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780 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 781

Differential Diagnosis during screening programs or family studies of individuals with severe
Differential diagnosis is usually achieved by Hb electrophoresis. HbC HbE disorders, or on routine evaluation of a blood film with significant
moves to a cathodic position, comigrating with HbA , HbE, and HbO Arab microcytosis without anemia. HbE–β-thalassemia is a rather hetero-
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on alkaline pH (cellulose acetate) electrophoresis. The distinction from geneous group of disorders varying from a mild thalassemia interme-
these Hbs can be made by electrophoresis on citrate agar in acid pH where dia like phenotype to severe transfusion dependent thalassemia major
HbE and HbA comigrate with HbA; HbO Arab has a HbS-like mobility, and (Chap. 48). Part of this heterogeneity results from the type of coinher-
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HbC has a unique migration pattern. Alternatively, newer diagnostic meth- ited β-thalassemia mutation. Patients who are compound heterozygotes
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ods can be used; these include isoelectric focusing, where HbC can readily for HbE and one of the mild β -thalassemia mutations (such as the
be distinguished from other Hbs with similar mobility on cellulose acetate mild promoter mutation, –28A→G) have a mild to moderate anemia,
electrophoresis. In cation exchange HPLC and capillary electrophoresis, whereas patients with compound heterozygosity for HbE and one of
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HbC has a distinct elution pattern and can be distinguished from HbE and the more severe β -thalassemia mutations (such as IVS I nucleotide 5
HbO Arab ; these latter methods also have the advantage of separating and or IVS II nucleotide 654 mutations) do have a more severe phenotype
quantifying HbA in HbC homozygotes and in HbC trait. This confers the with severe anemia and transfusion dependency. There is also a large
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advantage of readily differentiating between HbCC and rare cases of HbC– heterogeneity among patients with HbE–β -thalassemia; these patients
β –thalassemia (where HbA is significantly higher, ~5 percent). do not produce any HbA and have only HbE and varying amounts of
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HbF. Known factors that influence the phenotype include the ability
Therapy to produce HbF and the presence of concomitant α-thalassemia. Indi-
The vast majority of HbCC individuals do not require any therapeu- viduals who have the propensity to synthesize significant amounts of
tic intervention. Cholecystectomy may be required in individuals who HbF (such as those who have the Xmn I C→T mutation in the γ-globin
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have symptomatic gallstones. Few patients with HbCC develop hyper- promoter) are able to ameliorate the globin chain imbalance and thus
splenism with a reduction in white cell and platelet counts, and occa- have a milder phenotype. Concomitant α-thalassemia also mitigates the
sionally worsening of anemia. In such instances, splenectomy should course of the disease by decreasing globin chain imbalance. In some
be considered. Another indication for splenectomy is pain associated cases, there may be nonglobin modifiers that impact on the phenotype.
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with an enlarged spleen. It is important to apply the usual precautions Patients with severe forms of HbE–β -thalassemia have clinical features
in patients considered for splenectomy (appropriate vaccinations, pro- very similar to β-thalassemia major; they develop complications such
phylactic antibiotic use, and delaying splenectomy in young children). as hypersplenism, iron overload, increased susceptibility to infections,
Folic acid supplementation, as usually done in many chronic hemolytic thromboembolic complications, and heart failure, and have a shortened
states, is of no proven value. life expectancy. Splenectomized HbE–β-thalassemia patients have
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more pronounced intravascular hemolysis, markers of endothelia cell
HEMOGLOBIN DISEASE activation, and activation of coagulation with increased levels of cell
Definition and History free Hb, sE-selectin, sP-selectin, high-sensitivity C-reactive protein,
and thrombin–antithrombin complex compared to nonsplenectomized
HbE (β26Glu→Lys) was the fourth abnormal Hb described. It is patients. 407
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most commonly found in Southeast Asia; in some areas (in the bor-
der between Thailand, Laos, and Cambodia, the so-called HbE triangle)
the reported gene frequency may reach as high as 0.50. This high fre- Laboratory Features
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quency is thought to be from a protective effect against malaria. HbE is HbE-trait individuals have a borderline microcytosis (MCV in the
also found in other malaria-endemic areas such as Bangladesh, India, lower 80s) but are not anemic. Homozygotes for HbE are usually only
and Madagascar. HbE now has a wide distribution as a result of the borderline or mildly anemic (Hb 11 to 13 g/dL), but they are microcytic
large population movements from Southeast and South Asia to Western (MCV ~70 fL). Blood film shows target cells, hypochromia, and micro-
Europe and North America, and may now be the most common Hb cytosis (see Fig. 49–11H). Osmotic fragility of the red cells is decreased.
variant worldwide. Hb electrophoresis shows greater than 90 percent HbE and 5 to 10 per-
cent HbF. Certain chromatography techniques that can separate HbE
Etiology and Pathogenesis from HbA reveal elevated levels of HbA . Patients with mild forms of
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The GAG→AAG mutation in codon 26 of the β-globin gene not only HbE–β -thalassemia (Chap. 48) have Hb levels in the 9.0 to 9.5 g/dL
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leads to a missense mutation (Glu→Lys) at this position, but also acti- range, whereas those with severe HbE–β -thalassemia are more severely
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vates a cryptic donor splice site at the boundary of exon 1 and intron 1 anemic (Hb 6.5 to 8.0 g/dL). Individuals with HbE–β -thalassemia have
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by increasing the sequence similarity of this site to a consensus splice varying degrees of anemia, depending on their ability to produce HbF;
sequence. The resultant aberrant splicing through this alternate site leads these patients have HbE in the 40 to 60 percent range, with the remain-
to a decrease in the correctly spliced messenger RNA and hence a β -tha- der being HbF. Patients with higher HbF values are less anemic.
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lassemic phenotype. This is reflected in the fact that heterozygotes for
HbE have 25 to 30 percent of the variant; in the presence of concomitant
α-thalassemia, this quantity decreases even further. The coinheritance of Therapy
HbE with a host of other globin mutants (α-thalassemia, β-thalassemia, HbE homozygotes do not require any therapy. Patients with severe
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other Hb variants), which are also common in the populations where HbE–β -thalassemia are similar to thalassemia intermedia or major;
HbE is prevalent, results in a wide spectrum of hemoglobinopathies most of the latter patients should be on a chronic transfusion regimen
with varying degrees of severity (HbE disorders or HbE syndromes). aiming at Hb levels of approximately 10 g/dL; iron chelation should be
The most significant of these is HbE–β-thalassemia syndromes. HbE has a part of standard therapy. Splenectomy should be considered when
also been reported in combination with HbS (HbSE disease). hypersplenism develops. Patients with a thalassemia intermedia-like
phenotype may require sporadic transfusions. Hydroxyurea can increase
Clinical Features HbF levels and decrease ineffective erythropoiesis in HbE–β-thalas-
Individuals with homozygous HbE are asymptomatic. Most patients do semia. AHSCT (including umbilical cord blood–derived stem cells in
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not have hepatosplenomegaly or jaundice. They are usually diagnosed one patient) has also been used in HbE–β-thalassemia.

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