The intracellular polymerization of sickle hemoglobin and its relevance to sickle cell disease.

In the last few years. the understanding of the molecular basis of sickle cell disease has progressed rapidly. It is now possible to describe the structure of the gel of polymerized deoxyhemoglobin S at molecular and atomic levels and to begin to understand the mechanism of formation of this gel from hemoglobin solutions. There are several current hypotheses for the pathophysiology of this disease based on molecular as well as cellular studies. Recently, it has become possible to measure the amounts of polymerized hemoglobin within et ythrocyte populations and thereby demonstrate the existence of polymer in cells at very high oxygen saturation values.This unexpectedly low solubility of deoxyhemoglobin S in sickle erythrocytes can be largely accounted for by the theory of protein nonideality. with some contribution from cell heterogeneity. These results show that hemoglobin S in the erythrocyte behaves as it does in very concentrated hemoglobin solutions. There are strong indications, for both SS and AS cells, of the existence of cells with significant amounts of polymerized deoxyhemoglobin S but without morphological deformation (sickling). On the basis of these and other results. two models relating these biophysical findings to pathophysiol-