Hypothesis : Changes in the 02 Dissociation Curve and Sickling : A

T HE RELATIONSHIP between oxygen tension and the sickling phenomenon has been recognized for over 45 years’ and has become central to our thinking about sickle cell disease. It has been emphasized that sickling of red cells depends to a large degree upon the absolute concentration of reduced sickle hemoglobin.2 In the past two decades many therapeutic strategies have been explored in the management of sickle cell disease. These include the formation of methemogbobin,3 carboxyhemoglobin,4 alkalinization,2 and most recently, carbamylation of hemoglobin with cyanate5 or with carbamyl phosphate.6 The treatments enumerated have in common the fact that they produce a left shift in the oxygen dissociation curve. When such an experimental therapeutic agent is shown to diminish the amount of sickling observed at a given partial pressure of oxygen, the question arises whether the observed effect is due to a direct effect of the experimental agent upon sickle hemoglobin, or whether the decreased sickling is due merely to the lower concentration of reduced hemoglobin present at a given P#{176}2 level. Recently, it has been implied that effect of cyanate on sickling was due to decreases in the proportion ofdeoxyhemoglobin present at any particular PO2.7M Our own studies on the viscosity of partially deoxygenated hemoglobin solutions has demonstrated that even at a constant per cent saturation of sickle hemoglobin with oxygen, cyanate produces a marked decrease in viscosity.9 Indeed, we have found that all alterations of hemoglobin that lead to a left-shifted dissociation curve produce a decrease of sickling at a given per cent saturation, while all modifications that cause a right shift of the dissociation curve produce an increase of hemoglobin viscosity at a fixed per cent saturation.9” Similar findings with respect to 2,3-DPG were recently reported by others)2 Some of our previously published data and newer findings are summarized in Table 1. It seems worthwhile to speculate about the reason for this consistent effect based on current concepts of hemoglobin function. To understand our view of this general phenomenon it is important to distinguish between the percentage of hemoglobin which is in the oxy-conformation, on the one hand, and the percentage saturation of the hemoglobin solution with oxygen, on the other. Monod et al.,’3 in presenting models to explain the action of allosteric enzymes, called attention to the fact that