The hemoglobinopathies are inherited disorders, some of
which are autosomal dominant (unstable hemoglobins) and
others autosomal recessive (Hgb S).
The term "hemoglobin disease" is the occurence of a
disease causing gene in the homozygous state or the
heterozygous occurence of a dominant hemolytic disease
The term "hemoglobin trait" is the usually asymptomatic
heterozygous occurence of a disease causing gene.
The most common hemoglobinopathies are thalassemia and
sickle cell disease/trait.
Thalassemia, a production abnormality with decreased
rates of globin chain synthesis is discussed in the
'thalassemia' section of Decreased RBC production (See
Sickle cell disease and trait will be discussed in the
following cards where the discussion focuses on structural
Sickle cell disease
Sickle cell trait
Hemoglobin C disease
Hemoglobin C trait
Hemoglobin D disease
Hemoglobin E disease
Hemoglobin S-b thalassemia
Hemoglobin C-b thalassemia
Hemoglobin E-b thalassemia
Hemoglobin S-a thalassemia
The most common of the hemoglobinopathies is Hgb
In sickle cell anemia a point mutation (GAG
Æ GTG) in the ß-chain at codon position
6 results in encoding of a valine instead of the
normal glutamine. The resulting abnormal ßs
chains combine with normal a-chains to form the abnormal
The abnormal position of the ß-6 valine* on the
outside of the ß tetramer allows it to stick to the
ß-85 phenylalanine and the ß-88 leucine on
adjacent b tetramers.
The resulting abnormal ßs chains combine with
normal a-chains to form the
abnormal hemoglobin 'S'.
Hb S is poorly soluble in low oxygen tension situations,
forming a gel and polymerizing into fibrilary structures or
tactoids. This distorts the red cells causing them to become
rigid and sickled.
* The normal glutamate is tucked inside the tetramer.
The PBS chacteristically shows sickle cells or
drepanocytes. These cresent shaped RBCs are said to be
"irrevesibly" sickled. Polychromasia, spherocytes, target
cells, and Howell-Jolly bodies may also be seen. NRBCs may
be present in sickle cell crisis.
The sickle cell solubility test is a widely used
screening method for sickle cell anemia. The sickle cell
solubility test relies on the relative insolubility of Hgb S
in concentrated phosphate buffers compared to Hgb A and
other Hgb variants. Hgb S precipitates causing a cloudy
Hgb CHarlem also will also cause a positive
Hemoglobin electrophoresis is the
most important diagnostic test for Hgb S.
In children diagnosis of Hgb S is best done after age 6
months when Hgb F levels have declined to "mature"
Hgb Electrophoresis Review
RBCs are lysed and electrophoresed on cellulose acetate
at pH 8.4 separating the hemoglobin proteins into bands by
charge. After staining hemoglobins can be identified by
their position and quantitated.
A citrate gel electrophoresis at pH 6.2 in which
hemoglobins migrate to different positions.
Note that certain Hgbs migrate together on one gel but
differently on the other. Compare the controls on each gel.
The different migration patterns can be used to identify Hgb
For instance, how would you determine if the band in the
C position at pH 8.6, is really C or is it A2 , or E?
In sickle cell disease (Hgb SS)100% of the hemoglobin is
Most people with sickle cell disease have chronic severe
hemolytic anemia Hgb levels of 60-80 g/L; yet, the symptoms
of anemia are frequently milder than expected as Hb S gives
up oxygen (O2) to tissue with ease compared to Hb
A. The O2-dissociation curve of
Hgb S is right shifted.
Although some patients live a near normal life, most
develop "sickle crises". Three types of "crises" are
Hemolytic crises are characterized by increased
hemolysis resulting in an acute drop of the Hct and Hgb.
This is accompanied by extraordinary reticulocytosis.
Aplastic crises in which an acute drop in Hct and
Hgb is accompanied by a fall in reticulocytes. Aplastic
crises are most often associated with infections (>90%
due to parvovirus B19).
Vascular-occlusive crises are the "classic" sickle
cell crises. These may be caused by infection, acidosis,
dehydration or hyoxia (altitude, anesthesia, circulatory
stasis, pregnancy, strenuous exercise, etc). Sickled RBCs
block small vessels causing infarcts, splenic sequestration
(RBC trapping), and priapism .
Infarcts may occur in any organ, but are most
notable in bones (childhood dactylitis of small bones may
cause variable length digits), lungs, kidney, skin (leg
ulcers), spleen, eye, and CNS.
The acute chest syndrome (respiratory distress;
roentgenographic infiltrates of chest), caused by vascular
occlusion commonly results in death.
The clinical manifestations of Hb SS are variable. While
splenomegaly may be present in childhood, recurrent infarcts
lead to autosplenectomy in most adults. Although some
patients live a near normal life, most develop recurrent
illnesses, severe crises, and organ failure.