Sickle
Cell AnemiaIntroduction: This form of anemia is
due to a genetic abnormality in the synthesis of the hemoglobin molecule of the
red blood cell. In the adult the normal hemoglobin A is replaced by the sickle
cell hemoglobin, called hemoglobin S. The difference is an exchange of the amino
acid valine by glutamic acid from the genetic abnormality. This is confined almost
exclusively to blacks and about 0.3% of black people in the US have this genetic
constellation in the pure (homozygous) form meaning they are symptomatic with
regard to sickle cell anemia. About 10% of blacks in the US have a milder version
(heterozygous for the sickle cell gene) and they are not anemic. Patients with
this trait need to be under the care of a hematologist who can help to alleviate
some of the symptoms. The red blood cells are distorted into sickle shape forms
(seen by microscope). These are more rigid than normal red blood cells and plug
capillaries leading to infarction of tissues. Symptoms of sickle
cell anemia:
Most
symptoms are confined to the pure form (homozygous form) of sickle cell anemia.
The skin is pale and mild jaundice may be present. A large heart is common (cardiomegaly)
and the doctor can hear a murmur with the stethoscope (“ejection murmur”).
There can be acute bouts (called “crises”) of pain in the bones, the spleen,
the lungs and the kidneys. On a microscopic level these painful bouts are caused
by infarctions in the tissues and the resulting ischemia (lack of oxygen). However,
it is not always clear why these bouts occur. Some of the precipitating factors
can be an infection, fever or a local trauma, but many times no apparent reason
can be found. The doctor will often find an enlarged spleen and liver (called
“hepatosplenomegaly”). As this is a genetic condition, it occurs already in
infants and toddlers. In the more severe autosomal forms the growth pattern will
be influenced leading to a characteristic appearance with a short trunk, long
legs and arms and a skull shaped like a tower. Chronic leg ulcers that have a
punched-out appearance are commonly found in the area of the ankles. By the time
the patients are adults they have experienced so many bouts of mini-infarctions
in liver and spleen that the organs have become fibrotic and the spleen that is
particularly vulnerable will be small. Patients with sickle cell anemia are more
prone to develop gall stones (cholelithiasis). Avascular necrosis of the femoral
head is another common complication. In children an acute chest syndrome is particularly
common, which leads to complications with death in 10%. When this occurs, it usually
starts with a fever, chest pains and infiltrates of the lungs visible on X-rays.
These infiltrates start in the base of the lungs (bilateral lower lobe infiltrates)
and there may be water in the chest cavities (pleural effusions). Bacterial pneumonia
may set in as well. As these changes are from mini infarcts in the tissues of
the lungs and the heart, a severe lack of oxygen (hypoxemia) develops rapidly.
In chronic recurrent bouts patients may develop pulmonary hypertension as another
complication. In young men priapism can develop, which may lead to erectile dysfunction.
Also, ischemic strokes and vasculitis in the brain may occur. Diagnostic
tests: There is a rapid screening test (tube test), which relies
on the fact that hemoglobin S is less soluble than normal hemoglobin A. The usual
screening tests for hemolytic anemias are done, which will show a normocytic anemia
with reticulocytosis (more than 10%). Hemoglobin electrophoresis is done, which
will show the hemoglobin S peak. A blood smear will show the sickle shaped red
blood cells. The hemolysis leads to an elevate bilirubin level, which can be measured
in a blood sample. The urine will test positive for urobilinogen, which is a breakdown
product of bilirubin. The patient would by now referred to a hematologist (or
if a child to a pediatrician). Further tests may be required such as a bone marrow.
After a painful crisis with infection the bone marrow may have become aplastic
meaning that precursor cells of blood cells are missing. Hematuria (blood in urine)
can occur during a painful crisis, particularly when kidney pains are present.
This can be detected with a dipstick. Electrophoresis is useful in detecting the
difference between the more severe homozygous state of sickle cell anemia and
the less problematic heterozygous state. The homozygous state shows only hemoglobin
S on electrophoresis, with varying amounts of hemoglobin F (which is also abnormal
in toddlers, older children or adults). In contrast with electrophoresis the heterozygous
state shows more hemoglobin A than hemoglobin S. In the meantime geneticists have
developed more direct PCR techniques that show the genetic defect directly. Treatment
and Prognosis: Patients with the homozygous state of sickle cell
anemia need close medical supervision.They can expect to live longer than age
50 (which was rare in the past). With the better understanding of the cellular
mechanisms (pathophysiology) of this anemia the physician can now modify the severity
of the crises with less tissue damage. The common complications in homozygous
patients that can cause death occur in association with the acute chest syndrome,
pulmonary emboli, and infarctions of the heart, liver, bone marrow, lungs or brain
and secondary infections. Unfortunately there is no anti-sickling drug available.
As a result the physician will mainly treat supportively during the approximate
5 days of crisis where pain and fever come to a peak. Strong pain relievers are
given. Fluid intake and output are monitored and balanced. The patient is monitored
for oxygenation of the blood. Removal of the spleen has not made a difference
in survival, but sometimes has to be done, if complications (ruptured spleen)
set in. Hospitalization is required for serious infections that require antibiotics,
for acute chest syndrome, or if the anemia is so severe (hemoglobin count less
than 5 grams/deciliter) that transfusions are required. Transfusions need to be
spaced as much apart as possible, but close enough to avoid clots in the brain
(recurrent cerebral thrombosis) in children less than 18 years where this is more
common. Other reasons to hospitalize are aplastic crises, acute stroke, acute
chest syndrome or specific organ failures. When oxygen tension is less than 65mm
mercury (measured by blood gases) the physician likely will also hospitalize the
patient. Because of the recurrent immune weakness the patient is vaccinated against
the major bacterial strains: H. influenzae vaccine, meningococcal vaccine and
pneumococcal vaccine. Prophylactic antibiotics (oral penicillin from the age of
4 months to 6 years) have also contributed to less childhood mortality. Folate
is given daily (1 milligram orally. Hydroxyurea works by increasing fetal hemoglobin
(hemoglobin F), which cuts the painful crises by 50%. It also helps to reduce
the frequency of the need for transfusions and reduces the severity of the acute
chest syndrome. The amount of hydroxyurea is dependent on the hemoglobin F level,
which can be monitored with blood tests. The beneficial effect may be amplified
when this is combined with erythropoietin (about 50,000 units per week). Fortunately
with good medical care patients with heterozygous trait sickle cell anemia (10%
of blacks in the US) have much less complications and a normal life expectancy.
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