We have demonstrated that spleen-mediated vesiculation is an integral part of the physiological aging process, and we postulate that vesicle-mediated removal of damaged hemoglobin occurs mostly in the liver during the second half of the eryth-rocyte lifespan [27, 28]. We have recently obtained data suggesting that vesicles may also serve to remove damaged membrane components, and that alterations in band 3 structure are involved in the vesiculation process (Bosman et al., unpublished observations). The mechanism by which vesicles are formed is largely unknown, but it is known that an artificial increase in the intracellular calcium concentration results in the formation of various types of vesicles [22]. In a series of pilot experiments we observed that upon incubation with a calcium ionophore in the presence of low concentrations of Ca2+, erythrocytes from various NA patients produced both microvesicles and nanovesicles that were qualitatively and quantitatively different from the vesicles that were produced by erythrocytes from control donors (Bosman and Salzer, unpublished observations). This conclusion, although mostly based on preliminary findings, constitutes another indication for a disease-related alteration in the membrane organization of erythrocytes of NA patients.

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