Predisposing factors, promoters, and triggers of aHUS and secondary HUS. Under physiological conditions, regulation of complement is always at a higher level than the activation challenge. (Right) Regulation consists of the role of the membrane regulators CD35, CD46, CD55, and CD59, and the plasma regulators factors H and I. Regulation is compromised by mutations in complement regulators, autoantibodies against factor H, or potentially some infections in which microbes remove sialic acids from the surface of self cells. Regulation is enhanced by upregulation of complement protein expression in liver (eg, because of acute phase reaction or pregnancy) or introduction of additional regulators by plasma exchange. (Left) Activation of complement consists of continuous alternative pathway activation and occasional (or longer standing) physiological or pathological activation. The level of complement activation can be increased by mutations in complement proteins C3 or factor B, infections, iatrogenic phenomena (eg, transplantation, plasma exchange, or certain drugs), pregnancy, or malignancy. The net result of all the activation and regulation boosting or inhibiting effects may dictate whether activation overrides regulation leading or contributing to a pathological process.