The small-molecule Syk inhibitor R788 inhibits hematopoiesis and worsens anemia in sickle cell disease mice

Vaso-occlusive crises, thrombosis, inflammation, and immune dysregulation contribute to organ damage and poor outcomes in sickle cell disease (SCD). Because neutrophils and dysregulated extracellular trap formation (NETosis) contribute to sickle pathophysiology, and the spleen tyrosine kinase (Syk) signaling pathway is a key driver of NETosis, we investigated the effect of targeting Syk with fostamatinib (R788). Specifically, we studied the effect of a selective Syk inhibitor, R788, on hematologic and biochemical parameters, NETosis, platelet P-selectin expression, and platelet-neutrophil aggregate formation in Townes sickle mice at baseline and after exposure to pathophysiological stressors (tumor necrosis factor α [TNF-α] and hypoxia-reoxygenation). Our results showed that at baseline R788 impaired hematopoiesis, and worsened anemia and neutropenia in sickle mice. Additionally, R788 at nontoxic doses had little, if any, effect on NETosis and platelet activation induced by TNF-α or hypoxia-reoxygenation. Severe anemia and neutropenia induced by R788 in the sickle mouse model suggests that concomitant use of Syk inhibitors with hydroxyurea in patients with SCD should be approached cautiously. Further research is required to clarify the benefits and risks of selective Syk inhibition in SCD and other hemolytic conditions exhibiting stress hematopoiesis.