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 erythrocyte 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 pathophysiology are discussed. First, it is likely that with deoxygenation there is a continuum of cellular changes. Initially, small amounts of polymer form; only with severe and prolonged deoxygenation do large domains of highly ordered, polymerized hemoglobin form in the erythrocyte and cause it to sickle. Second, we combine this model of cellular changes with information from rheologic studies to suggest an alternative model for the pathophysiology of the disease. We postulate that flexibility, governed by the amount and alignment of intracellular polymer, is the principal determinant of the flow of sickle erythrocytes. While cells that have large amounts of ordered polymer may be caught in the capillaries and venules, some cells at relatively high oxygen saturation, with polymer but not deformation, may have difficulty traversing the constriction of the precapillary arterioles. The implications of these recent molecules and cellular studies, as well as of the several models, for the therapy of sickle cell disease are discussed. In general, our analysis suggests that a therapeutically effective strategy is feasible and that certain approaches seem particularly propitious.