Sickle Cell Disease by Dr. Virginia Tran and Dr. Natasha
Archer.
Learning Objectives.
By the end of this video, the learner will be able to discuss
the pathophysiology of sickle cell disease, identify the
common complications seen in this condition, and describe the
management options of sickle cell disease and its
complications.
Introduction.
Sickle cell disease is an inherited blood disorder
characterized by the production of a structural hemoglobin
variant that is prone to polymerization resulting in
abnormal crescent shaped red blood cells, hemolysis, and
vaso-occlusion. Annually approximately 2000 babies are
born with the disease in the United States, 300,000
Worldwide. There are several different genotypes depending on
which hemoglobin beta globin components are inherited. The
most common sickle cell disease genotype is hemoglobin SS, where
an individual inherits two sickle cell genes or "s" genes.
Another mutation and beta hemoglobin chains can cause a
structural variant called hemoglobin C. If an individual
inherits a copy of hemoglobin C from one parent and a copy of
hemoglobin S from the other, they have the genotype
hemoglobin SC, which is usually a milder form of sickle cell
disease. Other mutations and beta globin genes cause beta
thalassemia or decreased production and beta globin
chains. Beta thalassemia can either be beta plus thalassemia
where there is decreased production of beta globin or
beta-zero thalassemia, where there is no production of beta
globin. When an individual inherits beta thalassemia from
one parent and a copy of hemoglobin S from the other,
they have the genotype hemoglobin S-beta-thalassemia,
which is also usually a milder form of sickle cell disease.
There are also more rare mutations in hemoglobin which
when inherited with hemoglobin S create other compound
heterozygote variants of sickle cell disease. These other
genotypes make up less than 2% of those with sickle cell
disease. When an individual inherits one copy of normal
hemoglobin or hemoglobin A from one parent and a copy of
hemoglobin S from the other they have sickle cell trait. Sickle
cell trait means that an individual is a carrier of the
hemoglobin S gene, but it does not mean that they have sickle
cell disease. The prevalence of sickle cell trait amongst
African Americans is one in 13. The homozygous state is
inherited in an autosomal recessive pattern. The mutation
is located on chromosome six and two copies one from each parent
are required to have the disease. Those with compound
heterozygous sickle cell disease like hemoglobin SC, or
hemoglobin S-beta-thalassemia, inherit one hemoglobin S beta
globin gene mutation from one parent and another pre cycling
beta globin gene mutation from the other. For two individuals
with sickle cell trait who made and procreate there's a one in
four chance of having an affected offspring. Since May 1
of 2006. All 50 states and the District of Columbia require
universal newborn screening for sickle cell disease an
intervention which has shown to improve outcomes.
Pathophysiology.
In unaffected individuals, the predominant hemoglobin is
hemoglobin A made up of alpha and beta subunits. Other
subtypes include fetal hemoglobin or hemoglobin F made
up of alpha and gamma subunits, and hemoglobin A2 made up of
alpha and delta subunits. In sickle cell, a mutation in the
first coding region of the beta globin gene results in glutamic
acid being substituted by valine at the sixth amino acid
position. This leads to the production of sickled hemoglobin
or hemoglobin S. While glutamic acid is hydrophilic, valine is
hydrophobic. This is problematic because as hemoglobin S becomes
deoxygenated the hydrophobic valine shields itself by binding
to a hydrophobic region of another hemoglobin S tetramer.
This results in the formation of a rigid polymer a helical 14
strand structure which distorts the shape of the red blood cell
and decreases its deformability. This classic sickling of red
blood cells results in two important phenomena hemolysis
and vaso-occlusion. Sickled red blood cells are mechanically
unstable and thus prone to intravascular hemolysis. They're
also rigid and inflexible, leading to entrapment in the
spleen and extravascular hemolysis. Abnormal adhesion of
sickle cells to endothelium and any other process that leads to
delay transit time can result in obstruction of microvasculature
and subsequent hypoxia, tissue damage, necrosis, and organ
dysfunction. The propensity of these red blood cells to cause
hemolysis and vaso-occlusion leads to complications in many
different organ systems. Note, infants under the age of six
months are usually protected from these complications by high
levels of hemoglobin F.
Complications.
The most common complication of sickle cell disease is
vaso-occlusion. While individuals with sickle cell
disease most commonly present to care for pain, the clinician
must also be cognizant of possible tissue damage and organ
dysfunction and appropriately treat it. For example, while
vaso-occlusion can cause headaches, it is imperative that
the clinician also determine if the individual has had a
transient ischemic attack, stroke, or retinal artery
occlusion as such complications should be treated with more than
just pain medication. Equally devastating is the fact that
neurocognitive dysfunction is also possible in the absence of
clear symptoms. Another example is vaso-occlusion of the small
vessels in the lungs, or acute chest syndrome, which can lead
to chest pain and symptoms similar to pneumonia.
Individuals with asthma have worse outcomes associated with
acute chest syndrome due to decreased oxygenation secondary
to obstruction. Older individuals with sickle cell
disease are likely to develop at least one major cardiovascular
complication. Pulmonary hypertension also secondary to
vaso-occlusion can be exacerbated in sickle cell
disease, either by the failure of pulmonary capillaries to
dilate due to reduce nitric oxide bioavailability or
increase thrombosis secondary to hypercoagulation. Two separate
autopsy studies series have demonstrated that vaso-occlusion
and sickle cell disease places individuals at high risk for
myocardial infarction, a combination of chronic anemia
and hypoxia with increased cardiac output can lead to
increased left ventricular stroke volume leading to left
ventricular dilation and cardiomyopathy. In the kidneys
vaso-occlusion can lead to renal infarction resulting in kidney
dysfunction ranging from hypothenuria to end stage renal
disease. In addition, vaso-occlusion can also cause
priapism a prolonged erection without sexual desire. In the
musculoskeletal system vaso-occlusion in the small
bones of the hands and feet caused dactylitis which is more
common in infants. Vaso-occlusion can also lead to
bone infarction and avascular necrosis from infarction of bone
trabeculae. Individuals are at risk of osteomyelitis, which is
often caused by staphylococcus aureus or salmonella bacteria.
Due to chronic hemolytic anemia and a compensatory increase in
erythropoietin activity, individuals can also suffer from
osteoporosis. Furthermore, vaso-occlusion in the skin leads
to chronic leg ulcers.
In the spleen splenic sequestration, which results in
the trapping of circulating blood in the spleen is a serious
complication of sickle cell disease. And splenectomy is
often performed following the first acute event in order to
prevent reoccurrence. Chronic splenic infarction causes
functional asplenia by six months of age and increases
one's risk for infection by encapsulated organisms. In terms
of development, children with sickle cell disease often
experienced delayed puberty and reduced growth. Although the
exact pathogenesis is uncertain, it may be due to hypogonadism
hypopituitarism, and hypothalamic insufficiency.
Chronic hemolysis and compensatory high red blood cell
turnover often results in the production of jaundice and
pigmented gall stones, or bilirubinate. Furthermore,
infection with human parvovirus B19, which leads to temporary
bone marrow suppression characterized by reticular
cytopenia can lead to aplastic crisis and marked anemia.
Because individuals are often treated with transfusion, they
are at increased risk of iron overload and ensuing cardiac and
hepatic complications. Finally, it is important to consider the
psychosocial complications of living with chronic pain. The
prevalence of negative attitudes towards blacks, especially those
with pain and our health care system often can lead to
depression and hopelessness within the sickle cell
population. It is therefore important for providers to not
only have a comprehensive approach to pain management, but
also be sensitive to how their management of disease can affect
individuals emotionally and physically.
Management.
Hydroxyurea is one of the US FDA approved therapies for the
prevention of pain episodes and acute chest syndrome. The US
Department of Health and Human Services recommends that all
individuals with hemoglobin SS and hemoglobin beta-zero
thalassemia be offered hydroxyurea one of the most
widely used FDA approved therapies for the prevention of
pain episodes and acute chest syndrome starting at nine months
of age irrespective of symptoms. Hydroxyurea increases hemoglobin
F, which blocks the polymerization of hemoglobin S
tetramers. There are several new drugs currently undergoing
clinical trials given the need for better therapies for this
underserved population. Due to increased consumption from the
ongoing hemolytic anemia, there's a compensatory increase
in erythropoiesis. Thus, in regions where foods like bread,
rice and cereal are not supplemented with folic acid,
individuals are often given folic acid supplementation.
So how is this condition treated? The only cure at this
time for sickle cell disease is hematopoietic stem cell
transplantation, which is not readily available to the
majority of individuals with this disease because closely
matched donors are often challenging to find, especially
due to the ethnic makeup of existing stem cell banks. The
chance of cure varies from 50 to 95% depending on how closely
matched the donor is with the individual.
Gene therapy, another potential cure currently being
investigated during which the patient's own hematopoietic stem
cells are genetically modified would increase access to cure
and high resourced countries. Because these therapies are not
readily available, long term management of sickle cell
disease is focused on the prevention of possible
complications. Since individuals with sickle cell disease become
functionally asplenic they are especially susceptible to
infection by encapsulated organisms. Infection prevention
is provided with immunization against streptococcus pneumonia,
neisseria meningitidis, and haemophilus influenza type B
along with the standard recommendations. All children
with sickle cell disease should also receive an annual influenza
vaccine as pain episodes and secondary bacterial infections
can occur in the setting of influenza infection. In addition
to the above immunizations, a COVID-19 vaccine should be given
to all eligible children with sickle cell disease as they are
more susceptible to contracting coronavirus. In addition to
vaccination prophylaxis with penicillin, or with azithromycin
in those allergic to penicillin is started at the time of
diagnosis and given until age five to decrease the incidence
of serious bacterial infections. Fevers greater than 38.5 Celsius
are also treated aggressively with empiric broad spectrum
antibiotics after obtaining a complete blood count with
differential, reticulocyte count, and blood culture.
Antibiotics are continued in those who are hemodynamically
unstable, have a positive blood culture, and or other focal
signs of infection. Without intervention, up to 11% of
individuals with sickle cell disease will have a clinically
apparent stroke by 20 years of age. By 45 years of age, the
incidence increases to 24%. Thus, individuals with
hemoglobin SS and hemoglobin beta-zero thalassemia are
screened annually with transcranial Doppler ultrasound
beginning of two years and until 16 years of age. Children who
are found to have elevated blood vessel velocities on
transcranial ultrasound and individuals who have had a
stroke are typically treated with chronic prophylactic
transfusion to prevent new or recurrent stroke. The TWITCH
trial has shown that regular blood transfusions for at least
one year coupled with lifelong hydroxyurea is non inferior to
lifelong prophylactic transfusion alone for primary
prophylaxis. Acute Pain episodes are managed with a comprehensive
approach to pain management, drug type, dosing, and route of
administration are tailored to the individual's level of pain.
Medications commonly used include NSAIDs and opioids. In
addition, adjunct medications such as acetaminophen, ketamine
infusions, regional and topical anesthesia, as well as non
pharmacologic pain therapies such as reiki, acupuncture, and
massage can be administered based on the individual
preference. Biobehavioral skills such as guided imagery and
progressive muscle relaxation and cognitive behavioral
therapy, when regularly practiced, may also decrease
pain and improve coping during pain episodes.
Most life threatening sickle cell disease complications such
as acute chest syndrome, splenic sequestration, and stroke are
treated with transfusion. However, repeated transfusions
come with additional complications including risk of
iron overload and alloimmunization.
Alloimmunization, the formation of antibodies directed against
red blood cell antigens, occurs in approximately 30% of
transfused individuals with sickle cell disease. Risk of
alloimmunization include number of transfusions and the female
sex. This can result in deadly transfusion reactions and or
difficulty finding compatible units for transfusion. Iron
overload, liver iron concentration of greater than
three milligrams per gram or transparent saturation of
greater than 50%, most commonly occurs in individuals that are
chronically transfused and can result in iron related
complications such as cardiomyopathy. Conditions for
which individuals with sickle cell disease are at increased
risk such as infection and myocardial infarction are
treated as they would be treated in non sickle cell disease
individuals, keeping in mind the decreased oxygen carrying
capacity of sickle cell disease individuals due to their chronic
anemia. Despite progress in the management of sickle cell
disease and its complications, the median age of survival still
ranges from 48 to 60 years, which is significantly less than
the life expectancy of the general population.
Summary.
Sickle cell disease is an inherited blood disorder caused
by mutation in the beta globin gene, leading to hemoglobin
polymerization and the production of abnormal crescent
shaped red blood cells. Sickled red blood cells are prone to
hemolysis and vaso-occlusion leading to complications
affecting many different organ systems. Currently,
hematopoietic stem cell transplantation is the only cure
for sickle cell disease. However, this treatment is not
readily available for most individuals living with this
condition. Management of sickle cell disease is aimed at the
prevention of complications. And treating sickle cell disease
related pain requires not only a comprehensive multidisciplinary
approach to pain management, but also the vigilance to identify
possible life threatening complications and the
sensitivity to address the psychosocial impact of living
with a chronic painful disease.
Thank you for watching this video on sickle cell disease.