Proposed model for the contribution by erythrocyte-derived ROS to SCD pathophysiology. Erythrocyte NADPH oxidase-derived ROS, along with that derived from HbS auto-oxidation, induces structural damage in the RBC that renders the cell more vulnerable to lysis or sickling deformation and vaso-occlusion. Additionally, ROS escaping from the RBC effect changes in plasma proteins, WBC, endothelial cells, and platelets, which in conjunction with RBC lysis and vaso-occlusion induce a state of chronic systemic inflammation. Extracellular signaling molecules associated with this inflammatory state act back on the RBC, via cell surface receptors, to induce higher levels of NADPH oxidase activity, closing a positive-feedback loop that drives hemolysis, irreversible sickling, and vaso-occlusion.