284
U N I T 3
Hematopoietic Function
with two HbS genes). Approximately 8% of African
Americans are heterozygous for HbS and 0.1% to 0.2%
are homozygous.
5
In parts of Africa, where malaria is
endemic, the gene frequency approaches 30%, attrib-
uted to the slight protective effect it confers against
Plasmodium falciparum
malaria.
5
The abnormal structure of HbS results from a point
mutation in the
β
chain of the hemoglobin molecule,
with an abnormal substitution of a single amino acid,
valine, for glutamic acid (Fig. 13-9). In the heterozygote,
only approximately 40% of the hemoglobin is HbS, but
in the homozygote, 80% to 95% of the hemoglobin is
HbS.
5
Variations in proportions exist, and the concen-
tration of HbS correlates with the risk of sickling. HbS
polymerizes when deoxygenated, creating a semisolid
gel that makes the erythrocyte rigid, distorts its shape,
and causes structural damage to the red cell membrane
(see Figure 13-8C). The sickled cell may return to its
normal shape with oxygenation in the lungs. However,
after repeated episodes of deoxygenation, the cells
remain permanently sickled. The person with sickle cell
trait who has less HbS has little tendency to sickle and is
virtually asymptomatic. Fetal hemoglobin (HbF) inhib-
its the polymerization of HbS; therefore, most infants
with sickle cell disease do not begin to experience the
effects of the sickling until after 8 to 10 weeks of age,
when the HbF has been replaced by HbS.
6
There are two major consequences of red blood cell
sickling—chronic hemolytic anemia and blood vessel
occlusion. Premature destruction of the cells due to the
rigid, nondeformable membrane occurs in the spleen,
causing hemolysis and anemia from a decrease in red
cell numbers. Overall, the mean life span of red cells in
persons with sickle cell disease averages only 20 days
(one sixth of normal).
5
Vessel occlusion disrupts blood
flow, causing tissue ischemia and a pain crisis. Recent
evidence suggests that vessel occlusion is a complex pro-
cess involving an interaction among the sickled cells,
vessel endothelial cells, platelets, and other blood com-
ponents.
7
The process is initiated by the adherence of
sickled cells to the vessel endothelium, causing endo-
thelial cell activation with liberation of inflammatory
mediators and substances that increase platelet activa-
tion and promote blood coagulation.
5–7
Factors associated with sickling and vessel occlusion
include cold, stress, physical exertion, infection, and ill-
nesses that cause hypoxia, dehydration, or acidosis. The
rate of HbS polymerization is affected by the concentra-
tion of hemoglobin in the cell. Dehydration increases
the hemoglobin concentration and contributes to the
polymerization and resultant sickling. Acidosis reduces
the affinity of hemoglobin for oxygen, resulting in more
deoxygenated hemoglobin and increased sickling. Even
such trivial incidents as reduced oxygen tension induced
by sleep may contribute to the sickling process.
Clinical Course.
Persons who are homozygous for the
HbS gene experience severe hemolytic anemia, chronic
hyperbilirubinemia, and vaso-occlusive crises. The
hyperbilirubinemia that results from the breakdown
products of hemoglobin often leads to jaundice and the
formation of pigment gallstones.
The complications of sickle cell disease are numerous,
with two of the most common being vaso-occlusive pain
crisis and acute chest syndrome.
7–9
An acute pain episode
results from tissue hypoxia due to vessel occlusion and
can occur suddenly in almost any part of the body.
7–12
Common sites obstructed by sickled cells include the
abdomen, chest, bones, and joints. Many areas may be
affected simultaneously. Infarctions caused by sluggish
blood flowmay cause chronic damage to the liver, spleen,
heart, kidneys, retinas, and other organs (Fig. 13-10).
Acute chest syndrome
is an atypical pneumonia result-
ing from pulmonary infarction. It is the second lead-
ing cause of hospitalization in persons with sickle cell
disease and is characterized by pulmonary infiltrates,
shortness of breath, fever, chest pain, and cough. The
syndrome can cause chronic respiratory insufficiency
and is a leading cause of death in sickle cell disease.
Children may experience growth retardation and sus-
ceptibility to osteomyelitis. Painful bone crises may be
caused by marrow infarcts of the bones of the hands and
feet, resulting in swelling of those extremities. Another
major complication is stroke. Approximately 25% of
persons with sickle cell disease have neurologic compli-
cations, including stroke, related to vessel occlusion.
10
Point
mutation
Glutamic acid
Valine
Oxygenated
Deoxygenated
Reversibly
sickled
Irreversibly
sickled
Increased red cell adhesiveness and
adherence to vessel wall
Hemolysis
Vessel occlusion
Tissue ischemia and infarction
HbA
HbS
C
G
C
G
T
A
C
G
C
G
A
T
FIGURE 13-9.
Mechanism of sickling and its consequences in
sickle cell disease.
