Editorial: Delay time of gelation: a possible determinant of clinical severity in sickle cell disease.

By William A. Eaton, James Hofrichter, and Philip D. Ross T HE FACTORS which determine the frequency of crises and overall severity in sickle cell disease are still not clear. Although Allison,’ Charache and Conley,2 and others3’4 have considered that the kinetics of sickling may be important clinically, accurate measurements of the rates of hemoglobin S gelation and cell sickling have only been made recently.5’5 Measurements on cells under physiologic conditions,8 and extrapolation of gelation data to near physiologic conditions,6” indicate that sickling in vivo may take place in times comparable to capillary and venous transit times. Furthermore, the rate of both gelation and sickling are found to be sensitive to very small changes in physiologic parameters. ’4 These results suggest the hypothesis that sickling kinetics play an important role in determining the clinical course of sickle cell disease. In this editorial we briefly describe the molecular basis for the observed kinetics and comment on possible clinical and therapeutic implications ofthese new findings. Gelation consists of a highly concerted polymerization of hemoglobin S molecules into fibers and the alignment of these fibers to form some kind of crystalline phase) ’8 The aligned fibers rigidify the red cell and produce the distortion referred to as morphological sickling. Gelation may be induced either by deoxygenating a concentrated oxyhemoglobin S solution, or by heating an already deoxygenated solution from a temperature (T), where deoxyhemoglobin S is completely soluble, to some elevated temperature (T’) at which it will eventually gel. If the deoxygenation and temperature “jump”