The anemia results from the markedly shortened circulatory survival of SS cells, together with a limited erythropoietic response. Both independent properties of Hb S-polymerization of the deoxy-Hb and instability of the oxy-Hb-contribute to early red cell destruction by effects on the Hb and on the red cell membranes. The erythroid response is limited mainly by the low oxygen affinity of SS cells, caused by the polymer and the increased 2,3-DPG. But the worst culprits in these processes are the dense, dehydrated SS cells (including the ISCs), most of which are formed rapidly from non-Hb F-reticulocytes by cation transport mechanisms triggered by polymerization. Since the clinical consequences of microvascular occlusion far exceed those of anemia per se, measures to lessen the anemia must also inhibit polymerization and sickling.