We have demonstrated that the extent of intracellular polymerization of deoxyhemoglobin S can be predicted from knowledge of intracellular hemoglobin concentration, composition and oxygen saturation. Furthermore, we have demonstrated that polymer, which appears to be the main determinant of abnormal red cell rheology, can be detected in sickle erythrocytes at high oxygen saturation values and is not significantly affected by membrane and other cellular constituents. Some of the factors which modify the pathophysiology of sickle cell anemia can be classified as genetic or cellular. To analyze in more detail the genetic factors, we examined 12 sickle syndromes. When the effects of these genotype differences are analyzed for their changes in hemoglobin composition and concentration, we found that polymer formation can account for 80% of the variation in hemolytic and clinical severity. Cell heterogeneity can also modify polymer formation. The premature increases in erythrocyte density (intracellular hemoglobin concentration) in sickle cell anemia increases polymerization tendency. Homozygous alpha-thalassemia in sickle cell patients reduces this increase in cell heterogeneity and improves the hemolytic aspect of the sickle cell disease. For homozygous sickle cell patients we find that the broader density distributions (higher degree of cell heterogeneity) are associated with those cell populations with greater tendency of polymer formation. However, the major utility of our knowledge of intracellular polymerization appears to be its value in defining quantitatively the goals of the major therapeutic approaches with respect to how much inhibition of polymerization would be necessary to achieve various levels of amelioration of disease processes. The primary determinant of the amount of polymer formation within the SS erythrocyte is the extent of oxygen saturation. We measured intracellular polymer formation in SS erythrocytes using carbon-13/proton double nuclear magnetic resonance. As the oxygen saturation is decreased below about 90% oxygen saturation, we begin to see the appearance of polymer which steadily increases with decreasing oxygen saturation. The total intracellular hemoglobin concentration also affects the amount of polymer formed. By examining polymer formation in fractionated subpopulations of SS erythrocytes at various density values (or intracellular hemoglobin concentrations) we demonstrated that the polymer fraction increased with increasing intracellular hemoglobin concentration for any given oxygen saturation.(ABSTRACT TRUNCATED AT 400 WORDS)