Anemia in sickle cell disease increases hypoxia induction of erythropoietin (EPO) in the kidney to stimulate bone marrow erythropoiesis and red blood cell (RBC) production. In the circulation, polymerization of deoxygenated sickle hemoglobin leads to repeated sickle (SS) erythrocyte sickling and unsickling, increased red blood cell fragility, and oxidative stress that causes intravascular hemolysis. The release of cell-free heme in the circulation promotes a proinflammatory state and increases interferon-α (IFN-α) that increases erythroid expression of suppressor of cytokine signaling family member, CISH. CISH decreases erythropoietin signaling in erythroid cells, resulting in impaired bone marrow erythropoiesis. Professional illustration by Somersault18:24.