Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease pathophysiology

This review will discuss the current level of understanding of these membrane defects, including their potential pathophysiologic roles which, depending on defect, vary from unlikely to conceivable to virtually certain. The concluding sections will examine the broader perspective of overall pathophysiology and put forth the hypothesis that the true impact of sickle RBC membrane defects on clinical phenotype is to add a stochastic influence, thereby modulating (and obscuring the theoretical predictability of) the fundamental predisposition to disease severity conferred by genetic determinants of Hb polymerization