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C H A P T E R 45

RED BLOOD CELL MEMBRANE DISORDERS

Patrick G. Gallagher

Characterization of the structure and function of red blood cell horizontal defect resides in the junctional complex, where the distal
(RBC) membrane proteins and their genes (Fig. 45.1) has led to ends of spectrin tetramers connect to actin, in conjunction with
considerable advances in our understanding of the molecular pathol- protein 4.1R. In patients with severely dysfunctional spectrin muta-
ogy of membrane-associated disorders, including the definition and tions, the weakened spectrin dimer-dimer self-association disrupts the
characterization of mutations of membrane proteins as a well-defined skeletal lattice, leading to a marked skeletal instability and cell frag-
cause of hereditary hemolytic disease. Likewise, knowledge of the ments. In patients with mildly dysfunctional spectrins, RBC shape is
molecular mechanisms underlying changes in RBC deformability, that of biconcave elliptocytes. It is speculated that elliptocytes are
structural integrity, and shape has advanced. RBC shape abnormali- permanently deformed cells because the weakened horizontal interac-
ties often provide a clue to the pathobiology and diagnosis of the tions facilitate a shear stress-induced rearrangement of skeletal pro-
underlying disorder. This chapter categorizes RBC membrane disor- teins, precluding recovery of the normal biconcave shape. This
ders according to the following morphologic and clinical phenotypes: hypothesis is not applicable to all forms of elliptocytosis. For example,
(1) hereditary spherocytosis (HS); (2) hereditary elliptocytosis (HE), in SAO, the elliptocytic/ovalocytic cells containing mutant band 3
hereditary pyropoikilocytosis (HPP), and related disorders; (3) protein are rigid and “hyperstable” rather than unstable.
Southeast Asian ovalocytosis (SAO); (4) hereditary and acquired
acanthocytosis; and (5) hereditary and acquired stomatocytosis
(Tables 45.1 and 45.2). Acanthocytosis, Stomatocytosis, and the Bilayer
Couple Hypothesis

VERTICAL AND HORIZONTAL INTERACTIONS The mechanism of acanthocytosis and stomatocytosis associated with
OF MEMBRANE PROTEINS AND DISORDERS defects of membrane proteins is much less clear. Most forms of
acanthocytosis are associated with either acquired or inherited abnor-
OF RED BLOOD CELL SHAPE malities of membrane lipids (e.g., acanthocytosis in end-stage liver
disease or abetalipoproteinemia). In rare cases with acanthocytosis,
For better understanding of the pathobiology of membrane disorders, membrane protein abnormalities have been detected, but the associ-
membrane protein-protein and protein-lipid interactions are classi- ated mechanisms leading to acanthocyte formation are unknown.
fied in two categories, vertical and horizontal interactions. Vertical These abnormalities occur in the McLeod phenotype, the chorea-
interactions, which are perpendicular to the plane of the membrane, acanthocytosis syndrome, and other rare disorders. In acanthocytosis
stabilize the lipid bilayer. These interactions include spectrin- erythrocytes, agents that interact with the lipids of the inner lipid
ankyrin–band 3 interactions, spectrin-protein 4.1R–junctional bilayer leaflet normalize the shape. These studies suggest that the
complex proteins linkage, spectrin-ankyrin–Rh multiprotein complex shape abnormalities reflect an asymmetry in the distribution of
linkage, and the weak interactions between the skeletal proteins and membrane lipids between the two halves of the RBC lipid bilayer as
the negatively charged lipids of the inner half of the membrane lipid predicted by the bilayer couple hypothesis. According to the bilayer
bilayer. Horizontal interactions, which are parallel to the plane of the hypothesis, the shape of the RBC reflects the ratio of the surface areas
membrane, support the structural integrity of erythrocytes after their of the two hemileaflets of the bilayer. The preferential expansion of
exposure to shear stress. Horizontal interactions involve the spectrin the outer leaflet leads to RBC crenation (echinocytosis or acanthocy-
heterodimer association site, where spectrin heterodimers assemble tosis), whereas expansion of the inner lipid bilayer produces a cup
into tetramers, the principal building blocks of the membrane skel- shape (stomatocytosis) and surface invaginations.
eton, and the contacts of the distal ends of spectrin heterodimers with
actin and protein 4.1R within the junctional complex. Although
interactions between proteins of the erythrocyte membrane are sig- Hereditary Spherocytosis
nificantly more complex than can be classified by horizontal and
vertical interactions, the model serves as a useful starting place for Introduction and Epidemiology
understanding erythrocyte membrane protein interactions, particu-
larly in reference to membrane-related disorders. The typical features of HS include a dominantly inherited hemolytic
According to the vertical/horizontal model, HS is considered a anemia of mild to moderate severity, spherocytosis on the peripheral
disorder of vertical interactions. Although the primary molecular blood film, and a favorable response to splenectomy. The clinical
defects in HS are heterogeneous (including deficiencies or dysfunc- spectrum of HS is variable and includes both mild and asymptomatic
tions of α- and β-spectrin, ankyrin, band 3, and protein 4.2), one forms, as well as severe forms that appear in infancy. The previously
common feature of HS RBCs is a weakening of the vertical contacts reported HS prevalence in Western populations of 1 in 4000 persons
between the skeleton and the overlying lipid bilayer membrane is an underestimation, because milder forms of HS might be asymp-
together with its integral proteins. Consequently, the lipid bilayer tomatic, suggesting a prevalence of 1 in 2000 individuals. HS has
membrane is destabilized, leading to release of bilayer lipids from the been reported worldwide, particularly in Japanese and African popu-
cells in the form of skeleton-free lipid vesicles. This lipid loss, in turn, lations, but its prevalence in other ethnic groups is unknown.
results in membrane surface area deficiency and spherocytosis.
In most patients with HE and the related disorder HPP (see
Hereditary Elliptocytosis and Related Disorders), the principal lesion Pathobiology
involves horizontal membrane-protein associations, primarily spectrin
dimer-dimer interactions. In a subset of HE patients with a deficiency Two major factors are involved in HS pathophysiology: (1) an
or a dysfunction of protein 4.1R or glycophorin C (GPC), the intrinsic RBC defect and (2) an intact spleen that selectively retains

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