Toxicity pathways driven by hemolysis. From a biochemical perspective, hemolysis drives toxicity by Hb oxidation, which generates free heme, and by a sequence of consumptive NO reactions (top panels). The bottom panels symbolize the main targets of hemolysis-driven disease in the immune system, blood vessels, and kidneys. After intravascular hemolysis, cell-free tetrameric Hb dissociates into dimers. Hb dimers can translocate across tissue barriers, leading to toxic exposures of functionally critical compartments, such as vascular smooth muscle cells of arteries or renal glomeruli, leading to vasoconstriction and renal injury. Another toxicity pathway progresses via Hb oxidation, free heme generation, and heme-ligation of TLR4 on endothelial cells and leukocytes, leading to adhesion pathway activation. Finally, Hb and heme exposure of the immune system causes phagocyte dysfunction, suppression of inflammation, and impaired antigen presentation.