Hemolysis releases erythroid DAMP molecules to drive vascular injury and sterile inflammation, which contribute to the pathogenesis of sickle cell disease. Hemolysis releases cell free hemoglobin (Hb), which is normally scavenged by haptoglobin and CD163. Free hemoglobin reacts with and scavenges NO via the dioxygenation reaction and also reacts with hydrogen peroxide to generate hydroxyl radicals via the Fenton reaction. This process leads to endothelial dysfunction and pathological vascular remodeling. Oxidized hemoglobin releases free heme, which can trigger a sterile inflammatory reaction involving TLR4 activation, and stimulates neutrophils to release NETs. These inflammatory events are proposed to cause vasoocclusion and acute chest syndrome in sickle cell disease. There are several potential therapies using the indicated agents (shown in red text) that target multiple stages of this proposed pathophysiological pathway. RBC, red blood cell. Professional illustration by Debra T. Dartez.