In vivo polymerization of sickle-cell hemoglobin: a theoretical study.

Several studies on the gelation and oxygenation state of sickle red blood cells have been done under conditions of equilibrium. The kinetics of sickle hemoglobin (HbS) polymerization have also been studied extensively in fully deoxygenated HbS solutions. The issue of the relevance of these investigations to the physiological in vivo situation has not been addressed. Here, we use a theoretical model to compare theoretical equilibrium predictions of HbS polymer concentration and cellular oxygen content, previously validated against equilibrium data, with the corresponding values under physiologic oxygen unloading conditions. We also use the model to simulate polymerization in almost completely deoxygenated sickle erythrocytes, validate the theoretical polymerization curves against published data, and compare them with the corresponding curves from the dynamic oxygen unloading analyses. Our model shows that equilibrium predictions severely overestimate intracellular polymer concentrations and underestimate cellular oxygen content, during the unloading of oxygen. Also, the delay times to significant polymerization in the physiologic situation are substantially longer than the corresponding values measured in completely deoxygenated HbS solutions. These results indicate that in vivo HbS polymerization is strongly influenced by the rate of oxygen desaturation. Equilibrium estimates of intracellular polymer content, or polymerization kinetic data from fully deoxygenated solutions, could be misleading and should be used in the proper perspective.