How do sickle cells become dehydrated?

In sickle cell anemia, dehydrated erythrocytes (SS RBC) are involved in the propagation of the vasoocclusive process, which results in the most severe complication in sickle cell disease (e.g. stroke). Deoxygenation leads to red cell dehydration, and hence increases the rate of hemoglobin S (HbS) polymer formation, which subsequently sickles the cell and retards RBC transit through the microvasculature. Dehydrated SS RBC exhibit decreased filterability and poor deformability, contributing to acute and chronic vaso-occlusive episodes and organ damage and to early removal from the circulation, uncompensated by erythropoiesis, resulting in hemolytic anemia. The hydration state and the hemoglobin F (HbF) content of RBC are known to in ̄uence their in vivo survival: SS RBC, and especially denser fractions, have a much shorter lifespan than normal RBC; and, the lifespan of cells with high levels of HbF (F cells), particularly in SS patients, is six to eight weeks, whereas that of non-F cells is only about two weeks. Populations of SS RBC are highly heterogeneous with respect to age, density, HbF and cation contents (Figure 1). The densest SS cells are, on average, younger than lesser dense cells, and, in vivo, subpopulations of young cells dehydrate at di€erent rates, with a fraction (mostly reticulocytes) being susceptible to rapid dehydration after deoxygenation in vitro. Dehydration is the result of a cationic loss, followed by Cl and water leaks to maintain electroneutrality and osmolarity of the cell. Deoxygenation-induced sickling leads to a permeabilization of the SS RBC membrane for mono and divalent cations, resulting in a net movement of Na, K, Mg and Ca along their electrochemical gradients, a process named sickling-induced pathway (SIP). Stimulation of SIP leads to initially balanced Na and K ̄uxes, but by increasing the Nai/Ki ratio, this stimulation results in the activation of the Na/K pump and slow dehydration. The contribution of this mechanism is considered to be minor and cannot account for the extreme K depletion of highly dense cells. Two K transporters have a high capacity for mediating rapid K loss and dehydration in RBC: the Ca-activated K channels (KCa channels) and the K/Cl cotransport (KCl-cot). KCa channels, if maximally activated, dehydrate normal RBC very rapidly. They are activated in deoxygenated SS RBC, following the stimulation of Ca in ̄ux by SIP. However, as HbF delays and decreases HbS polymerization and hence reduces SIP, KCa-channel activation will exclude most of the F cells. KCl-cot is highly active in SS RBC, and particularly in young RBC, where it can promote a rapid dehydration when activated by cell swelling or acid pH. Until recently, it was thought that KCl-cot is inhibited by deoxygenation.