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

Course and Prognosis Etiology and Pathogenesis
The prognosis is dependent upon the clinical phenotype. Patients with Several different mechanisms lead to the instability of the globin mol-
milder phenotypes tend to do well. Severe HbE–β-thalassemia patients ecule with precipitation in the red cell leading to hemolysis. These are
require chronic red cell transfusion and iron-chelation therapy; this summarized below.
places a great burden on the economies of countries where this disease Substitutions Near the Heme Pocket Heme is inserted into a
is prevalent. AHSCT, although potentially curative, will not be available hydrophobic pocket in each globin molecule where it is in contact with
for the vast majority of these patients. Prenatal diagnosis and neona- a number of invariant nonpolar amino acid residues (see Fig. 49–2).
tal screening should be an important part of the strategies to decrease Substitution of these invariant nonpolar residues will decrease the sta-
the disease burden and improve care. Long-term use of hydroxyurea bility of heme-globin association and ultimately lead to the instability
and other novel HbF-inducing agents as modifiers of disease (histone of the globin moiety. Hb Zurich (β63His→Arg), Hb Koln (β98Val→Met), and
deacetylase inhibitors and DNA methyltransferase 1 inhibitors) can be Hb Hammersmith (β42Phe→Ser) are examples of this group.
an important addition to therapy. Disruption of Secondary Structure (α-Helix) The secondary
structure of globin chains is 75 percent in the conformation of an α
helix (see Fig. 49–1). Proline residues cannot participate in an α helical
HEMOGLOBIN D DISEASE conformation. Thus, the substitution of a proline residue for any other

HbD was the third Hb variant identified. The substitution in HbD is a amino acid except for the first three residues of an α helix will disrupt
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glutamic acid to glutamine at the 121st amino acid of the β-globin chain the secondary structure and lead to the disruption and precipitation of
(β121Glu→Gln). HbD has an S-like mobility on alkaline electrophoresis, the mutant globin chain.
but comigrates with HbA on acid pH. Subsequently, a number of other Mutations in α β Interface The first step in the assembly of the
1 1
Hb variants with the same electrophoretic properties were discovered Hb tetramer is the formation of an αβ dimer. This structure is stabilized
and named HbD (HbD Ibadan , HbD Gainesville , etc.). The most common HbD by a secondary structure that exposes the charged amino acids (gluta-
is HbD Los Angeles (β121Glu→Gln), the originally discovered HbD, which is mic acid, aspartic acid, lysine, and arginine) on the surface of the mol-
identical to HbD Punjab . It is most commonly found in Punjab, India where ecule in contact with water and stabilizes the interior of the molecule
2 to 3 percent of the population have the HbD gene. Subsequently, it has (α β interface) with hydrophobic interactions. Substitution of a charged
1 1
also been found in a number of other populations including Europeans (polar) residue for a nonpolar amino acid involved in α β contact will
1 1
of Mediterranean region, and Americans of African descent. 410 disrupt and destabilize this dimer formation and lead to the precipita-
HbD heterozygotes are asymptomatic, are not anemic, and have tion of the Hb molecule.
normal red cell indices. Homozygotes for HbD Los Angeles are asymptom- Amino Acid Deletions Deletion of one or more amino acid resi-
atic and are hematologically normal with normal red cell indices. Blood dues is expected to disrupt the secondary structure of the globin chains
films may show target cells (see Fig. 49–11G). Osmotic fragility may be and may lead to instability of the mutant chain. Mutant globins with
decreased. Compound heterozygotes for HbD Los Angeles and a β -thalas- deletion of one or more residues have been reported. Examples of this
0
semia mutation have mild microcytic anemia and show minimal hemo- type include Hb Leiden (β6 or β7Glu→0), Hb Gun Hill (β91-95→0), and Hb Frei-
lysis. Coinheritance of HbD Los Angeles with HbS results in a severe SCD burg (β23Val→0).
phenotype not different from homozygous HbS. Elongated Globin Chains Some variants result from either a
HbD Los Angeles should be distinguished from HbS. This can be done mutation in the termination codon or a frameshift leading to the syn-
by a combination of routine alkaline and acid Hb electrophoretic thesis of longer than normal globin chains. These variants tend to be
methods. Techniques such as isoelectric focusing, HPLC, and capillary unstable because of the presence of a nonfunctional fragment. Examples
electrophoresis readily provide this distinction. Such methods allow include Hb Cranston and Hb .
Tak
accurate diagnosis of SCD from compound heterozygosity for HbS and Whatever the underlying mechanism may be, unstable Hb vari-
HbD . ants precipitate within developing red cell precursors forming hemi-
Los Angeles
chromes (intermediate substances in Hb denaturation) and ultimately
aggregates that attach to the inner layer of red cell membrane (Heinz
UNSTABLE HEMOGLOBINS bodies). Heinz bodies can be visualized with supravital stains, such as
Unstable Hbs form an important group of clinically significant Hb vari- brilliant cresyl blue. Red cells with Heinz bodies have impaired rheo-
ants. Several different mechanisms lead to the generation of unstable logic properties (deformability and filterability) and are trapped in the
variants, which result in a congenital hemolytic anemia with inclusion splenic circulation (Chaps. 6, 34, and 56) with pitting of the membrane
bodies in red cells (Heinz bodies), hence the term congenital Heinz body attached bodies. Hemolysis ultimately ensues. The degree of hemolysis
hemolytic anemia. is proportionate to the quantity and the instability of the variant.
Clinical Features
Definition and History Patients with unstable Hb variants have varying degrees of hemolytic
Cathie reported a 10-month-old child with hemolytic anemia, jaundice, anemia. This can range from a compensated, asymptomatic hemolytic
and splenomegaly in 1952. Splenectomy did not result in improve- state to severe, life-threatening hemolysis. Generally, hemolytic ane-
411
ment. The patient’s red cells had large Heinz bodies (Chap. 31). Similar mia is mild to moderate and does not require therapeutic intervention.
cases were reported from around the world, and the observation that Typically, hemolysis is exacerbated by increased oxidant stress such as
these cases were characterized by the precipitation of their hemolysate infections and the use of oxidant drugs. Patients may have jaundice and
upon exposure to heat, suggested a Hb abnormality as the cause. Sub- splenomegaly. As is the case with other chronic hemolytic states, gall-
sequently, nearly all of similar cases were found to have a variant Hb, stones may develop. Hypersplenism can be a problem in some cases.
and Cathie’s case was found to have Hb-Bristol (β67Val→Asp). To date, Many unstable Hb variants that are associated with mild, compensated
146 unstable variants have been reported; the vast majority is sporadic hemolysis are diagnosed fortuitously or during population screening
cases reported only once. Few have been observed repeatedly in differ- for hemoglobinopathies. Unstable variants are inherited in a mende-
ent populations. lian pattern; they usually manifest in the heterozygous state. There are

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