Sickle cell disease: the proportion of liganded haemoglobin needed to prevent crises

In an attempt to predict the likelihood of successfully treating sickle cell disease by increasing haemoglobin S (HbS) oxygen affinity, two liganded derivatives of Hb S have been studied in an in vitro system that measures deoxy-Hb S polymerization. The participation of these liganded forms in the polymers has been quantitated in terms of an exclusion factor that relates their behaviour to that of deoxy-Hb S. Carbonmonoxy-Hb S has an oxy-Hb-like conformation and did not participate significantly in the polymerization. It was calculated that 30% carbonmonoxy-Hb S would have to be maintained in vivo to prevent sickling. Met-Hb S has a conformational equilibrium intermediate between oxy- (or carbonmonoxy-) and deoxy-Hb S and behaved in a similarly intermediate manner with regard to deoxy-Hb S polymerization. 60% met-Hb S would be needed to prevent in vivo sickling. It is concluded that stabilizing the oxy(R)-conformation is a potentially useful way of preventing sickling, and that a level of 30% R-state Hb S would have to be maintained for this to be successful.