Role of hybrid tetramer formation in gelation of haemoglobin S

Abstract

THE transformation of erythrocytes containing haemoglobin (Hb) S from pliable biconcave disks into rigid pointed “sickled” forms, which underlies the pathology of sickle cell disease, results from the tendency of this mutant haemoglobin to polymerise and produce an intracellular gel on deoxygenation. In the genetic variants of sickle cell disease, the different types and proportions of non-S haemoglobins present in the red cells together with Hb S are important in determining the extent of the sickling tendency and the severity of the disease. Red cells containing Hb S along with a substantial proportion of foetal haemoglobin (Hb F, α₂γ₂), sickle less readily than cells having a similar proportion of the normal adult type, Hb A (α₂β₂). Such differences can be demonstrated with solutions of haemoglobin mixtures in vitro by measuring the minimum gelling concentrations (MGC), that is, the minimum concentration of total haemoglobin at which the mixture will form a gel on complete deoxygenation. The higher MGC of Hb S–F mixtures compared with S–A mixtures correlates with the lesser sickling tendency of the former combination within red cells.