Schematic representation of sources and mechanism of ROS accumulation inside the SCD RBCs. Auto-oxidative unstable HbS (1), membrane-bound hemichrome (2), dissociated heme (3), NADPH oxidase (4), heme free iron (5), excessive adenosine triphosphate utilization with higher rate of polymerization of HbS (6), and abnormally retained mitochondria (7) are the major intracellular sources and mechanisms reported for the excessive ROS accumulation that may cause shorter lifespan because of PS exposure followed by removal by reticuloendothelial system or caspase-mediated intravascular hemolysis.