Requirements for therapeutic inhibition of sickle haemoglobin gelation

Abstract

KINETIC studies on haemoglobin S gelation have shown that following initiation of the reaction there is a pronounced delay before the appearance of the polymer^1–5. The delay time is extremely sensitive to physiological variables, such as total haemoglobin concentration and fractional saturation with ligand, and moderately sensitive to pH, salt concentration and temperature (near 37 °C)^1,5–10. Changes in these variables which decrease the delay time seem to be associated with increased clinical severity of sickle cell disease^1,11. These findings have been explained by a pathophysiological mechanism in which a decrease in the delay time of intracellular gelation, relative to the capillary transit time, increases the probability of intracapillary sickling; blockage of the microcirculation is then possible, with consequent tissue anoxia and organ damage. An increase in the delay time, permitting cells to escape the narrow capillaries before gelation has begun, is therefore predicted to result in amelioration of the disease^1,11. We present here results of kinetic experiments designed to help answer the question: how much must the delay time be increased to obtain a given therapeutic effect in patients?