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 through the 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 signs of 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 pain (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 this acute pain
occurs. 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 cell, which is a sickle shaped
red blood cell. 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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