Transport pathways contributing to sickle cell dehydration. Hemoglobin (Hb) S polymerization activates the sickling-induced pathway, permitting Ca⁺⁺ entry. Increased cytoplasmic Ca⁺⁺ activates the Gardos pathway, which mediates rapid K⁺ efflux, balanced by Cl⁻ exit via a chloride conductance pathway. High Hb S concentration resulting from abnormal regulation of K:Cl cotransport may potentiate Hb S polymerization in reticulocytes. Once initiated, the vicious cycle of sickling and dehydration intensifies and perpetuates itself. KCC indicates K:Cl cotransporter; SIP, sickling-induced pathway; G, Gardos pathway; and CC, Cl conductance pathway.