The Thalassaemia Syndromes
Ahmad Sh. Silmi
Msc Haematology, FIBMS
The Thalassaemia Syndromes
• The thalassaemia are heterogeneous group of
inherited disorders, which are characterized by
reduced or absent synthesis of one or more
globin chain type.
• The imbalance of globin chain synthesis, which
result leads to ineffective erythropoiesis and a
shortened red cell lifespan.
• In contrast to the structural
haemoglobinopathies, the affected globin chain
is structurally normal; it is only the rate at which
it is synthesized which is affected.
Incidence and Distribution
• The thalassaemia are most common in part of the world where
malaria is, or was recently, endemic: the result of positive selection
for a gene, which affords some protection against malaria.
• The distribution of the different forms of thalassaemia is not uniform:
each is most commonly found in certain populations.
• β Thalassaemia is most common in people from the Mediterranean,
Africa, India, SE Asia and Indonesia. The incidence of mutations,
which lead to β thalassaemia, reaches almost 10% in some parts of
Greece. The disorder is relatively rare in Northern and Western
Europeans and in native Americans.
• The clinically mild forms of α thalassaemia (α + thalassaemia) are
most common in American blacks, Indonesia, SE Asia, the Middle
East, India, and the Mediterranean. 30% of American blacks are
silent carriers of α + heterozygous, while 3% are homozygous.
Homozygous express minimal symptoms of disease.
• The clinically sever a thalassaemia (α0 thalassaemia) are common
in people from the Philippines, SE Asia and S China. The population
incidence of deletions, which leads to this form, reaches 25% in
some parts of Thailand.
Classification
The thalassaemias are classified according
to three criteria:
1- The affected globin gene(s) e.g. α , β , dδ , etc.
2- Whether the reduction in synthesis in the
affected gene is partial (β+) or absolute (β0).
3- The genotype e.g. homozygous β 0.
α -Thalassaemia
More than 95% of a thalassaemias result from the deletion
of one or both of a globin genes located on chromosome
16. This gives rise to five possible genotypes:
Type
Normal
 heterozygote
homozygote
heterozygote
homozygote
Double heterozygote
Genotype




Barts hydrops foetalis)
hemoglobin H disease)
β-Thalassaemia
Most  thalassaemia result from a point mutation within the 
globin gene complex. Each mutation can result in a reduction
or abolition of  globin gene function and so to or
thalassaemia. Therefore, the classification of  thalassaemia is
similar to that for  thalassaemia:
Type
Normal
heterozygote
homozygote
heterozygote
homozygote
Genotype





Pathophysiology
• The myriad manifestation of this complex
group of disorders result from the
imbalanced synthesis of α-like and non- α
-like globin chains.
• Under normal circumstances, the rate of
synthesis of α globin must be more or less
matched by the total synthesis of β, δ and
γ globin chains.
Pathophysiology
• Impaired synthesis of α globin results in
the accumulation of unpaired non- α
globins within the developing erythroblasts
and vice versa.
Pathophysiology
• Unpaired globin chains are unstable: they
form aggregates and precipitate within the
cell, causing decreased deformability,
membrane damage and selective removal
of the damaged cell by reticuloendothelial
system.
Pathophysiology
• Unpaired α globin chains are extremely
insoluble and causes sever damage to the
developing erythroblasts.
• Unpaired β globin chains, on the other hand,
form haemoglobin H, which is relatively stable
and only precipitate as the red cell ages. Thus
moderate impairment of β globin synthesis is
associated with a greater degree of ineffective
erythropoiesis and haemolysis than an
equivalent impairment of α globin synthesis.
α Thalassaemia
•
1234•
The affected individuals in this disease are
belonging to one of four groups according to
the increasing severity of their symptoms:
"silent" carriers
α thalassaemia trait
haemoglobin H disease
haemoglobin Barts hydrops foetalis
The groups correspond approximately to the
functional equivalent of the deletion of 1, 2, 3
or 4 a globin genes respectively.
1- "Silent" carriers
• Deletion of a single a globin gene has no
significant effect on the affected individual.
• As adults, no haematological abnormality can be
demonstrated using standard laboratory
techniques (excluding DNA analysis).
• Umbilical cord blood of newborns may contain
1% of haemoglobin Barts (γ4).
• Such individuals can only be defined with
complete reliability by DNA analysis.
2- α Thalassaemia Trait
• Individuals with deletion of two α globin
genes may be:
• α+ homozygous
(α-/α-)
or
α0
heterozygous (- -/ α α). It's important to
know to which group a given individual
belong
to
give
accurate
genetic
counseling.
• The
two
groups
are
clinically
indistinguishable and present identical
laboratory results.
Laboratory findings of Thalassaemia Trait
Affected individuals typically show:
1- Mild microcytic hypochromic anaemia
with no significant symptoms.
2- Precipitated haemoglobin H (- - /α -) can
be demonstrated by supravital stain in
small minority of red cells.
3- Umbilical cord blood contains up to 10%
of haemoglobin Barts.
3- Haemoglobin H Disease
• It's arises from the deletion of three α globin
genes.
• The severity of Hb H is highly variable.
• It's characterized by a moderately sever
anaemia and hepatosplenomegally.
• Typically, the haemoglobin level is maintained
around 8 g/dl, and transfusion support is
unnecessary.
• Extramedullary haemopoiesis and skeletal
abnormalities are uncommon.
Laboratory Findings
The Peripheral blood film includes:
• Microcytosis, hypochromasia, fragmented red
cells, poikilocytosis, and polychromasia and
target cells.
• Multiple haemoglobin H inclusions are seen in
most of the cells; these bodies cause haemolytic
anaemia, which characterizes the condition.
• Umbilical cord blood contains up to 40%
haemoglobin Barts.
• Adult's blood contains between 5-35% of
haemoglobin H.
4- Haemoglobin Barts Hydrops Foetalis
• The most sever form of a thalassaemia
results from the deletion of all four a globin
genes and so is associated with a
complete absence of a globin synthesis.
4- Haemoglobin Barts Hydrops Foetalis
• Because of the absence of a globin synthesis, no
functionally normal haemoglobins are formed after the
cessation of ζ globin synthesis at about 10 weeks
gestation.
• Instead, functionally useless tetrameric molecules such
as haemoglobin Barts (γ4) and haemoglobin H (β4) are
synthesized.
• Thus, although the haemoglobin concentration at
delivery typically is about 6 g/dl, functional anaemia is
much more sever.
• The severity of anaemia causes gross oedema
secondary to congestive cardiac failure and massive
hepatosplenomegally.
• Pregnancy usually terminates in a third trimester
stillbirth, often after a difficult delivery.
Laboratory Findings
• The peripheral blood smear shows marked
microcytosis, hypochromasia,
poikilocytosis, fragmentation and
numerous nucleated red cells.
Haemoglobin electrophoresis confirms this
abnormality.
β Thalassaemia
•
β Thalassaemia usually results from
point mutations within the β globin
gene cluster, β thalassaemia can be
classified according to the severity of
their symptoms into three groups:
1- β thalassaemia minor (or trait)
2- β thalassaemia major
3- β thalassaemia intermediate
1- β Thalassaemia minor
• It's the mildest form, which arises from the
inheritance of a single abnormal β globin
gene. Typically, the affected individual
exhibits no significant signs of the disease,
and may be unaware of the condition, and
generally live a normal lifespan.
Laboratory findings
•
•
•
•
•
Microcytic hypochromic anaemia, with
target cells a prominent feature in the
peripheral blood film.
Red blood cell count is high to
compensate for the generated anaemia.
Haemoglobin level is around 10-11 g/dl.
Reticulocyte is slightly increased.
White blood cells is normal
• Bone marrow :
Generally shows some degree of erythroid
hyperplasia
and
mild
ineffective
erythropoiesis. Iron storage is slightly
increased.
• Haemoglobin Electrophoresis:
Hb F(2 - 6 % ) Hb A2 ( 3 - 7 %) Hb A (87 - 95 %)
Beta thalassemia - heterozygous
(minor or trait)
2- β Thalassaemia major
•
•
123456-
β Thalassaemia major results from the inheritance of
two b thalassaemia genes. Affected individuals are
either homozygous or double heterozygous for two
distinct mutations.
In the absence of treatment, the condition is
characterized by :
sever anaemia
gross splenomegally
Frequently hepatomegally
Retarted growth
Facial mongoloid appearance
Rarely live beyond the second decay.
Laboratory findings
1.
peripheral blood
•
•
•
•
•
•
•
•
•
Sever haemolytic anaemia with Hb< 7.0 g/dl
Microcytic hypochromic due to decrease globin synthesis.
Marked anisocytosis and poikilocytosis.
Increased polychromatophilia.
Numerous target cells.
Howell-jolly bodies and sedrocyte are common.
Increased NRBC's ( 200 or more / 100 WBC's)
Increased reticulocyte.
WBC is slightly increased with occasional immature
granulocyte.
Platelets are slightly increased
•
2- Bone Marrow:
The bone marrow shows erythroid
hyperplasia,
and
excess
blood
transfusion & haemolysis will lead to
precipitation of iron in spleen and liver.
3- Biochemical tests:
•
Haptoglobin is decreased.
•
Bilirubin is increased.
4- Haemoglobin Electrophoresis
• Analysis of the haemoglobins present reveals a marked
increase in Hb F, the precise value of which is
dependent on the genetic defect(s) present. for example:
• In homozygous β0 thalassaemia: Hb F accounts for up
to 98 % of the total.
• In double heterozygous β+ thalassaemia: Hb F accounts
for 40-60 %
• Hb A2 is increased in both defects.
• The increase in d and g chains is a compensatory
mechanism due to the decrease in the production of β
chain.
Beta thalassemia major
Beta thalassemia major
treatment
• Transfusion
• Iron chelation
• stem cell transplant
3- β Thalassaemia intermedia
Typically, thalassaemia intermedia arise from one
of three circumstances:
•
•
•
Inheritance of mild β
thalassaemia
mutations.
Co-inheritance of a gene which increases the
rate of γ globin synthesis.
Co-inheritance of α thalassaemia. Reduction
in a globin synthesis reduces the imbalance
in α: non-α globin synthetic ratio.
3- β Thalassaemia intermedia
• Thalassaemia intermedia encompass all cases of β
thalassaemia with significant symptoms of disease which do
not require regular transfusion to maintain their haemoglobin
level above 7 g/dl.
• The laboratory and clinical features of this condition mirror
those of the more sever phenotype. The major cause of
morbidity is due to iron overload as a result of increase
gastrointestinal absorption of dietary iron in anaemic patients;
these results in increase total body iron.
• The bone marrow is massively imposed by erythroid
hyperplasia, this leads to increase demand of iron, which
exceeds the supply capacity of the reticuloendothelial system.
Thus functional iron deficiency is present, despite raised in
iron stores.
Stepwise approach to the diagnosis of thalassemia
What Is Thalassemia?
• Thalassemia is an inherited blood
disorder that causes mild or severe
anemia (uh-NEE-me-uh). The anemia is
due to reduced hemoglobin (HEE-muhglow-bin) and fewer red blood cells than
normal. Hemoglobin is the protein in red
blood cells that carries oxygen to all parts
of the body.
•
In people with thalassemia, the genes
that code for hemoglobin are missing
or variant (different than the normal
genes). Severe forms of thalassemia
are usually diagnosed in early
childhood and are lifelong conditions.
The two main types of thalassemia
• alpha and beta, are named for the two
protein chains that make up normal
hemoglobin. The genes for each type of
thalassemia are passed from parents to
their children. Alpha and beta
thalassemias have both mild and severe
forms.
Alpha thalassemia
• occurs when one or more of the four
genes needed for making the alpha globin
chain of hemoglobin are variant or
missing. Moderate to severe anemia
results when more than two genes are
affected. The most severe form of alpha
thalassemia is known as alpha
thalassemia major. It can result in
miscarriage.
Beta thalassemia
• occurs when one or both of the two genes
needed for making the beta globin chain of
hemoglobin are variant. The severity of
illness depends on whether one or both
genes are affected and the nature of the
abnormality. If both genes are affected,
anemia can range from moderate to
severe. The severe form of beta
thalassemia is also known as Cooley’s
anemia. Cooley’s anemia is the most
common severe form of thalassemia in the
United States.
Alpha Thalassemias
• Alpha thalassemia “silent carrier”
• Mild alpha thalassemia, also called alpha
thalassemia minor or alpha thalassemia
trait
• Hemoglobin H disease
• Hydrops fetalis, or alpha thalassemia
major
Beta Thalassemias
• Beta thalassemia minor, also called
thalassemia minor or thalassemia trait
• Beta thalassemia intermedia, also called
thalassemia intermedia or mild Cooley’s
anemia
• Beta thalassemia major, also called
thalassemia major or Cooley’s anemia
• Mediterranean anemia
Cooley ’s anemia
• Cooley’s anemia is another name for the
severe form of beta thalassemia. The
name is sometimes used to refer to any
type of thalassemia that requires treatment
with regular blood transfusions.
• Thalassemia is caused by variant or
missing genes that affect how the body
makes hemoglobin. Hemoglobin is the
protein in red blood cells that carries
oxygen. People with thalassemia make
less hemoglobin and fewer circulating
red blood cells than normal. The result
is mild or severe anemia
• Many possible combinations of variant genes
cause the various types of thalassemia.
Thalassemia is always inherited (passed
from parents to children). People with
moderate to severe forms of thalassemia
received variant genes from both parents. A
person who inherits a thalassemia gene or
genes from one parent and normal genes
from the other parent is a carrier
(thalassemia trait). Carriers often have no
signs of illness other than mild anemia, but
• Hemoglobin includes two kinds of protein
chains called alpha globin chains and beta
globin chains. If the problem is with the
alpha globin part of hemoglobin, the
disorder is alpha thalassemia. If the
problem is with the beta globin part, it is
called beta thalassemia. There are both
mild and severe forms of alpha and beta
thalassemia. Severe beta thalassemia is
often called Cooley’s anemia.
Alpha Thalassemia
Four genes are involved in making the
alpha globin part of hemoglobin—two from
each parent. Alpha thalassemia occurs
when one or more of these genes is
variant or missing.
• People with only one gene affected are called
silent carriers and have no sign of illness.
• People with two genes affected (called alpha
thalassemia trait, or alpha thalassemia minor)
have mild anemia and are considered
carriers.
• People with three genes affected have
moderate to severe anemia, or hemoglobin H
disease.
• Babies with all four genes affected (a
condition called alpha thalassemia major, or
hydrops fetalis) usually die before or shortly
after birth.
• If two people with alpha thalassemia
trait (carriers) have a child, the baby
could have a mild or severe form of
alpha thalassemia or could be healthy.
Beta Thalassemia
Two genes are involved in making the beta
globin part of hemoglobin—one from each
parent. Beta thalassemia occurs when one
or both of the two genes are variant.
• If one gene is affected, a person is a carrier
and has mild anemia. This condition is called
beta thalassemia trait, or beta thalassemia
minor.
• If both genes are variant, a person may have
moderate anemia (beta thalassemia
intermedia, or mild Cooley’s anemia) or
severe anemia (beta thalassemia major, or
Cooley’s anemia).
• Cooley’s anemia, or beta thalassemia major,
is a rare condition. A survey in 1993 found
518 Cooley’s anemia patients in the United
States. Most of these persons had the severe
If two people with beta thalassemia trait (carriers) have a
baby, one of three things can happen:
• The baby could receive two normal genes (one
from each parent) and have normal blood (1 in 4
chance, or 25 percent).
• The baby could receive one normal gene from one
parent and one variant gene from the other parent
and have thalassemia trait (2 in 4 chance, or 50
percent).
• The baby could receive two thalassemia genes
(one from each parent) and have a moderate to
severe form of the disease (1 in 4 chance, or 25
percent).
Who Is At Risk for
Thalassemia?
1. Thalassemia is passed from parents to children
through their genes.
2. Thalassemia affects both males and females.
3. Beta thalassemias affect people of
Mediterranean origin or ancestry (Greek, Italian,
Middle Eastern) and people of Asian and
African descent.
4. Alpha thalassemias mostly affect people of
Southeast Asian, Indian, Chinese, or Filipino
origin or ancestry.
What Are the Signs and Symptoms
of Thalassemia?
• The symptoms of thalassemia depend on
the type and severity of the disease.
Symptoms occur when not enough oxygen
gets to various parts of the body due to
low hemoglobin and a shortage of red
blood cells in the blood (anemia).
• “Silent carriers” and persons with alpha
thalassemia trait or beta thalassemia
trait (also called carriers) usually have
no symptoms. Those with alpha or beta
thalassemia trait often have mild
anemia that may be found by a blood
test.
In more severe types of thalassemia, such as Cooley’s
anemia, signs of the severe anemia are seen in early
childhood and may include:
1. Fatigue (feeling tired) and weakness
2. Pale skin or jaundice (yellowing of the
skin)
3. Protruding abdomen, with enlarged
spleen and liver
4. Dark urine
5. Abnormal facial bones and poor growth
• Babies with all four genes affected (a
condition called alpha thalassemia major, or
hydrops fetalis) usually die before or shortly
after birth
How Is Thalassemia
Diagnosed?
1. Thalassemia is diagnosed using blood tests,
including a complete blood count (CBC) and special
hemoglobin studies.
2. A CBC provides information about the amount of
hemoglobin and the different kinds of blood cells,
such as red blood cells, in a sample of blood. People
with thalassemia have fewer red blood cells than
normal and less hemoglobin than normal in their
blood. Carriers of the trait may have slightly small
red blood cells as their only sign.
3. Hemoglobin studies measure the types of
hemoglobin in a blood sample.
Cooley’s anemia
• is usually diagnosed in early childhood
because of signs and symptoms, including
severe anemia. Some people with milder
forms of thalassemia may be diagnosed after a
routine blood test shows that they have
anemia. Doctors suspect thalassemia if a child
has anemia and is a member of an ethnic
group that is at risk for thalassemia.
• To distinguish anemia caused by iron
deficiency from anemia caused by
thalassemia, tests of the amount of iron in the
blood may be done. Iron-deficiency anemia
occurs because the body doesn’t have
enough iron for making hemoglobin. The
anemia in thalassemia occurs not because of
a lack of iron, but because of a problem with
either the alpha globin chain or the beta globin
chain of hemoglobin. Iron supplements do
nothing to improve the anemia of thalassemia,
because missing iron is not the problem.
• Family genetic studies are also helpful
in diagnosing thalassemia. This
involves taking a family history and
doing blood tests on family members.
• Prenatal testing can determine if an
unborn baby has thalassemia and how
severe it is likely to be.
How Is Thalassemia Treated?
Treatment for thalassemia depends on the type and
severity of the disease.
• People who are carriers (they have thalassemia trait)
usually have no symptoms and need no treatment.
• Those with moderate forms of thalassemia (for
example, thalassemia intermedia) may need blood
transfusions occasionally, such as when they are
experiencing stress due to an infection. If a person
with thalassemia intermedia worsens and needs
regular transfusions, he or she is no longer
considered to have thalassemia intermedia; instead,
the person is said to have thalassemia major, or
Cooley’s anemia.
1. Those with severe thalassemia have a
serious and life-threatening illness.
They are treated with regular blood
transfusions, iron chelation (ke-LAYshun) therapy, and bone marrow
transplants. Without treatment,
children with severe thalassemia do
not live beyond early childhood.
People with severe thalassemia who
are able to continue therapy
successfully may live into their thirties,
1. Blood Transfusions
• Severe forms of thalassemia are treated
by regular blood transfusions. A blood
transfusion, given through a needle in a
vein, provides blood containing normal red
blood cells from healthy donors. In
thalassemia treatment, blood transfusions
are done on a schedule (often every 2–4
weeks) to keep hemoglobin levels and red
blood cell numbers at normal levels.
Transfusion therapy can allow a person
with severe thalassemia to feel better,
enjoy normal activities, and live longer.
• Transfusion therapy, while lifesaving, is
expensive and carries a risk of transmitting
viral and bacterial diseases (for example,
hepatitis). Transfusion also leads to excess
iron in the blood (iron overload), which can
damage the liver, heart, and other parts of
the body. To prevent damage, iron chelation
therapy is needed to remove excess iron
from the body.
2-Iron Chelation Therapy
• Iron chelation therapy uses medicine to
remove the excess iron that builds up in
the body when a person has frequent
blood transfusions. If the iron is not
removed, it damages body organs, such
as the heart and liver.
• The medicine, deferoxamine (deh-fer-ROXuh-meen), works best when given slowly
under the skin, usually with a small portable
pump overnight. This therapy is demanding
and sometimes is mildly painful, so some
people stop chelation therapy. A pill form of
iron chelation therapy, deferasirox, was
approved in November 2005 for use in the
United States.
• People who have iron overload should not
take vitamins or other supplements that
contain iron.
3-Surgery
• Surgery may be needed if body organs,
such as the spleen or gall bladder, are
affected. For example, if the spleen
becomes inflamed and enlarged, it may be
removed. If gallstones develop, the gall
bladder may be removed.
A-Bone Marrow or Stem Cell
Transplants
• Bone marrow or stem cell transplants have
been used successfully in some children
with severe thalassemia. This is a risky
procedure, but it offers a cure for those
children who qualify.
4-Other Treatments
• People with severe thalassemia are more
likely to get infections that can worsen their
anemia. They should get an annual flu shot
and the pneumonia vaccine to help prevent
infections.
• Folic acid is a B vitamin that helps build red
blood cells. People with thalassemia
should take folic acid supplements.
• Researchers are also studying other
treatments, such as gene therapy and fetal
5-Gene therapy
• Someday, it may be possible to cure
thalassemia in an unborn child by inserting
a normal gene into the child’s stem cells.
6-Fetal hemoglobin
• Researchers are studying ways to enhance
production of fetal hemoglobin in people with
thalassemia. Fetal hemoglobin is the type of
hemoglobin made by the body before birth.
After birth, the body usually switches from
making fetal hemoglobin to the adult form of
hemoglobin. Some children have a gene variant
that prevents the switch, and their continuing
production of fetal hemoglobin lessens the
severity of their illness. Researchers are testing
ways to enhance fetal hemoglobin production
after birth.
How Can Thalassemia Be
Prevented?
• Although thalassemia cannot be
prevented, it can be identified before
birth by prenatal diagnosis.
• People who have or believe that they
may carry the thalassemia genes can
receive genetic counseling to avoid
passing the disorder to their children.
Living With Thalassemia
1. The Cooley’s Anemia Foundation offers
support to people with various types of
thalassemia through its Thalassemia
Action Group.
2. If you have moderate or severe
thalassemia, you need to take care of
your overall health.
• Follow your treatment plan. See your doctor
regularly for checkups and treatment.
• If you must have regular blood transfusions and
iron chelation therapy, it is important to continue
with treatment as recommended.
• If you have regular blood transfusions, you should
avoid taking vitamins or other supplements
containing iron.
• Maintain a healthy diet. Your doctor may also give
you a supplement of folic acid (a B vitamin) every
day to help your body make new red blood cells.
• Get a flu shot every year and the pneumococcal
vaccine to prevent infect
Key Points
• Thalassemia is an inherited blood disorder
that can cause mild to severe anemia.
• Thalassemia involves problems with the
production of hemoglobin in red blood
cells. As a result, a person with
thalassemia doesn’t have enough
hemoglobin or red blood cells to carry
oxygen throughout the body (anemia).
• Two main types of thalassemia are alpha
and beta thalassemia. Alpha thalassemia
occurs when there is a problem with the
alpha globin chain that is part of
hemoglobin. Beta thalassemia occurs when
there is a problem with the beta globin
chain.
• Mild, moderate, and severe forms of
thalassemia occur. Severe beta
thalassemia is often called Cooley’s
anemia.
• The most common severe form of
thalassemia seen in the United States is
beta thalassemia major, or Cooley’s
anemia. It mainly affects people from
Mediterranean countries and Asia.
• Some people are “silent carriers” with no
symptoms. Other carriers have mild anemia
but usually need no treatment. Carriers can
pass thalassemia genes on to their children.
• Severe thalassemia is treated with
frequent blood transfusions and iron
chelation therapy to remove excess iron
that builds up in the body from the
transfusions.
• Bone marrow or stem cell transplants
have cured thalassemia in some
children, but this treatment is not
available for most people with
thalassemia.
• Researchers are studying new
treatments, including ways to cure
Chapter 12
Thalassemia
80
Thalassemia
In Chapter 12, you will be introduced to the •
thalassemias. You will learn about the
pathophysiology, clinical signs and
symptoms, laboratory test results, and
treatments for both the alpha and beta
forms of thalassemia. Subclasses of each
major form of thalassemia will be
discussed.
82
Introduction to
Thalassemia
83
Thalassemia
1 of 2
Diverse group of disorders which manifest as
anemia of varying degrees.
Result of defective production of globin portion of
hemoglobin molecule.
Distribution is worldwide.
May be either homozygous defect or heterozygous
defect.
Defect results from abnormal rate of synthesis in
one of the globin chains.
Globin chains structurally normal (is how
differentiated from hemoglobinopathy), but have
imbalance in production of two different types of
chains.
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•
•
•
•
•
•
Thalassemia
2 of 2
Results in overall decrease in amount of •
hemoglobin produced and may induce
hemolysis.
Two major types of thalassemia: •
Alpha (α) - Caused by defect in rate of synthesis –
of alpha chains.
Beta (β) - Caused by defect in rate of synthesis –
in beta chains.
May contribute protection against malaria. •
85
Genetics of Thalassemia
Adult hemoglobin composed two alpha and •
two beta chains.
Alpha thalassemia usually caused by gene •
deletion; Beta thalassemia usually caused
by mutation.
Results in microcytic, hypochromic anemias •
of varying severity.
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Beta
Thalassemia
87
Classical Syndromes of Beta
Thalassemia
88
Silent carrier state – the mildest form of
beta thalassemia.
Beta thalassemia minor - heterozygous
disorder resulting in mild hypochromic,
microcytic hemolytic anemia.
Beta thalassemia intermedia - Severity
lies between the minor and major.
Beta thalassemia major - homozygous
disorder resulting in severe transfusiondependent hemolytic anemia.
•
•
•
•
Silent Carrier State for β
Thalassemia
Are various heterogenous beta mutations •
that produce only small decrease in
production of beta chains.
Patients have nearly normal beta/alpha •
chain ratio and no hematologic
abnormalities.
Have normal levels of Hb A2. •
89
Beta Thalassemia Minor
1 of 2
Caused by heterogenous mutations that affect
beta globin synthesis.
Usually presents as mild, asymptomatic hemolytic
anemia unless patient in under stress such as
pregnancy, infection, or folic acid deficiency.
Have one normal beta gene and one mutated beta
gene.
Hemoglobin level in 10-13 g/dL range with normal
or slightly elevated RBC count.
90
•
•
•
•
Beta Thalassemia Minor
2 of 2
Anemia usually hypochromic and microcytic with
slight aniso and poik, including target cells and
elliptocytes; May see basophilic stippling.
Rarely see hepatomegaly or splenomegaly.
Have high Hb A2 levels (3.5-8.0%) and normal to
slightly elevated Hb F levels.
Are different variations of this form depending
upon which gene has mutated.
Normally require no treatment.
Make sure are not diagnosed with iron deficiency
anemia.
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•
•
•
•
•
Beta Thalassemia Intermedia
1 of 2
Patients able to maintain minimum hemoglobin (7
g/dL or greater) without transfusions.
Expression of disorder falls between thalassemia
minor and thalassemia major. May be either
heterozygous for mutations causing mild decrease
in beta chain production, or may be homozygous
causing a more serious reduction in beta chain
production.
See increase in both Hb A2 production and Hb F
production.
Peripheral blood smear picture similar to
thalassemia minor.
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•
•
•
•
Beta Thalassemia Intermedia
2 of 2
Have varying symptoms of anemia, jaundice,
splenomegaly and hepatomegaly.
Have significant increase in bilirubin levels.
Anemia usually becomes worse with infections,
pregnancy, or folic acid deficiencies.
May become transfusion dependent as adults.
Tend to develop iron overloads as result of
increased gastrointestinal absorption.
Usually survive into adulthood.
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•
•
•
•
•
•
Beta Thalassemia Major
1 of 3
Characterized by severe microcytic, hypochromic •
anemia.
Detected early in childhood: •
Infants fail to thrive. –
Have pallor, variable degree of jaundice, abdominal –
enlargement, and hepatosplenomegaly.
Hemoglobin level between 4 and 8 gm/dL. •
Severe anemia causes marked bone changes due •
to expansion of marrow space for increased
erythropoiesis.
See characteristic changes in skull, long bones, •
94
and hand bones.
Beta Thalassemia Major
2 of 3
Have protrusion upper teeth and Mongoloid facial
features.
Physical growth and development delayed.
Peripheral blood shows markedly hypochromic,
microcytic erythrocytes with extreme
poikilocytosis, such as target cells, teardrop cells
and elliptocytes. See marked basophilic stippling
and numerous NRBCs.
MCV in range of 50 to 60 fL.
Low retic count seen (2-8%).
Most of hemoglobin present is Hb F with slight
increase in Hb A2.
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•
•
•
•
•
•
Beta Thalassemia Major
3 of 3
Regular transfusions usually begin around one •
year of age and continue throughout life.
Excessive number of transfusions results in •
tranfusional hemosiderosis; Without iron
chelation, patient develops cardiac disease.
Danger in continuous tranfusion therapy: •
Development of iron overload. –
Development of alloimmunization (developing –
antibodies to transfused RBCs).
Risk of transfusion-transmitted diseases. –
Bone marrow transplants may be future treatment, •
along with genetic engineering and new drug
therapies.
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Comparison of Beta
Thalassemias
GENOTYPE
HGB A
HGB A2
HGB F
NORMAL
Normal
Normal
Normal
SILENT
CARRIER
Normal
Normal
Normal
MINOR
Dec
INTERMEDIA
Dec
Normal to
Inc
Usually Inc
MAJOR
Dec
Normal to
Inc
Normal to
Inc
Usually Inc
Usually Inc
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Other Thalassemias Caused by
Defects in the Beta-Cluster Genes
1. Delta Beta Thalassemia •
2. Hemoglobin Lepore •
3. Hereditary Persistence of Fetal •
Hemoglobin (HPFH)
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Delta Beta Thalassemia
Group of disorders due either to a gene •
deletion that removes or inactivates only
delta and beta genes so that only alpha and
gamma chains produced.
Similar to beta thalassemia minor. •
Growth and development nearly •
normal. Splenomegaly modest. Peripheral
blood picture resembles beta thalassemia.
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Hemoglobin Lepore
Rare class of delta beta thalassemia. •
Caused by gene crossovers between delta •
locus on one chromosome and beta locus
on second chromosome.
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Hereditary Persistence of Fetal
Hemoglobin (HPFH) 1 of 2
Rare condition characterized by continued
synthesis of Hemoglobin F in adult life.
Do not have usual clinical symptoms of
thalassemia.
Little significance except when combined with
other forms of thalassemia or
hemoglobinopathies.
If combined with sickle cell anemia, produces
milder form of disease due to presence of Hb
101
F.
•
•
•
•
Hereditary Persistence of Fetal
Hemoglobin (HPFH) 2 of 2
Hb F more resistant to denaturation than Hb •
A. Can be demonstrated on blood smears
using Kleihauer Betke stain. Cells
containing Hb F stain.
Classified into two groups according to •
distribution of Hb F among red cells:
Pancellular HPFH - Hemoglobin F uniformly –
distributed throughout red cells.
Heterocellular HPFH - Hemoglobin F found in –
102
only small number of cells.
Beta Thalassemia with Hbg S
Inherit gene for Hb S from one parent and gene for •
Hb A with beta thalassemia from second parent.
Great variety in clinical severity. Usually depend •
upon severity of thalassemia inherited. Production
of Hb A ranges from none produced to varying
amounts. If no Hb A produced, see true sickle cell
symptoms. If some Hb A produced, have
lessening of sickle cell anemia symptoms.
103
Beta Thalassemia with Hgb C
Shows great variability in clinical and •
hematologic symptoms.
Symptoms directly related to which type •
thalassemia inherited.
Usually asymptomatic anemia •
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Beta Thalassemia with Hgb E
Is unusual because results in more severe •
disorder than homozygous E disease.
Very severe anemia developing in •
childhood.
Transfusion therapy required. •
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Alpha
Thalassemia
106
Alpha Thalassemia
1 of 2
Has wide range clinical expressions. •
Is difficult to classify alpha thalassemias due to •
wide variety of possible genetic combinations.
Absence of alpha chains will result in increase of •
gamma chains during fetal life and excess beta
chains later in life; Causes molecules like Bart's
Hemoglobin (γ4) or Hemoglobin H (β4), which are
stable molecules but physiologically useless.
107
Alpha Thalassemia
2 of 2
Predominant cause of alpha thalassemias is large •
number of gene deletions in the alpha-globin
gene.
Are four clinical syndromes present in alpha •
thalassemia:
Silent Carrier State
Alpha Thalassemia Trait (Alpha Thalassemia Minor)
Hemoglobin H Disease
Bart's Hydrops Fetalis Syndrome
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–
–
–
–
Silent Carrier State
Deletion of one alpha gene, leaving three
functional alpha genes.
Alpha/Beta chain ratio nearly normal.
No hematologic abnormalities present.
No reliable way to diagnose silent carriers
by hematologic methods; Must be done by
genetic mapping.
May see borderline low MCV (78-80fL).
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•
•
•
•
•
Alpha Thalassemia Trait
(Alpha Thalassemia Minor)
Also called Alpha Thalassemia Minor.
Caused by two missing alpha genes. May be
homozygous (-a/-a) or heterozygous (--/aa).
Exhibits mild microcytic, hypochromic anemia.
MCV between 70-75 fL.
May be confused with iron deficiency anemia.
Although some Bart's hemoglobin (γ4) present at
birth, no Bart's hemoglobin present in adults.
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•
•
•
•
•
•
Hemoglobin H Disease
1 of 2
Second most severe form alpha thalassemia. •
Usually caused by presence of only one gene •
producing alpha chains (--/-a).
Results in accumulation of excess unpaired •
gamma or beta chains. Born with 10-40% Bart's
hemoglobin (γ4). Gradually replaced with
Hemoglobin H (β4). In adult, have about 30-50%
Hb H.
γ4
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β4
Hemoglobin H Disease
1 of 2
Live normal life; however, infections, pregnancy, •
exposure to oxidative drugs may trigger hemolytic
crisis.
RBCs are microcytic, hypochromic with marked •
poikilocytosis. Numerous target cells.
Hb H vulnerable to oxidation. Gradually •
precipitate in vivo to form Heinz-like bodies of
denatured hemoglobin. Cells been described has
having "golf ball" appearance, especially when
stained with brilliant cresyl blue.
112
Bart’s Hydrops Fetalis
Syndrome
Most severe form. Incompatible with life. Have no
functioning alpha chain genes (--/--).
Baby born with hydrops fetalis, which is edema and ascites
caused by accumulation serous fluid in fetal tissues as
result of severe anemia. Also see hepatosplenomegaly
and cardiomegaly.
Predominant hemoglobin is Hemoglobin Bart, along with
Hemoglobin Portland and traces of Hemoglobin H.
Hemoglobin Bart's has high oxygen affinity so cannot carry
oxygen to tissues. Fetus dies in utero or shortly after birth.
At birth, see severe hypochromic, microcytic anemia with
numerous NRBCs.
Pregnancies dangerous to mother. Increased risk of
toxemia and severe postpartum hemorrhage.
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•
•
•
•
•
Comparison of Alpha Thalassemias
Genotype
Hb A
Hb Bart
Hb H
Normal
97-98%
0
0
Silent Carrier
96-98%
0-2%
0
Alpha Thalassemia
Trait
85-95%
5-10%
0
Dec
25-40%
2-40%
0
80% (with 20%
Hgb Portland)
0-20%
Hemoglobin H
Disease
Hydrops Fetalis
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Alpha Thalassemia with Hgb S
Alpha thalassemia can occur in combination •
with hemoglobin S. Is fairly common
combination in populations of African
descent.
Patient usually asymptomatic. Have less Hb •
S present than those with sickle cell
trait. Have increased presence of Hb F.
115
Laboratory
Diagnosis of
Thalassemia
116
Laboratory Diagnosis of
Thalassemia
Need to start with patient's individual history •
and family history. Ethnic background
important.
Perform physical examination: •
Pallor indicating anemia.
Jaundice indicating hemolysis.
Splenomegaly due to pooling of abnormal cells.
Skeletal deformity, especially in beta
thalassemia major.
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–
–
–
–
CBC with Differential
1 of 2
See decrease in hemoglobin, hematocrit, •
mean corpuscular volume (MCV), and mean
corpuscular hemoglobin (MCH). See
normal to slightly decreased Mean
Corpuscular Hemoglobin Concentration
(MCHC). Will see microcytic, hypochromic
pattern.
Have normal or elevated RBC count with a •
normal red cell volume distribution (RDW).
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Decrease in MCV very noticeable when •
CBC with Differential
2 of 2
Elevated RBC count with markedly •
decreased MCV differentiates thalassemia
from iron deficiency anemia.
On differential, see microcytic, hypochromic •
RBCs (except in carrier states). See mild to
moderate poikilocytosis. In more severe
cases, see marked number of target cells
and elliptocytes. Will see polychromasia,
basophilic stippling, and NRBCs.
119
Reticulocyte Count
Usually elevated. Degree of elevation •
depends upon severity of thalassemia.
120
Osmotic Fragility
Have decreased osmotic fragility. •
Is not very useful fact for diagnosing •
thalassemia. Is an inexpensive way of
screening for carrier states.
121
Brilliant Cresyl Blue Stain
Incubation with brilliant cresyl blue stain •
causes Hemoglobin H to
precipitate. Results in characteristic
appearance of multiple discrete inclusions golf ball appearance of RBCs. Inclusions
smaller than Heinz bodies and are evenly
distributed throughout cell.
122
Acid Elution Stain
Based on Kleihauer-Betke procedure. Acid •
pH will dissolve Hemoglobin A from red
cells. Hemoglobin F is resistant to
denaturation and remains in cell. Stain slide
with eosin. Normal adult cells appear as
"ghost" cells while cells with Hb F stain
varying shades of pink.
Useful way to differentiate between •
pancellular HPFH and heterocellular HPFH.
123
Hemoglobin Electrophoresis
Important role in diagnosing and differentiating •
various forms of thalassemias.
Can differentiate among Hb A, Hb A2, and Hb F, •
as well as detect presence of abnormal
hemoglobins such as Hemoglobin Lepore,
hemoglobin Bart's, or Hemoglobin Constant
Spring.
Also aids in detecting combinations of thalassemia •
and hemoglobinopathies.
124
Hemoglobin Quantitation
Elevation of Hb A2 excellent way to detect •
heterozygote carrier of beta
thalassemia. Variations in gene expression
in thalassemias results in different amounts
of Hb A2 being produced.
Can also quantitate levels of Hb F. •
125
Routine Chemistry Tests
Indirect bilirubin elevated in thalassemia •
major and intermedia.
Assessment of iron status, total iron binding •
capacity, and ferritin level important in
differentiating thalassemia from iron
deficiency anemia.
126
Other Special Procedures
Globin Chain Testing - determines ratio of •
globin chains being produced.
DNA Analysis - Determine specific defect at •
molecular DNA level.
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Differential Diagnosis of Microcytic,
Hypochromic Anemias
RDW
Serum
Iron
TIBC
Serum
Ferritin
FEP
Inc
Dec
Inc
Dec
Inc
Alpha Thal
Norm
Norm
Norm
Norm
Norm
Beta Thal
Norm
Norm
Norm
Norm
Norm
Hgb E Disease
Norm
Norm
Norm
Norm
Norm
Anemia of
Chronic Disease
Norm
Dec
Dec
Inc
Inc
Inc
Inc
Norm
Inc
Dec
Norm
Norm
Norm
Norm
Inc
Iron Deficiency
Sideroblastic
Anemia
Lead Poisoning
128
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