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Chapter 42 Sickle Cell Disease 607

δ-globin gene by the crossover. Hb F levels vary. The peripheral smear the production of Hb F to adult Hb. A more recently discovered
shows microcytosis, hypochromia, and ISCs. Vasoocclusive complica- variety of HPFH is not caused by a deletion but by one of many
tions occur, and splenomegaly is common. point mutations that upregulate the expression of the γ-globin gene.
The clinical expression of deletional and nondeletional HPFH differs
in that the 15% to 35% Hb F in the former is distributed in a pancel-
Sickle Cell–Hb D Disease 247 lular fashion, the 1% to 5% Hb F in the latter is distributed in a
heterocellular fashion, and certain mild types of nondeletional HPFH
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Because Hb D Punjab or Hb D Los Angeles (α 2β 2 Glu→Gln) has express high Hb F levels not in simple heterozygosity but only in
a similar electrophoretic mobility to Hb S under alkali conditions, conditions of erythropoietic stress, such as compound heterozygosity
Hb SD disease was first reported as an unusual case of sickle cell with the sickle cell gene. It is likely that many cases of apparent sickle
anemia. Hb D can be distinguished from Hb S by acid electrophoresis cell anemia with unexplained elevations of Hb F are the result of a
or isoelectric focusing. There is moderately severe hemolytic anemia, nondeletion HPFH mutation.
and the peripheral smear shows marked anisocytosis and poikilocy- The gene frequency of the deletional HPFH locus is 0.0005
tosis, target cells, and ISCs. The clinical manifestations of this syn- among African Americans, resulting in a calculated incidence for
drome are similar to those of sickle cell anemia. compound heterozygous sickle cell–deletional HPFH of 1/100 that
of sickle cell anemia. Sickle cell–deletional HPFH provided the first
evidence that Hb F was a potent inhibitor of Hb S polymerization:
Sickle Cell–Hb O Arab Disease 248 individuals with pancellular distribution of 25% Hb F were generally
neither anemic nor affected with vasoocclusive manifestations (see
250
127
Although Hb O Arab (α 2β 2 Glu→Lys) was first described in an Table 42.10). Hb electrophoresis revealed only Hb S, F, and A 2,
Israeli Arab family, its distribution is widespread. Sickle cell–O Arab which resembles sickle cell anemia, sickle cell–β°-thalassemia, and
disease resembles Hb SC disease on alkaline electrophoresis, but Hb sickle cell–δβ°-thalassemia. Notable differences, however, are the
O Arab can be distinguished from Hb C by acid electrophoresis or pancellular distribution of 15% to 35% Hb F, Hb A 2 levels less than
251
isoelectric focusing. This syndrome is associated with moderately 2.5%, and the absence of anemia. The generally benign course of
severe hemolytic anemia, and the peripheral smear shows anisocytosis, sickle cell–deletional HPFH is uncommonly associated with vasooc-
poikilocytosis, and ISCs. clusive complication.
Sickle Cell–Hb E Disease 249 Sickle Cell Anemia With Coexistent α-Thalassemia

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Hb E (α 2 β 2 Glu→Lys) is a β-thalassemic hemoglobinopathy found Prevalences of the silent carrier of α-thalassemia syndrome (genotype
predominantly in southeast Asia (see Chapter 40). The structural −α/αα) and α-thalassemia trait (genotype −α/−α) among African
252
mutant has an electrophoretic mobility similar to Hb C under Americans are approximately 30% and 2%, respectively. The
alkaline conditions but can be resolved by acid electrophoresis or peripheral blood smear contains less polychromasia and fewer sickle
isoelectric focusing. The GAG→AAG mutation in codon 26 activates forms and more hypochromia and microcytosis, commensurate with
E
a cryptic splice site within the first intron of the β gene, causing the numbers of α-globin genes deleted. Increased Hb A 2 levels are
alternate splicing and decreased expression of the structural mutant. associated with increasing α-globin gene deletions; the Hb F levels
As a result, Hb E makes up only 30% of the total Hb in compound are not consistently affected.
heterozygosity for the sickle cell and Hb E genes. Hb SE disease is Clinically, the impact of α-globin gene deletions on sickle cell is
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essentially benign in at least 50% and possibly most patients, with not as consistent as that of high Hb F. Because of the powerful effect
only mild hemolysis, no vasoocclusive complications, and no remark- of Hb S concentration on the kinetics and extent of Hb S polymeriza-
able abnormality of RBC morphology. However, vasoocclusive tion (see Chapter 41), the lower MCHC from α-globin gene deletions
complications and manifestations of chronic hemolytic anemia such decreases the hemolytic rate, and anemia is milder in subjects with
as pain crisis, splenic infarction, recurrent pneumonia, and frontal both α-thalassemia syndrome (genotype −α/αα) and trait (genotype
bossing have been reported. −α/−α) (see Table 42.1). There is a decreased incidence of leg ulcers
but an increased incidence of osteonecrosis. The frequency of retinal
vessel closure is higher but not the incidence of retinopathy. Com-
Coinherited Hemoglobin Abnormalities That Interact plications related to hemolysis (e.g., leg ulcers, chronic renal damage)
With Sickle Cell Disease: Hereditary Persistence of may be decreased, but the heterogeneity of the patients in previous
Fetal Hemoglobin and α-Thalassemia Trait studies and mixed results make conclusions difficult. Similarly, the
influence of α-gene deletions on survival in patients with SCD is not
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Sickle Cell–Hereditary Persistence of Fetal well understood.
Hemoglobin
SUGGESTED READINGS
Adult Hb (or in the case of sickle cell anemia Hb S) replaces Hb F
as a result of the switch from γ- to β-globin synthesis that occurs in Strasser BJ: Perspectives: molecular medicine. “Sickle cell anemia, a molecular
fetuses. Because of the inhibitory effect of Hb F on Hb S polymeriza- disease”. Science 286:1488, 1999.
tion and cellular sickling (see Chapter 41), the high fraction of Hb Wong TE, Brandow AM, Lim W, et al: Update on the use of hydroxyurea
F at birth masks the expression of SCD until Hb S levels increase to therapy in sickle cell disease. Blood 124:3850, 2014.
75% at approximately 6 months of age (see Fig. 42.3). Conditions Yawn BP, Buchanan GR, Afenyi-Annan AN, et al: Management of sickle
that preserve elevated levels of Hb F into adulthood similarly modu- cell disease: summary of the 2014 evidence-based report by expert panel
late the course of SCD. The compound heterozygous conditions members. JAMA 312:1033, 2014.
sickle–HPFH (Hb SS–HPFH) and sickle cell–β°-thalassemia–HPFH
both have higher Hb F levels and milder clinical courses than are
characteristic of sickle cell anemia. 123 REFERENCES
Hereditary persistence of Hb F results from one of several large
deletions of the δ- and β-globin genes that retard the switch from For the complete list of references, log on to www.expertconsult.com.