Stored-RBC-dependent acute lung and kidney injury is prevented by hemopexin, heme addition promotes endothelial and epithelial injury [36,57,59], and multiple studies have shown heme to be a mediator of acute inflammatory injury to all major organ systems in sickle cell disease and sepsis via multiple overlapping mechanisms including TLR4 activation, oxidative stress, immune cell dysfunction, and suppression of phagocytosis [44–47,58,62,63]. Here, TLR4 is linked to sickle cell disease.