Hydroxyurea reduces infections in children with sickle cell anemia in Uganda

Namazzi, Ruth; Bond, Caitlin; Conroy, Andrea L.; Datta, Dibyadyuti; Tagoola, Abner; Goings, Michael J.; Jang, Jeong Hoon; Ware, Russell E.; Opoka, Robert; John, Chandy C.

doi:10.1182/blood.2023021575

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2024

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Cited by 5 publications

References 20 publications

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Weekly dihydroartemisinin–piperaquine versus monthly sulfadoxine–pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial

Idro,

Nkosi-Gondwe,

Opoka

et al. 2024

The Lancet Infectious Diseases

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Weekly dihydroartemisinin–piperaquine versus monthly sulfadoxine–pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial

Idro,

Nkosi-Gondwe,

Opoka

et al. 2024

The Lancet Infectious Diseases

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Malaria prophylaxis in sickle cell anaemia: some answers, more questions

Williams,

Ware

2024

The Lancet Infectious Diseases

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Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice

El-Awaisi,

Perrella,

Mayor

et al. 2024

Preprint

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Sickle cell disease (SCD) leads to hemolytic anemia, vaso-occlusive crisis (VOC), hypoperfusion, and progressive organ damage. Hemin, released during hemolysis in SCD, induces platelet activation through CLEC-2, endothelial activation through TLR4, neutrophil adhesion and NETosis, all of which are regulated by spleen tyrosine kinase (Syk). In this study, we assessed neutrophil and platelet recruitment to the pulmonary, renal, splenic, and hepatic microvasculature in control and SCD mice following hemin injection and the effect of Syk inhibition on cell recruitment and organ perfusion. Compared to controls, SCD mice exhibited higher baseline neutrophil and platelet recruitment to the lungs without alterations in lung perfusion as measured by laser speckle contrast imaging. Injection of hemin increased cell recruitment to the pulmonary and renal vasculature with a concomitant reduction in organ perfusion. However, hemin injection did not change cell recruitment or organ perfusion in the spleen and liver, both of which were altered at baseline in SCD mice. Pretreatment of SCD mice with the Syk inhibitor BI-1002494 mitigated baseline and hemin-induced neutrophil and platelet adhesion in the pulmonary and renal microvasculature, with a corresponding normalization of perfusion. Syk regulates vascular integrity in the lung of SCD mice; whilst high concentrations of BI-1002494 increased bleeding, lowering drug concentrations preserved the inhibitory effect on platelet and neutrophil recruitment and lung perfusion and protected from bleeding complications. These data substantiate Syk as a mediator of vascular thrombo-inflammation and hypoperfusion in the lung and kidney of SCD and provide a rationale for pharmacological inhibition as a therapeutic strategy.

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Hydroxyurea reduces infections in children with sickle cell anemia in Uganda

Cited by 5 publications

References 20 publications

Weekly dihydroartemisinin–piperaquine versus monthly sulfadoxine–pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial

Weekly dihydroartemisinin–piperaquine versus monthly sulfadoxine–pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial

Malaria prophylaxis in sickle cell anaemia: some answers, more questions

Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice

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