Abstract
BACKGROUND: Sickle cell disease (SCD) is a challenging genetic disorder characterized by hemolytic anemia, vaso-occlusive crises (VOC), and progressive organ damage. Despite its severity, effective treatments are limited. The recent withdrawal of promising therapies, such as the anti-P-selectin antibody Crizanlizumab and the hemoglobin polymerization inhibitor Voxelotor, highlights the urgent need for innovative approaches to alleviate vaso-occlusion and thromboinflammation. METHODS: In this study, we used advanced techniques, including intravital microscopy, laser speckle contrast imaging, and histological analysis, to examine the role of syk (spleen tyrosine kinase) in platelet and neutrophil recruitment, and blood perfusion in the lung, kidney, liver, and spleen of SCD mice. RESULTS: In the Berkeley SCD model, hemin-induced vaso-occlusion and impairment in pulmonary blood perfusion were independent of red cell congestion and fibrin deposition. Hypoperfusion was driven by adhesion of neutrophils and platelets in the microcirculation and exacerbated by pulmonary emboli. Hemin-induced cell adhesion and hypoperfusion were also observed in the renal microcirculation, whereas it was limited in the liver and spleen of SCD mice, suggesting that organ-specific mechanisms drive hypoperfusion and vaso-occlusion. To explore therapeutic options, we investigated the potential of Syk inhibition in improving blood perfusion and reducing thrombo-inflammation in different organs. Selective Syk inhibition, using BI-1002494, reduced cellular adhesion in the pulmonary and renal microvasculature, effectively restoring blood perfusion and reducing thrombo-inflammation. Low-dose Syk inhibitor was effective in reducing neutrophil adhesion and improving blood perfusion without inducing bleeding. Increasing the dose exacerbated hemin-induced bleeding in the lungs, likely due to off-target activity againt other kinases, including Src. CONCLUSIONS: These findings underscore the critical role of Syk in platelet and neutrophil mediated-thrombo-inflammation and hypoperfusion in SCD, suggesting that Syk inhibition is a promising strategy to reduce organ-specific vaso-occlusion, improve renal and pulmonary perfusion, and reduce organ damage.