Sickle cell anemia

Sickle cell anemia is one of a group of inherited disorders known as sickle cell disease.
It affects the shape of red blood cells, which carry oxygen to all parts of the body.
Red blood cells are usually round and flexible, so they move easily through blood
vessels. In sickle cell anemia, some red blood cells are shaped like sickles or crescent
moons.

These sickle cells also become rigid and sticky, which can slow or block blood flow.
The current approach to treatment is to relieve pain and help prevent complications of
the disease.

However, newer treatments may cure people of the disease.

Red blood cells are usually round and flexible. In sickle cell anemia, some red blood cells
look like sickles used to cut wheat. These unusually shaped cells give the disease its name.

• Symptoms

Symptoms of sickle cell anemia usually appear around 6 months of age. They vary from
person to person and may change over time. Symptoms can include:

• Anemia. Sickle cells break apart easily and die. Typical red blood cells usually live
for about 120 days before they need to be replaced.

But sickle cells usually die in 10 to 20 days, leaving a shortage of red blood cells. This is
known as anemia. Without enough red blood cells, the body can’t get enough oxygen. This
causes fatigue.

• Episodes of pain. Periodic episodes of extreme pain, called pain crises, are a major
symptom of sickle cell anemia.

Pain develops when sickle-shaped red blood cells block blood flow through tiny blood
vessels to the chest, abdomen and joints.

The pain varies in intensity and can last for a few hours to a few days. Some people have
only a few pain crises a year. Others have a dozen or more a year. A severe pain crisis
requires a hospital stay.

Some people with sickle cell anemia also have chronic pain from bone and joint damage,
ulcers, and other causes.
 • Swelling of hands and feet. Sickle-shaped red blood cells block blood circulation
in the hands and feet, which can cause them to swell.

• Frequent infections. The spleen is important for protecting against infections.

Sickle cells can damage the spleen, raising the risk of developing infections.

Babies and children with sickle cell anemia commonly receive vaccinations and
antibiotics to prevent potentially life-threatening infections, such as pneumonia.

• Delayed growth or puberty. Red blood cells provide the body with the oxygen and
nutrients needed for growth. A shortage of healthy red blood cells can slow growth
in babies and children and delay puberty in teenagers.
• Vision problems. Tiny blood vessels that supply blood to the eyes can become
plugged with sickle cells.

This can damage the portion of the eye that processes visual images, called the retina, and
lead to vision problems.

• Causes

Sickle cell anemia is caused by a change in the gene that tells the body to make
hemoglobin. Hemoglobin is the iron-rich compound in red blood cells that allows these
cells to carry oxygen from the lungs to the rest of the body.

The hemoglobin associated with sickle cell anemia causes red blood cells to become rigid,
sticky and misshapen.

For a child to have sickle cell anemia, both parents must carry one copy of the sickle cell
gene and pass both copies to the child.

If only one parent passes the sickle cell gene to the child, that child will have the sickle cell
trait. With one typical hemoglobin gene and one sickle cell gene, people with the sickle cell
trait make both typical hemoglobin and sickle cell hemoglobin.

Their blood might contain some sickle cells, but they generally don’t have symptoms.
They’re carriers of the disease. That means they can pass the gene to their children.

• COMPLICATIONS :

Sickle cell anemia can lead to a host of complications, including:

Stroke. Sickle cells can block blood flow to the brain. Signs of stroke include seizures,
weakness or numbness of the arms and legs, sudden speech difficulties, and loss of
consciousness.

If your child has any of these signs or symptoms, seek medical treatment right away. A
stroke can be fatal.

Acute chest syndrome. A lung infection or sickle cells blocking blood vessels in the lungs
can cause this life-threatening complication. Symptoms include chest pain, fever and
difficulty breathing. Acute chest syndrome might need emergency medical treatment.

Avascular necrosis. Sickle cells can block the blood vessels that supply blood to the
bones. When the bones don’t get enough blood, joints may narrow and bones can die. This
can happen anywhere but most often happens in the hip.

Pulmonary hypertension. People with sickle cell anemia can develop high blood pressure
in their lungs. This complication usually affects adults. Shortness of breath and fatigue are
common symptoms of this condition, which can be fatal.

Organ damage. Sickle cells that block blood flow to organs deprive the affected organs of
blood and oxygen. In sickle cell anemia, blood also is low in oxygen. This lack of oxygen-
rich blood can damage nerves and organs, including the kidneys, liver and spleen, and can
be fatal.

Splenic sequestration. Sickle cells can get trapped in the spleen, causing it to enlarge.
This may cause abdominal pain on the left side of the body and can be life-threatening.
Parents of children with sickle cell anemia can learn how to locate and feel their child’s
spleen for enlargement.

Blindness. Sickle cells can block tiny blood vessels that supply blood to the eyes. Over
time, this can lead to blindness

Leg ulcers. Sickle cell anemia can cause painful open sores on the legs.

Gallstones. The breakdown of red blood cells produces a substance called bilirubin. A
high level of bilirubin in the body can lead to gallstones.

Priapism. Sickle cell anemia can cause painful, long-lasting erections, known as
priapism. Sickle cells can block the blood vessels in the penis, which can lead to
impotence over time.

Deep vein thrombosis. Sickled red blood cells can cause blood clots, increasing the
risk of a clot lodging in a deep vein, known as deep vein thrombosis. It also increases
the risk of a blood clot lodging in a lung, known as pulmonary embolism. Either can
cause serious illness or even death.

Pregnancy complications. Sickle cell anemia can increase the risk of high blood
pressure and blood clots during pregnancy. It also can increase the risk of miscarriage,
premature birth and low birth weight babies.

Diagnosis

A blood test can check for the form of hemoglobin that underlies sickle cell anemia. In
the United States, this blood test is part of routine newborn screening. But older children
and adults can get the test too.

In adults, a blood sample is taken from a vein in the arm. In young children and babies,
the blood sample is usually collected from a finger or heel. The sample then goes to a
laboratory to be screened for the sickle cell form of hemoglobin.

If you or your child has sickle cell anemia, your healthcare professional might suggest
other tests to check for possible complications of the disease.

• Treatment:

Management of sickle cell anemia is usually aimed at avoiding pain episodes, relieving
symptoms and preventing complications. Treatments might include medicines and blood
transfusions. For some children and teenagers, a stem cell transplant might cure the
disease. Gene therapies also are being developed that may offer cures for people with
sickle cell disease..

2. ( Autoimmune hemolytic anemia)

Autoimmune hemolytic anemia (AIHA) occurs when a person’s immune system

produces antibodies directed against their own red blood cells (RBCs).

These antibodies attach to red cells, causing them to break down (lyse), and reducing
the number of oxygen-carrying red blood cells in circulation (anemia)
.The antibodies are usually directed against common red cell antigens, therefore they
also bind to allogenic or transfused red cells and cause them to lyse.

Autoimmune haemolytic anaemia can be caused by different types of antibodies with

reactivity at different temperatures.

The one caused by IgG antibodies is called warm-immune haemolytic anaemia and
has an incidence of 5-10 cases per million whereas ‘cold agglutinin disease’ is caused
by IgM antibodies with an incidence of 1-1.8 cases per million.

Signs and symptoms.

Symptoms of AIHA may be due to the underlying anemia; including shortness of breath
or dyspnea, fatigue, headache, muscle weakness and pallor.

Jaundice is a common sign of haemolytic anemia.

It is caused by the accumulation of bilirubin in skin, and sclera. Bilirubin is produced by

degradation of heme molecule and as red cells lyse and release intracellular contents,
the free heme decomposes to bilirubin causing jaundice.

Jaundice can also be accompanied by dark (tea coloured urine) due to free
hemoglobin.

Spherocytes are found in immunologically mediated hemolytic anemias.

Signs of hemolysis that are present in AIHA include low hemoglobin (blood count),
alterations in levels of cell markers of hemolysis; including elevated lactate
dehydrogenase (LDH), decreased haptoglobin and elevated unconjugated bilirubin.

Reticulocytosis, or an increase in circulating immature red blood cells, may be seen.

Causes.

The causes of AIHA are poorly understood.

The disease may be primary, or secondary to another underlying illness.

The primary AIHA is idiopathic (the two terms used synonymously) and accounts for
more than 60% of unselected cases.
Secondary AIHA can result from many other illnesses usually the ones that also affect
immune system.

The most common causes of secondary AIHA include lymphoproliferative disorders

(e.g., chronic lymphocytic leukemia, lymphoma), immune dysregulation disorders such
as autoimmune lymphoproliferative syndrome (ALPS) and common variable
immunodeficiency (CVID) and other autoimmune disorders (e.g., systemic lupus
erythematosus, rheumatoid arthritis,

scleroderma, Crohn’s disease, ulcerative colitis), infections (as HIV, EBV, hepatitis,
mycoplasma, viral pneumonia, and other respiratory infections) and drugs

Less common causes of warm-type AIHA include neoplasms other than lymphoid, and
bone marrow / solid organ transplant

Secondary warm type AIHA has been observed in cases of Covid-19.

Secondary cold type AIHA is also caused primarily by lymphoproliferative disorders

but is also commonly caused by infection, especially by mycoplasma, viral pneumonia,

infectious mononucleosis, and other respiratory infections.

Less commonly, it can be caused by concomitant autoimmune disorders.

Secondary causes of autoimmune hemolytic anemia include:

• Autoimmune diseases, such as lupus

• Chronic lymphocytic leukemia
• Non-Hodgkin’s lymphoma and other blood cancers
• Epstein-Barr virus
• Cytomegalovirus
• Mycoplasma pneumonia
• Hepatitis
• HIV

Pathophysiology.

AIHA can be caused by different antibody classes with IgG and IgM antibodies being
the primary antibody types. IgA autoantibodies can also rarely cause AIHA.

Pathophysiology of warm or IgG mediated AIHA differs from cold or IgM mediated AIHA.

Warm AIHA means immune haemolysis is caused by auto-antibodies which bind to red
cells at body temperature (37 degree Celsius).
These are usually IgG but can be IgM in rare cases.

In warm AIHA, red cells coated by IgG undergo antibody mediated cell death in the
reticuloendothelial system of liver and spleen leading to extravascular haemolysis.

These IgG antibodies are also capable of activating the complement cascade with
variable efficacy, further leading to opsonisation and destruction of red cells in
reticuloendothelial system (RE) system or intravascular haemolysis via terminal
complement.

Red cell autoantibodies causing cold agglutinin disease are of IgM class.

These bind to RBC antigens at lower temperatures.

The antibody/RBC antigen complex then activates the classical complement pathway
leading to complement mediated hemolysis of RBCs in RE system.

Diagnosis.

Diagnosis of AIHA should be suspected in a patient presenting with acute onset of

anemia (fatigue, pallor, SOB), jaundice, dark urine etc.

It is essential to consider the secondary causes of AIHA such as infections,

lymphoproliferative conditions, drugs, immune dysregulation and autoimmune
conditions.

Laboratory investigations are carried out to determine the aetiology of the anemia.

These include complete blood count, reticulocyte count, markers of hemolysis

(haptoglobin, LDH and bilirubin) and red cell morphology on peripheral smear.

3. (G6PD Deficiency Anemia)

G6PD deficiency is a genetic disorder that affects your red blood cells.

It happens when your body doesn’t have enough G6PD enzyme.

G6PD prevents harmful substances from damaging your red blood cells.

While most people with this condition don’t have symptoms, it does increase your risk of
hemolytic anemia (low red blood cells).

The most common medical problem associated with glucose-6-phosphate

dehydrogenase deficiency is hemolytic anemia, which occurs when red blood cells are
destroyed faster than the body can replace them.

This type of anemia leads to paleness, yellowing of the skin and whites of the eyes
(jaundice), dark urine, fatigue, shortness of breath, and a rapid heart rate.

In people with glucose-6-phosphate dehydrogenase deficiency, hemolytic anemia is

most often triggered by bacterial or viral infections or by certain drugs (such as some
antibiotics and medications used to treat malaria).

Glucose-6-phosphate dehydrogenase deficiency is also a significant cause of mild to

severe jaundice in newborns.

Many people with this disorder, however, never experience any signs or symptoms and
are unaware that they have the condition.

2. Etiology (Cause):

Genetic inheritance: X-linked recessive pattern (primarily affects males).

Mutation in the G6PD gene: Causes reduced enzyme activity or instability.

Epidemiology:

Most common in people of African, Mediterranean, Middle Eastern, and Southeast

Asian descent.

Affects over 400 million people globally.

Pathophysiology:

G6PD is essential for producing NADPH.

NADPH maintains glutathione in a reduced form, which detoxifies reactive oxygen

species (ROS).
Without sufficient G6PD:

• RBCs can’t handle oxidative stress.

• Hemoglobin gets oxidized, forming Heinz bodies.
• RBCs become rigid and are removed prematurely in the spleen (extravascular
hemolysis).
• Severe oxidative stress may cause intravascular hemolysis.

Laboratory Findings:

Peripheral smear: Bite cells, Heinz bodies .

CBC: Normocytic anemia, reticulocytosis.

Serum bilirubin: Increased indirect (unconjugated) bilirubin.

LDH: Elevated.

Haptoglobin: Decreased.

Direct antiglobulin test (Coombs test): Negative (rules out autoimmune hemolytic
anemia).

Enzyme assay: Confirmatory test—measures G6PD activity.

Diagnosis:

Based on clinical history and hemolytic episodes.

Confirmed with a quantitative G6PD enzyme assay.

Treatment:

Avoidance of triggers is the primary strategy.

Supportive care during hemolytic episodes:

Hydration

Oxygen (if needed)

4. (Thalassemia)
Thalassemias are a group of inherited blood disorders that manifest as the production of
reduced hemoglobin.

Symptoms depend on the type of thalassemia and can vary from none to severe,
including death.

Often there is mild to severe anemia (low red blood cells or hemoglobin) as
thalassemia can affect the production of red blood cells and also affect how long the red
blood cells live.

Symptoms include tiredness, pallor, bone problems, an enlarged spleen, jaundice,

pulmonary hypertension, and dark urine.

Children’s’ growth and development may be slower than normal.

Thalassemias are genetic disorders.

Alpha thalassemia is caused by deficient production of the alpha globin component of
hemoglobin, while beta thalassemia is a deficiency in the beta globin component.

The severity of alpha and beta thalassemia depends on how many of the four genes for
alpha globin or two genes for beta globin are faulty.

Diagnosis is typically by blood tests including a complete blood count, special

hemoglobin tests, and genetic tests.

Diagnosis may occur before birth through prenatal testing.

Treatment depends on the type and severity.

Clinically, thalassemia is classed as Transfusion-Dependent Thalassemia (TDT) or non-

Transfusion-Dependent Thalassemia (NTDT), since this determines the principal
treatment options.

TDT requires regular blood transfusions, typically every two to five weeks.

TDTs include beta-thalassemia major, hemoglobin H disease, and severe HbE/beta-

thalassemia.

NTDT does not need regular transfusions but may require transfusion in case of an
anemia crisis.

Complications of transfusion include iron overload with resulting heart or liver disease.

Other symptoms of Thalassemia include enlargement of the spleen, frequent infections,

and osteoporosis.

Symptoms.

Symptoms depend on the type and severity of thalassemia.

Carriers of thalassemia genes may have no symptoms (thalassemia minor) or very mild
symptoms with occasional crisis (thalassemia intermedia)

individuals who are homozygous for the mutation have severe and life threatening
symptoms (thalassemia major).

Alpha thalassemia major is generally fatal to the unborn child, as the absence of alpha
globin means that zero functional hemoglobin is produced during gestation.
Unmatched gamma globin chains cluster to form hemoglobin Bart’s, which is ineffective
at transporting oxygen.

In this situation, a fetus will develop hydrops fetalis, a form of edema, which can be
detected on prenatal ultrasound.

The child will normally die before or shortly after birth, unless intrauterine blood
transfusion is performed.

. Less severe alpha thalassemia may affect growth and development.

Beta thalassemia symptoms typically begin to show during the first six months of life, as
the body winds down production of fetal hemoglobin HbF.

In a normal individual, this would be replaced by adult hemoglobin HbA.

If thalassemia is untreated or undetected in the infant, this can lead to developmental

issues such as slowed growth, delayed puberty, bone abnormalities, and intellectual
impairment.

More generally, impaired production of hemoglobin causes anemia, resulting in

tiredness and a general lack of energy, shortness of breath, rapid or irregular heartbeat,
dizziness, pale skin, yellowing of the skin and eyes (jaundice).

In thalassemia, ineffective erythropoiesis causes the bone marrow to expand.

This expansion is a compensatory response to the damage caused to red blood cells by
the imbalanced production of globin chains.

Bone marrow expansion can lead to abnormal bone structure, particularly in the skull
and face.

Expansion of the bone marrow in the developing child leads to a distinctive facial shape
often referred to as “Chipmunk facies”.

Other skeletal changes include osteoporosis

growth retardation, and malformation of the spine.

Diagnosis.

The initial tests for Thalassemia are:

 • Complete blood count (CBC): Checks the number, size, and maturity of blood
cells.
• Hemoglobin of less than 10 g/dl may indicate a carrier, below 7 g/dl is indicative
of thalassemia major.
• In thalassemia major, mean corpuscular volume (MCV) are less than 70 fl, in
thalassemia intermedia, MCV levels are below 80 fl (The normal range for MCV
is 80–100 fl).

• The Mentzer index can be a pointer for diagnosis of thalassemia; it can be

calculated from a CBC report.

• Peripheral blood smear: A blood smear examined under a microscope can show
red blood cells that are abnormal in shape (poikilocytosis or codocytes), color
(hypochromic), or size (microcytic), as well as those with abnormal inclusions .

Serum iron and ferritin: these tests are needed to rule out iron-deficiency anemia.