In 1927, scientists Hahn and Gillespie discovered that sickling of RBCs of
diseased individuals could be induced by hypoxio, which aroused great curiosity as
their primary function is the transport of oxygen. It was also noticed that sometimes
the RBCs from the relatives of the patient, showed similar sickling' tendencies when
deprived of oxygen but did not present with the 'disease' symptoms. It was not until
Dr. James V Neel, the Chairman and Founder of the department of human genetics at
the University of Michigan and Col. E. A. Beet, a military doctor posted in what is now,
Mozambique, independently discovered that sickle cell disease (SCD) was 'hereditary'.
Later, Dr. Linus Pauling and his colleague Dr. Harvey Itano, described the involvement of
abnormal chemical structure of 'hemoglobin' in SCD patients and coined the term 'molecular
disease' for the disorders that involved proteins with abnormal chemical structure. The amino
acid substitution in hemoglobin molecule was worked out by Dr. Vernon Ingram in 1956,
paving way to understand how RBCs were affected and improved modalities of detecting this
disease,
HUMAN HEMOGLOBIN
Oxygen molecules
Hemoglobin molecules
Red blood cell
Around 5% of the world's
population has been
estimated to have some
forun of hemoglobinopathy,
and it affects 4.4 of every
10,000 births across the world.
Hemoglobinopathies
"Hemoglobinopathies" is an umbrella term that encompasses several different forms of
disorders that affect hemoglobin including 'Sickle cell disease and 'thalassemias'. 'Hemoglobin'
is an iron-porphyrin complex (heme) containing molecule, present in the RBCs that carries oxygen
from the lungs to all the peripheral tissues of the body. Each hemoglobin molecule is made up of 2
alpha and 2 beta chain subunits containing heme at the centre of each subunit. Hemoglobinopathies
are thus genetic defects which results into an abnormal structure of one of the globin chain subunits.
Around 5% of the world's population has been estimated to have some form of hemoglobinopathy,
and it affects 4.4 of every 10.000 births across the world.
How do RBCs become 'Sickle-shaped'?
Normally RBCs are anucleated, biconcave structures. This unique feature allows them to squeeze
through the fine capillaries whose sizes range from 6-8 microns, depending upon the different
organs in which they are located. Normal hemoglobin contain HbA but sickle cells contain higher
percentage of HbS. These RBCs form long, inflexible chains of hemoglobin, causing the RBCs to
become sickle shaped and inelastic'. The sickling is prominent under low oxygen tension and can
block smaller blood vessels, stopping the blood flow to the downstream tissues and organs. This
results in a sharp, stabbing pain at the spot referred to as crisis' or 'vaso occlusive episode" (VOE)
which could range from mild to severe and from acute to chronic.
Inheritance pattern for sickle cell disease
There are two kinds of sickle cell disorders - Sickle cell trait and Sickle cell disease.
Sickle cell trait
When an individual has just one abnormal copy or "allele' of HbS, he is referred to as a "carrier'
or with a sickle cell trait' thus showing heterozygous condition.
Hand-foot syndrome
Swelling caused by sickled RBCs blocking blood flow to the extremities (or dactylitis) are the
first signs of this disease in babies. Pain medications are generally used to relieve the pain
associated with this complication. Increased fluid intake is also advised.
Infections
As the spleen (the organ that fights infection), gets damaged due to sickle cells, the body is
rendered susceptible to frequent infections, especially in infants and children. Pneumonia is
one of the major and leading causes of death due to infections in children suffering from sickle
cell disease. Some other bacterial infections that could be lifethreatening include Meningococcus,
Chlamydia, Influenza, Staphylococcus, etc
Vision problems
This happens as the sickle cells plug the tiny blood vessels in the eye and the retina. Individuals
with sickle cell disease should get their eye checkup done regularly to track any damage to their
retina from a specialist.
Acute chest syndrome
When the blood flow is blocked in the smaller blood
vessels of the lungs, it could result into lung infection, increased heart rate, fever, cough and
infiltrates seen in the X-ray, breathing difficulties, chest pain, etc, which are very similar to
pneumonia. Depending on the cause of the complication, treatment may include oxygen therapy,
medicines for infection, blood transfusion,
bronchodilators, etc. Hydroxyurea is the drug used to treat acute chest syndrome. People
undergoing hydroxyurea therapy are closely monitored and regularly tested to avoid any
further complications by adjusting the dosage
Priapism
Painful obstruction of blood vessels that supply blood to penis, which may result
into impotency if not addressed quickly.
Clinical or silent strokes
Clinical strokes result when the blood flow to a part of the brain in blocked. Depending on which
part of the brain is affected, the symptoms may be weakness or pain in the arm and leg on one
side of the body, speech difficulties, loss of balance, etc. Silent strokes do not show any obvious
signs or symptoms like clinical strokes. It can affect a person's learning ability, decision-making
ability or cause lifelong disabilities. A specialised transcranial doppler (TCD) ultrasound screening
is used to assess the risk of a patient, for silent strokes. If any abnormalities are found in TCD,
the doctor might recommend regular transfusions.
Avascular necrosis
Loss of bone and tissue due to lack or/restriction of blood supply
Aplastic crisis
Also known as 'Slapped Cheek syndrome' or 'Fifth disease', it is generally caused by parvovirus
B19 infection, where bone marrow production of RBCs is stopped in sickle cell disease patients.
Kidney problems
Kidneys find it hard to concentrate urine in presence of sickled-RBCs leading to 'nocturnal
enuresis' (uncontrolled urination during night time). It may also lead to leakage of blood
and proteins in the urine along with decreased kidney function.
Recent developments in treatment of sickle cell disease
A drug has been developed by National Institute of Health's scientists at National centre for
advancing translational sciences (NCATS) and its collaborators. This drug, Aes-103, is unique
in its ability to target the underlying molecular mechanisms of sickle cell disease. It directly
binds the abnormal hemoglobin, altering its structure, thereby reducing the tendency of the
RBCs to sickle. Phase II clinical trials to assess the utility of this drug and its safety and efficacy
has shown it to be significantly effective in reducing patients pain. Before the advent of this drug,
the only drug approved by FDA for sickle cell treatment was hydroxyurea, an anticancer drug, for
use in adults.
Diagnosis of sickle cell disorders and other forms of hemoglobinopathies
The ability of sickle cell anemia and many associated hemoglobinopathies to be transferred from
one generation to another makes them very disruptive and lethal. Also the fact that there is no
cure for them, warrants for more awareness. Therefore, it is important to understand the clinical
implications and ways to manage the same for a symptom-free, fulfilling life for self and the
progeny
Screening for such abnormal hemoglobins and understanding family history becomes
important. Premarital screening can help to understand the chances of the future generations
to be affected by such genetic abnormalities and testing for the same well in advance can enable
one to prepare themselves and take informed decisions. Screening during pregnancy is a good
way to find out if the baby is affected. Also, neonatal screening can be a preventive measure to
check or confirm any abnormalities that might impeded a child's normal upbringing and life.
Various methods for diagnosis and screening of sickle cell disorders and hemoglobinopathies
are available.
Common Diagnostic Test: Complete blood count hemoglobin
is one of the preliminary
tests done in case of a suspect for sickle cell anemia or related disorders. This test determines the
number of RBCs in the blood of the suspected individual and also the amount of hemoglobin present.
Other test includes blood smear or sickling test, which can be performed in addition to CBC to
check for the sickle-shaped RBCs under the microscope.
Specialised Diagnostic Tests This involves
other diagnosis and screening methods such as Hemoglobin fractionation by high-performance
liquid chromatography (hplc blood test), Hemoglobin Electrophoresis and Isoelectric Focusing (IEF).
Capillary Electrophoresis (CE) is one of the latest techniques used to study
hemoglobinopathies. This technique makes use of completely automated analyser, has a high
resolution and also facilitates online detection and direct quantification of normal and
abnormal Hb fractions .
Cation Exchange HPLC (CE-HPLC) is considered as one of the most dependable
methods for quantification of normal and abnormal hemoglobin fractions. This can also accurately
quantify levels of HbA2, Hbf and several abnormal hemoglobins. This makes it one of the
recommended tests, apart from CE, for detecting thalassemia which is essential
for genetic counseling.
Isoelectric Focusing (IEF) separates the hemoglobin fractions and also the hemoglobin variants
based on their isoelectric points. In some high-end laboratories, mass spectrometry is used for
the identification of structural abnormalities of hemoglobin. Various methods of mass spectrometry
such as electrospray mass spectrometry, MALDI-TOF or mass-mass spectrometry are used to
determine the exact location of variations. Identification or confirmation of the rare hemoglobin
variants can also be performed using molecular diagnostic techniques such as dot blot analysis,
reverse dot-blot analysis, the amplification mutation refractory system (ARMS), high resolution
melting (HRM), gap-PCR and restriction endonuclease analysis. These are less preferred due to
their prohibitive costs and higher expertise.
HOW DO YOU MANAGE SICKLE CELL DISEASE?
The disease has wide range of symptoms and diverse clinical manifestations. Again, the individuals'
response to this condition depends on their age, sex, ethnicity and overall health. Hence, a variety
of strategies can be implemented to manage and treat this deleterious condition.
1. Pain medications - Applicable for pain 'crisis' episodes experienced by
many afflicted by this disorder.
2. Hydroxyurea therapy -Administration of hydroxyurea helps in reducing the
frequency of crisis' episodes and acute chest syndrome.
3. Folic acid therapy - Helps in managing and preventing severe anemia in
patients.
4. Immunisations and antibiotic therapy - In cases where the patient is
deemed to be susceptible to any infections, the patient is vaccinated to prevent them.
Children, in particular, are more prone to pneumonia,meningitis (infection in the brain linings)
and osteomyelitis (infection within the bone), so antibiotics are administered as a
5. Blood transfusions - Patients are
transfused with normal blood at regular intervals to replace the abnormal sickled RBCs,
thus alleviating the probabilities of Blood Transfusion
associated complications.
6. Peripheral blood Stem cell Transplant (PBSCT) - This modality is used in
severe cases where it may provide complete cure to an individual. But, only a few are fortunate enough
to receive a compatible bone marrow donor and the facility is only available at specialised centres.
Moreover, the risks involved in this procedure and the prohibitive costs make it inaccessible for
most suffering from this disease.
Apart from the above mentioned modalities to manage this serious disease, one can take a few simple
measures to avoid associated symptoms and mitigate the need of any clinical interventions. Engage in
counseling. The tips and suggestions from clinical professionals to modify your lifestyle can do wonders
to enjoy your life to the fullest. Drink loads of water and have nutritious food to keep these symptoms
at bay. Knowledge of triggers such as heavy labour, high altitudes, cold weather and few medicines
(decongestants) which can constrict blood vessels can go a long way.
Understanding that it is a genetic
disorder and accepting that medications could be a life-long reality, will make a positive difference and
help to improve the quality of life. More awareness on the management of this disease is the need of the
hour for the medical practitioners, patients as well as their family members. Conscious efforts to screen
the newborns for such life-threatening diseases should be implemented.
Spread the awareness, test yourself and don't let the
sickle cells block the life running through your body!
