Both humans with SCD and Townes sickle mice demonstrate evidence for FXIIa and contact-pathway factor activation at baseline and display elevated surface FXIIa on neutrophils. TNFα challenge in sickle mice is associated with FXII-dependent activation of the complement pathway of inflammation and the intrinsic pathway of coagulation. Recapitulation of the sickle phenotype by transplantation of HbSS bone marrow into FXII-deficient mice (HbSS/FXII^–/–) attenuated these effects. Similarly, genetic FXII deficiency (HbSS/FXII^–/–) and treatment with an antibody to FXII (15D10) attenuated vascular stasis, and hepatic and renal congestion in sickle mice challenged with heme to induce vascular stasis, a model mimicking acute VOC in humans with SCD. Infusion of the antibody 15D10 also attenuated electrolytically induced femoral venous thrombosis and reduced stroke infarct volume and neutrophil adhesion in the pial blood vessels of sickle mice. Illustration by Bindu Gopalan.