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Chapter 45 Red Blood Cell Membrane Disorders 645

demonstrating delayed channel inactivation, indicating increased B, CD47, and protein 4.2 are also reduced or absent. Rh null erythro-
cation permeability may lead to dehydration of HX erythrocytes. cytes have increased osmotic fragility, reflecting a marked reduction
Piezo proteins are putative ion channels mediating mechanosensory in membrane surface area. These cells are also dehydrated, as indicated
transduction in mammalian cells. Animal models suggest mechani- by decreased cell cation and water content and increased cell density.
+
+
cally activated Piezo1 plays a critical role in erythrocyte volume The potassium transport and the Na /K pump activity are increased,
homeostasis. In a small subset of HX patients, defects of the Gardos possibly because of reticulocytosis. Phospholipid asymmetry is also
channel encoded by the KCNN4 gene have been described. altered.
Some of the reported cases of hereditary stomatocytosis share Although the clinical syndromes are the same, the genetic basis of
features of both hereditary stomatocytosis and xerocytosis categorized the Rh deficiency syndrome is heterogeneous, and at least two groups
as “intermediate” syndromes. These patients characteristically have have been defined. The amorph type is caused by defects involving
both stomatocytes and some target cells on the peripheral blood the RH30 locus encoding the RhD and RhE polypeptides. The regu-
smear. Osmotic fragility is either normal or slightly increased. Sodium latory type of Rh null and Rh mod phenotypes results from suppressor or
and potassium permeability is somewhat increased, but the intracel- modifier mutations at the RH50 locus. When one chain of the
lular cation concentration and the RBC volume are either normal or Rh-RhAG complex is absent, the complex either is not transported
slightly reduced. These cells were reported to have subnormal gluta- to or is assembled at the membrane.
thione content. In some patients, RBCs undergo in vitro hemolysis
at 5°C, hence the designation cryohydrocytosis. A similar susceptibility
to cold-induced cation permeability in which potassium and water Familial Deficiency of High-Density Lipoproteins
loss predominates and xerocytes instead of hydrocytes are present, has
also been described. Familial deficiency or absence of high-density lipoproteins (Tangier
A study of stomatocytosis, spherocytosis, and spherostomatocyto- disease) because of mutations in ABCA1, a protein involved in cel-
sis patients whose erythrocytes demonstrated significant cation leaks lular export of cholesterol, leads to accumulation of cholesterol esters
at 0°C and in some cases, band 3–deficient membranes, revealed a in many tissues. Clinical manifestations include large orange tonsils,
series of missense mutations located in an intramembrane domain of hepatosplenomegaly, lymphadenopathy, cloudy corneas, and periph-
band 3. In vitro studies suggest that these mutations convert band 3 eral neuropathy. Reported hematologic manifestations include a
from an anion exchanger to a nonselective cation leak channel. moderately severe hemolytic anemia with stomatocytosis and throm-
Several investigators have also reported a dominantly inherited bocytopenia. Erythrocyte membrane lipid analyses reveal a low free
hemolytic anemia with stomatocytosis, occasional target cells, sphe- cholesterol content, leading to a decreased cholesterol/phospholipid
rocytes, and a decreased osmotic fragility in which the main RBC ratio and a relative increase in phosphatidylcholine at the expense of
membrane abnormality involved a nearly 50% increase in phospha- sphingomyelin.
tidylcholine and a corresponding decrease in phosphatidylethanol-
amine. Because abnormalities in membrane phospholipid composition
have not been systematically investigated, it is uncertain whether the Sitosterolemia
disorder represents a distinct disease entity.
The results of splenectomy in this group of disorders are variable. Sitosterolemia or phytosterolemia is a recessive disorder associated
In some patients, the hemolytic anemia is improved, although often with elevated plasma levels of plant sterols. Affected patients exhibit
not fully corrected, by splenectomy, whereas in others, the severity of xanthomatosis and early-onset premature cardiovascular disease.
the hemolysis is unchanged. Splenectomy should be carefully consid- Reported hematologic manifestations include hemolytic anemia
ered in patients with hereditary stomatocytosis. Several patients with with stomatocytosis and macrothrombocytopenia. Mutations in the
stomatocytosis (both hydrocytosis and xerocytosis) have developed transporters ABCG5 or ABCG8 lead to gastrointestinal hyperab-
hypercoagulability after splenectomy, leading to catastrophic throm- sorption and decreased biliary elimination of plant sterols as well
botic episodes or chronic pulmonary hypertension. Fortunately, the as altered cholesterol metabolism. Plant sterols are not synthesized
majority of persons with hereditary stomatocytosis are able to main- endogenously in humans but are passively absorbed in the intestine.
tain an adequate hemoglobin level, so that splenectomy is not ABCG5 and ABCG8 actively pump plant sterols out of the intestinal
required. cells back into the intestine and out of liver cells into bile ducts. It
has been hypothesized that the stomatocytic phenotype is caused by
intercalation of plant sterols into the inner leaflet of the lipid bilayer.
Rh Deficiency Syndrome

Rh deficiency syndrome designates rare individuals who have either Acquired Stomatocytosis
absent (Rh null ) or markedly reduced (Rh mod ) Rh antigen expression,
mild to moderate hemolytic anemia associated with the presence of Stomatocytes have been noted in diverse acquired conditions, includ-
stomatocytes, and occasional spherocytes on the peripheral blood ing neoplasms, cardiovascular and hepatobiliary disease, alcoholism,
film. Hemolytic anemia is improved by splenectomy. and therapy with drugs, some of which are known to be stomatocy-
The Rh antigens are present in ~20,000 to 30,000 copies per cell togenic in vitro. In some of these conditions, the percentage of sto-
and reside on minor transmembrane proteins with an electrophoretic matocytes on the peripheral blood smear can approach 100%.
mobility of 28 to 33 kDa on SDS-PAGE. The Rh gene locus encodes However, the clinical significance of this observation is unclear
two closely linked genes, one encoding the D polypeptide and the because stomatocytes are absent in most patients with the conditions
other encoding the CcEe proteins, the antigenic expression of which listed. Furthermore, some stomatocytes can be found in normal
is a consequence of alternate splicing of their pre-mRNA. individuals (3–5%). The most consistent association is that of sto-
Rh proteins are part of a multiprotein complex that includes two matocytosis and heavy alcohol consumption.
Rh proteins and two Rh-associated glycoproteins (RhAG). Other
proteins that associate with this complex include CD47, LW, gly-
cophorin B, and protein 4.2. The Rh-RhAG complex interacts with RED CELL MEMBRANE VARIANTS AND
ankyrin to link the membrane skeleton to the lipid bilayer. The Rh INFECTIOUS DISEASE
proteins share sequence homology to the Mep/Amt family of ammo-
nium transporters in lower organisms and may participate in ammo- Viral, bacterial, and parasitic infection can all cause anemia. Multiple
nium transport. mechanisms leading to hemolysis have been described. As mentioned
Rh null erythrocytes have no Rh antigen and have reduced or absent earlier in this chapter, parvovirus B19 selectively infects erythroblasts
LW, Fy5, Ss, U, and Duclos antigens. Rh, RhAG, LW, glycophorin through interaction with globoside, which encodes the P blood group