Intracellular Red Cell Defects

Hemoglobinopathies. Hemoglobinopathies often result in a characteristic and

even diagnostic peripheral blood smear. They can be responsible for hemolysis
resulting from unstable hemoglobin variants or altered (decreased) hemoglobin
solubility.
Unstable Hemoglobin Variants: Unstable hemoglobin variants, unlike most
hemolytic hemoglobinopathies, rarely have a characteristic morphology, although
basophilic stippling and Heinz bodies may be noted on special staining of the
peripheral blood (Fig. 11-28). The Heinz bodies represent hemoglobin aggregates
that have precipitated intracellularly. RBCs in Heinz body anemia usually are
normocytic but may be hypochromic as a result of RBC splenic “pitting” of
precipitated hemoglobin. Because the precipitated hemoglobin may be mistaken for
reticulum, reticulocyte counts may be spuriously high. Methylene blue staining of
RBCs after they have incubated for a few hours can demonstrate the Heinz bodies.
Hemolysis may be mild (HgbKöln) or brisk (HgbBristol) or induced by drugs such as
sulfonamides (HgbZurich).
Unstable hemoglobinopathies have an autosomal dominant pattern of inheritance,
and affected individuals are heterozygotes. A homozygous state would, in most
cases, be incompatible with life. Congenital Heinz body hemolytic anemia is an
important cause of congenital hemolytic anemia. This condition, although frequently
a persistent process in the older infant, has been observed to resolve. At least some
of these self-limited cases may represent the presence of unstable γ -hemoglobin,
which normally disappears as the infant ages. The precipitate-unstable hemoglobin
secondarily increases membrane fragility, leading to the hemolysis seen in this
disorder.
Sickle Cell Disease: Of the hemoglobinopathies that have altered hemoglobin
solubility, none is as well known or as ubiquitous as sickle cell anemia. Substitution of
valine for glutamic acid at position 6 in the β -chain of the hemoglobin molecule
leads to the cross-linking of one β -chain to a second hemoglobin molecule’s β -chain
when the hemoglobin is in its deoxygenated state. This cross-linkage tips the
solubility balance, leading to the sickling of the RBC (see Fig. 11-26). Although sickle
cell disease is seen predominantly in black patients, it is by no means exclusive to
patients of African origin, with Mediterranean and Middle Eastern peoples also being
affected.
The clinical signs and symptoms of sickle cell anemia are due to decreased survival
and altered rheology of the sickled RBC. As with any chronic hemolytic state, marrow
cavity enlargement occurs, leading to maxillary hyperplasia and the so-called sickle
cell facies (Fig. 11-29). Sickle cells have altered rheology and lose the ability to
deform in the microcirculation (see Fig. 11-20). This leads to a logjam phenomenon,
causing tissue infarction and painful crises. This logjamming, also referred to as vaso-
occlusive crisis, when occurring in certain locations, gives rise to clinical
manifestations such as dactylitis (Fig. 11-30) in the toddler, priapism (Fig. 11-31),
splenic sequestration, and skin ulceration.
The vaso-occlusive phenomenon may also lead to life-threatening complications of
sickle cell disease: overwhelming infection with encapsulated organisms (most often
Pneumococcus), acute chest syndrome, and stroke. The increased infectious risk in
the sickle cell patient has multiple mechanisms, but by far the most important is
splenic dysfunction related to congested blood flow and then, ultimately, splenic
infarction.
The peripheral smear of a patient with sickle cell disease is often diagnostic of a
sickling disorder (see Fig. 11-26).
Sickle cell disease is an autosomal recessive disorder with the heterozygote having
a significant but less than 50% proportion of hemoglobin of the sickle cell type.
Heterozygous carriers of the sickle cell gene, although suffering a number of
difficulties (e.g., poor urine-concentrating ability, occasional episodes of renal
papillary necrosis with hematuria), have normal life expectancies and are virtually
free of any significant consequences of their heterozygous state.
An effective screening test—the sickle cell preparation—is widely available. It
identifies the child with at least 20% Hgb S. It is not useful for distinguishing sickle
cell disease from the heterozygous sickle cell trait. Additionally, it may fail to detect a
hemoglobinopathy related to a hemoglobin other than hemoglobin S, and it may also
fail to detect a neonate who has not yet started to synthesize significant amounts of
hemoglobin SS.
Hemoglobin C Disease: Though less common than sickle cell disease, disease
associated with Hgb C is not rare in the African-American population. As in sickle cell
disease, Hgb C disease occurs because of one amino acid change. The change, again
like Hgb S, is at the sixth position of the β -chain but is a lysine rather than a valine
replacement. In its homozygous form, Hgb C disease is a mild disorder characterized
by hemolytic anemia and splenomegaly. The tendency of Hgb C to aggregate into
precipitates is responsible for the characteristic target (actually a pseudotarget; see
Fig. 11-25B) morphology of the Hgb C homozygous and Hgb C trait (heterozygous)
cells on the peripheral blood smear. Vaso-occlusive phenomena are not associated
with this disease, although target cells are formed on the dried peripheral blood
smear. However, Hgb C, when paired in a double heterozygous state with Hgb S,
results in Hgb SC disease (see Fig. 11-27) and is associated with vaso-occlusive
phenomena, though less severe than Hgb SS.