Proposed mechanistic pathway (the “iron hypothesis”) explaining how transfusion of older stored RBCs may induce adverse effects in patients. Transfusion of stored, but not fresh, RBCs delivers an acute bolus of RBCs and RBC-derived iron to the monocyte/macrophage system, resulting in oxidative stress and inflammatory cytokine secretion. Some of the macrophage-ingested iron is also released back into the circulation (ie, NTBI), where it can also cause oxidative damage and enhance bacterial proliferation. SIRS, systemic inflammatory response syndrome. Reprinted from Hod et al⁶  with permission.