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In sickle cell trait (Hgb SA) 25 - 45% of the hemoglobin
is Hgb S; the remainder being Hgb A and as well as Hgb F and
Hgb A2.
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No anemia and normal RBC morphology is the rule in sickle
cell trait.
Only two rare complications, hematuria and splenic
infarction are associated with sickle trait.
There is no risk from anesthesia, surgery, pregnancy, or
strenuous physical activity. However, sickle cell trait has
been associated with an extremely small increase in sudden
death in individuals under severe stress (US Armed Forces
study).
Individuals with sickle cell trait have normal growth and
development, normal life spans and should not be considered
ill.
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Hb S may be combined with other defects of hemoglobin.
The most common is S-ß-thalassemia. People with
S-ß-thalassemia have the clinical manifestations of
sickle cell disease. The MCV is low as would be expected in
ß-thalassemia.
Also frequent is SC disease. Mild anemia and splenomegaly
is often present. The PBS shows numerous RBC targets and may
show intracellular Hgb C 'crystals'. The MCHC is often
increased due to loss of water. Larger amounts of Hgb S are
made in SC disease than in sickle trait (SA).
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Patients with SC disease have increased viscosity of the
blood causing a high incidence of proliferative retinopathy,
painful aseptic nerosis of the femoral head (more than in SS
disease), and acute chest syndrome.
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Aseptic necrosis of the femoral head. Note the
collapse and retraction of the bone underlying the
cartilage, causing deformation of the femoral head.
Slide courtesy Robert E Fechner.
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Hemoglobin C disease results in a mild - moderate anemia
with large numbers of RBC targets seen on the PBS. Hgb C
'crystals' can usually be found. Rhomboid 'Washington'
monument crystals may distort the cell. Spherocytes may also
be seen. Splenomegaly is common.
Persons with Hgb AC (trait or carrier state) have only a
few RBC targets.
The upper image shows numerous target cells. A crystal
distorts an erythrocyte in the lower image.
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The upper image shows numerous target cells. A
crystal distorts an erythrocyte in the lower image.
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Hemoglobin D causes a mild hemolytic anemia and
splenomegaly in the homozygous state (Hgb DD), where as no
morphologic or clinical abnormality is seen in the
heterozygous state (Hgb AD).
How would you distinguish Hgb D trait from sickle cell
trait?
It is difficult to distinguish Hgb D from Hgb G. Any
ideas?
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Hemoglobin E is the result of a ß-chain mutation
(AÆG) in codon 26 changing glutamine Æ Iysine.
This creates a new splice site which competes with the
normal splice site causing decreased production of an
unstable hemoglobin.
Hgb E disease (Hgb EE) causes a hypochromic microcytic
(Hgbª10; MCV ª60) anemia with many targets and
some basophilic stippling.
In Hgb E trait (Hgb AE) the anemia is mild with
microcytosis (Hgbª12; MCV ª75) and occasional
targets.
Hemoglobin E is unstable as tested for by heat and
isopropanol tests.
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Worldwide hemoglobin E is the second most common abnormal
hemoglobin (est. 80 million cases,1990), after Hgb S. Hgb E
is common in people of Southeast Asian ancestry.
When Hgb E is combined with ß-thalassemia trait,
the anemia is usually severe (Hgb 3-7; MCV ª50)
depending on the ß-thalassemia and splenomegaly is
present.
Hgb E/ß-thalassemia is becoming increasingly common
in the US.
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Microcytic hypochromic RBCs with target cells
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O-Arab, is found in African, Middle Eastern, Central
European, African- American, and Jamaican peoples. O-Arab is
a b-chain variant (b121 GluÆLys), characterized by
mild anemia with hemolysis, RBC targets and splenomegaly.
Hgb S/O-Arab has the phenotypic expression of sickle cell
disease.
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Unstable hemoglobin variants are an uncommon cause of
extravascular hemolysis. A variety of amino acid
substitutions cause instabilities in the Hgb molecule
resulting in Hgb denaturation. The denatured Hgb forms small
round masses called Heinz bodies. These intracellular Hgb
precipitates cause RBC destruction by splenic macrophages.
Heinz bodies can be visualized with crystal-violet
staining as small spheroidal blue-purple inclusions.
Many unstable Hgb variants cannot be detected by Hgb
electrophoresis. Positive heat and isopropanol tests are
characteristic of unstable Hgb variants.
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Heinz bodies are visible as faint blue
blushes in the RBCs. A recticulocyte is seen at
lower left.
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High O2 affinity hemoglobins, avidly bind O2, but do not
readily release O2 to tissue (left shift of O2-dissociation
curve). The resulting tissue hypoxia stimulates production
of erythropoietin and causes an erythrocytosis (≠Hgb, ≠Hct,
and ≠RBCs). Persons with high O2 affinity Hgbs (autosomal
dominant inheritance and virtually always heterozygous) are
asymptomatic. Homozygous forms are usually incompatible with
life.
Low O2 affinity hemoglobins readily release O2 to tissue,
but are poorly saturated, producing a right shift of the
O2-dissociation curve. Erythropoietin decreases as O2 tissue
levels increase, causing a mild anemia. Low O2 saturation
may result in cyanosis.
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The structural hemoglobin abnormalities introduced on the
preceding cards are due to polypeptide sequence alterations,
changing the molecular structure and, as a result, often
changing globin chain function.
In addition there are quantitative abnormalities of
hemoglobin secondary to decreased rates of globin chain
synthesis. Thalasemmia, the best example of such a decrease
is described in the section "decreased hgb synthesis" under
"Decreased RBC Production". See Navigational Outline.
Hemoglobinopathies whether structural or quantitative may
result in hemolysis due to changes in hemoglobin solubility
or because of an unstable hemoglobin molecule.
Following a few questions on hemoglobinopathies we will
begin a discussion of antibody mediated hemolytic anemia.
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Pathology
> Basic Hematology > Red Cell
Disorders > Structural Abnormalities of Hgb (Part 2)
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