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682 Part VI: The Erythrocyte Chapter 46: Erythrocyte Membrane Disorders 683

and propose that membrane proteins, specifically band 3, play a major a markedly high risk of hypercoagulability and life-threatening throm-
role in regulating the structure of the red cell. Band 3 tetramers are botic episodes after splenectomy, the procedure is contraindicated. 13
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attached to the spectrin skeleton and different configurations of band 3
that either face inward or outward can influence the topography of the HEREDITARY STOMATOCYTOSIS/
skeleton and the shape of the cell.
HYDROCYTOSIS
Definition and History
HEREDITARY XEROCYTOSIS Hereditary stomatocytosis, also known as hereditary hydrocytosis
Definition or overhydrated stomatocytosis, is characterized by a marked passive
Hereditary xerocytosis, also known as dehydrated HSt, is the most com- sodium leak, which causes red cell overhydration and macrocytosis.
mon form of the cation permeability defects. It is an autosomal dominant It is an autosomal dominantly inherited hemolytic anemia. The syn-
hemolytic anemia characterized by an efflux of K and red cell dehy- drome was first described in a girl with dominantly inherited hemolytic
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dration. Hereditary xerocytosis is part of a pleiotropic syndrome and anemia whose blood film contained stomatocytes. The hallmarks of
patients may also exhibit pseudohyperkalemia and perinatal edema. 177 abnormal cation transport and overhydration of the red cells were dis-
covered subsequently. 181
Etiology and Pathogenesis
The underlying membrane permeability defect is complex and involves Etiology and Pathogenesis
a net loss of potassium from the red cells that is not accompanied by a The red cell membrane of stomatocytes has enhanced permeability
proportional gain of sodium. Consequently, the net intracellular cat- toward monovalent cations, especially sodium ions. This marked pas-
ion content and cell water content are decreased. In some cases, ery- sive sodium leak into the cell represents the principal lesion in this
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throcytes exhibit an increase in phosphatidylcholine and reduced BPG disorder. The Na -K -ATPase pump, which normally maintains low
content. 13 intracellular sodium and high potassium concentrations, is stimulated
The genetic locus for this disorder was mapped to 16q23–q24. but this increase in active transport, coupled to enhanced glycolysis to
177
Subsequent refinement of the locus and exome sequencing of several provide ATP, is insufficient to overcome the leak. 175,182
large unrelated multigenerational kindred identified numerous missense The overhydrated red cells of some patients lack stomatin, a
mutations in the gene encoding the PIEZO1 protein. 178,179 Cosegregation 31-kDa integral membrane protein, but no gene mutations have been
of some of the mutations in families with multiple disease phenotypes found implying that the absence of the protein is a secondary phenom-
suggested a correlation between PIEZO and perinatal edema. PIEZO enon. 13,175 Stomatin interacts with GLUT-1 and converts it to a dehy-
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proteins were recently identified as mechanosensory molecules that droascorbic acid transporter, suggesting that it might be beneficial to
form part of stretch-activated cation channels. The PIEZO1 protein is inhibit this interaction in stomatocytes, because they require additional
present in red cell membranes and two PIEZO1 mutations, R2456H and glucose for their increased ATP needs. 175
R2488Q, were demonstrated to regulate a mechanosensitive transduc- In some stomatocytosis patients, missense mutations causing
tion channel, leading to increased cation transport in erythrocytes. 178,179 amino acid substitutions of conserved residues in the transmembrane
domain of the RhAG protein, a component of the band 3–Rh–RhAG
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Clinical Features multiprotein complex in the membrane, have been described. RhAG
Patients may present with symptoms of compensated hemolytic ane- is a transport protein that may function as a gas and/or ammonium
mia, including jaundice, splenomegaly, and gallstones. Some patients channel through pore-like structures. The mutations are thought to
may also exhibit pseudohyperkalemia and perinatal edema and even widen the pores allowing cations to leak through the membrane. A de
hydrops fetalis. 13,177 Variable penetrance is present in this disorder, with novo missense mutation in the transmembrane domain of band 3 has
significant disparity in clinical symptoms between affected individuals been described in one patient with stomatocytosis associated with dys-
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in the same kindred. Patients display a strong tendency to iron overload erythropoiesis. This changed the transport function of band 3 from
(Chap. 43). 175 an anion exchanger to a cation channel. The tyrosine phosphorylation
profile of the stomatocyte membranes revealed increased phosphoryla-
tion of band 3 and stomatin, as a result of enhanced activity of the Syk
Laboratory Features and Lyn tyrosine kinases, suggesting that phospho-signaling pathways
The hematologic picture is that of mild to moderate compensated hemo- involved in cell volume regulation may be perturbed. 184
lytic anemia (see Table 46–4) with an elevated reticulocyte count. The
K content is decreased and the Na content is increased, but the total
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monovalent cation content is reduced. The MCHC is increased reflect- Clinical Features
ing cellular dehydration and the MCV is frequently mildly increased. Moderate to severe anemia is present. Jaundice and splenomegaly are
175
Erythrocytes are resistant to osmotic lysis and the bell-shaped curve common, as are complications of chronic hemolysis, such as cholelith-
obtained by osmotic gradient ektacytometry is shifted to the left. Stoma- iasis. Patients exhibit a tendency for iron overload, independent of
tocytes are not a prominent feature on blood films, but some target cells transfusion status or splenectomy. No other organ system abnormalities
13,175
and spiculated cells are seen. In some of the cells, hemoglobin is concen- have been noted. A dyserythropoietic phenotype was noted in one
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trated (“puddled”) in discrete areas on the cell periphery. patient with mild anemia.
Laboratory Features
Therapy, Course, and Prognosis The blood film reveals striking stomatocytosis and up to 50 percent of
Most patients experience only mild anemia and therapy is not required. red cells may have abnormal morphology (Figs. 46–10E and 46–11D).
The patients should receive folate supplementation and be monitored In addition to the anemia, red cell indices show decreased MCHC and
for complications of hemolysis. Splenectomy does not significantly marked macrocytosis, as reflected by an elevated MCV, which can reach
improve the anemia, which suggests that xerocytes are detected and 150 fL in some severely affected patients (see Table 46–4). The K con-
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eliminated in other areas of the reticuloendothelial system. Because of tent is decreased and the Na content is markedly increased, leading
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