, not on a transfusion program, for whom plasma free HbS could be measured, a positive correlation was found between free HbS and IL-6 (r = 0.47, p = 0.049), consistent with our in vitro findings of TLR4-mediated monocyte activation by HbS.

Conclusion: Our study confirms that SCD is associated with chronic inflammation, positively correlated with hemolysis markers, even in steady-state patients receiving regular transfusions. This suggests that the provision of healthy AA red blood cells by transfusion therapy is insufficient to prevent chronic hemolysis of the remaining SS red blood cells and subsequent inflammation. Given the moderate effects observed with HU, other additional therapeutic strategies targeting persistent hemolysis with novel drugs such as pyruvate kinase activators should be considered in the future.

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2025
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