During the past 10 years, knowledge of the composition, function and supramolecular assembly of the red cell membrane has been greatly expanded by progress in molecular and cell biology. Detailed information on the organization of membrane cytoskeletal proteins and their molecular characterization has allowed us to correlate a number of protein abnormalities with clinical symptoms that are peculiar to hereditary hemolytic anemias (HHA). In particular, three general principles emerge that can help us to understand the pathogenetic mechanisms of HHA: (a) protein-protein and protein-lipid interactions greatly influence the correct assembly of the membrane skeleton; (b) the red blood cell (RBC) membrane skeleton mostly determines the shape (discocyte), deformability (theologic properties) and durability (half-life and resistence to shear stress) of the erythrocytes; (c) changes in cytoskeletal composition and/or organization can produce alterations in all of the above properties, and therefore they are responsible for the onset of the hemolytic damage. The aim of this chapter is to present an up-to-date short overview, evidencing the role of RBC membrane cytoskeleton in the pathogenetic mechanisms that underlie hemolytic anemias. Moreover, we will describe the different impact that various membrane molecular defects have on clinical appearance, and, finally, suggest the possible application of this information to diagnosis and therapy. Three major determinants contribute to the maintenance of normal discoidal shape: (a) lipid composition of the membrane bilayer and lipid-protein interactions (Op den Kamp et al., 1985); (b) protein composition, and reciprocal interactions; in this respect, spectrin appears to be crucial not only in the erythrocytes but also in other mammalian cells (Winkelmann and Forget, 1993; Jacobson et al., 1995), being assembled to form a continuous and regular meshwork associated with the inner surface of the plasma membrane (Fig. 14). Spectrin contains a number of helical repeating sequences (22 for spectrin alpha and 17 for spectrin beta) which render the molecule highly elastic and reversibly deformable. Its role in the maintenance of shape has been dearly demonstrated by experiments showing that RBC shape is retained after elution with hypertonic KCl when the other proteins are removed, but it is dramatically disrupted following the removal of spectrin or actin (Sheetz, 1979); (c) water, ion, and hemoglobin content in the cell. Alterations of one of the above determinants causes structural or functional uncoupling of different membrane constituents, leading from the normal discoidal shape (Figs 15 and 16) to different RBC shape changes, which are summarized in Fig. 17. The final red cell phenotype depends on the cascade of changes that occur in the associated molecular or supramolecular constituents.
