Definition

Thalassemia has many definitions. According to research conducted by Renzo Galanello,

thalassemia is a group of hereditary blood disorders that are characterized by reduced or no
synthesis of globin chains, causing reduced Hb in red blood cells, decreased production of red
blood cells and anemia. Most thalassemia is inherited as a recessive trait. According to research
conducted by Mohammad Azhar Ibrahim Kharza, thalassemia is an inherited disorder of
hemoglobin synthesis (Hb). This disorder varies, from asymptomatic to severe, and varies
according to the blood hemoglobin chain that is affected. Chains that have abnormalities affect
the age of symptom onset (α-Thalassemia affects the fetus, β-Thalassemia affects newborns).
According to a study conducted by Sylvia Morais de Souzaet al , thalassemia is the most
common monogenic disease and is characterized by hypochromatic and microcytic anemia,
which results from the absence or reduction of globin chain synthesis. According to a study
conducted by Deborah Rund and Eliezer Rachmilewitz, thalassemia is a hereditary anemia
caused by abnormalities in hemoglobin production.
Thalassemia causes the body to synthesize fewer healthy red blood cells and less
hemoglobin than usual. Hemoglobin is a protein rich in iron in red blood cells. Hemoglobin
works to carry oxygen to all parts of the body. Hemoglobin also carries carbon dioxide from the
body to the lungs to be released through breathing.
Thalassemia sufferers can experience mild or severe anemia. This condition is caused by
red blood cells that are lower than normal or insufficient hemoglobin in the red blood cells.

Etiology
Thalassemia occurs due to changes in the globin gene on human chromosomes. The
globin gene is part of a group of genes located on chromosome 11. The shape of the beta-globin
gene is regulated by the locus control region (LCR). Various mutations in genes or in the basic
elements cause defects in the initiation or termination of transcription, abnormal RNA division,
substitution, and frameshifts. The result is a decrease or stopping of the beta-globin chain
income, giving rise to beta thalassemia syndrome.
Beta-zero (β0) mutations are characterized by the absence of beta-globin production,
which is usually due to nonsense , frameshift or splicing mutations. While beta-plus (β +)
mutations are characterized by the production of several beta-globins but with few splicing
defects. Specific mutations have several relationships with different ethnic or group factors that
are prevalent in different parts of the world. Often, most individuals who inherit the disease
follow an autosomal recessive pattern, with heterozygous individuals having the gene disorder,
whereas in heterozygous or homozygous compound individuals, the disorder manifests as beta-
thalassemia major or intermedia.

Epidemiology
Throughout the world, thalassemia is a disease that is common in humans. Thalassemia
affects all ethnic groups in most countries throughout the world. For example, in Cyprus, one in
seven individuals is a genetic carrier of thalassemia, which will cause 49 marriages among
thalassemia carriers to produce 158 new cases of thalassemia major. A long-term longitudinal
study in Germany conducted by Elisabeth Konne and Enno Kleihauer from 1971 to with 2007
had found that out of 34,228 people, 34% of those studied were found to have a
hemoglobinopathy. Most cases involved thalassemia (25798 cases, 25.6%) and structural
abnormalities of hemoglobin (8,430 cases, 8.4%). 39 Of a a study conducted by M. Sengupta on
villagers in India, rather than 4635 ethnic communities, five common mutations and 12 rare
mutations have been reported. From a large-scale survey study in China conducted by Yi-Tao
Zeng and Shu-Zhen Huang, in the past two decades, out of one million people in 28 provinces,
reported α-thalassemia cases were 2.64% and for β- thalassemia is 0.66%. In one study
conducted in the UK by Hickman M et al, about 3000 babies born (0.47%) carried sickle cell
traits and 2800 (0.44%) carried thalassemia traits annually. About 178 (0.28 per 1000 births)
have sicklecell disease (SCD) and 43 (0.07 per 1000 births) have thalassemia beta major /
intermedia abnormalities.
Skull changes are more consistently severe in patients with thalassemia major than in
those with other conditions that produce bone marrow hyperplasia. In a study of 60 patients (ages
11-16) with thalassemia, Wisetsin observed that five (8.3%) had a 'hair-on-end' appearance. In
one study carried out on abnormalities found in thalassemia, radiological features found that 83%
was a change in trabecularity, 65% was thinning of the lamina dura, and 33% was a hair-on-end
appearance.
Patomechanism

Thalassemia includes mutations or deletions in genes for alpha or beta globin chains.
Hemoglobin in adults consists of forms A, A2 and F (fetal). Hemoglobin A (HbA) covers 95-
98% of the total amount of hemoglobin in the body and consists of tetramers made of 2 alpha
globin subunits and 2 beta globin subunits. Hemoglobin A2 (HbA2) covers the majority of the
remaining hemoglobin (<3.3%) and consists of 2 alpha globin subunits and 2 delta globin
subunits. <1% of hemoglobin is hemoglobin F (HbF) and consists of 2 alpha globin subunits and
2 gamma globin subunits. [4]

At the time of fetal development, the process of erythropoiesis initially occurs in the liver, then
into the spleen and in mid-pregnancy begins to switch to the bone marrow. At 6-10 weeks
gestation the majority of the hemoglobin present in infants is HbF, the majority of the globin
chains formed are alpha globin subunits and fetal globin subunits. At around 30 weeks, the
amount of fetal globin chain formation begins to decrease and the number of beta globin chains
increases so the amount of HbF decreases and HbA increases. After birth, the amount of HbF
formation will continue to decrease and HbA will increase so that 95-98% of the Hb in the body
is HbA. [1]

Thalassemia occurs when there are abnormalities in genes that affect the production of globin
chains so that Hb production decreases. The most frequent abnormalities in the formation of
globin chains are related to alpha globin and beta globin and cause alpha thalassemia and beta
thalassemia. There are various genotypes and clinical features of thalassemia. [1,4]

Alpha
Thalassemia Alpha gene Globin chain Hemoglobin Clinical picture

Normal αα / αα α2 β2 A Normal

Career αα / α- α2 β2 A Asymptomatic

α- / α-
- / αα
Trait (minor) α2 β2 A Asymptomatic
 Yellow,
Splenomegaly,

Sometimes need a
transfusion
Hb H disease - / -α α2 β2, β4 A, H

Severe, fetal death

in utero or
Barts,
immediately after
Portland
Hidrops fetalis -/- γ4, ξ2γ2 birth

Thalassemia
beta Beta gene Globin chain Hemoglobin Clinical picture

Normal β/β α2 β2 A Normal

β+/β
α2 β2, α2 δ2, α2
βo / β
Trait (minor) γ2 A, A2, F Asymptomatic

Phenotype between
thalassemia trait
β + / βo
α2 β2, α2 δ2, α2 and thalassemia
β+/β+
Intermedia γ2 A, F major

Requires chronic
α2 β2, α2 δ2, α2
transfusion, excess
β+/β+ γ2 A, A2, F
iron, chronic organ
βo / βo α2 δ2, α2 γ2 F, A2
Major damage

Table 1. Thalassemia genotypes, syndromes, and clinical features. Source: author's personal
work.

The gene for alpha globin is on chromosome 16 and is duplicated so that in each somatic
cell there are 4 copies of the alpha chain gene in each pair of homologous chromosomes. The
genes for beta, gamma, and delta globin occur on chromosome 11 and are not duplicated. Lots of
heterogenisities of alpha and beta thalassemia. Both of these diseases are inherited by autosoma l
recessive from parents.

In general, in both types of alpha and beta thalassemia there are abnormalities in the
process of erythropoiesis in which the number of red blood cells that are formed is less and what
is formed is also not perfect. Erythrocytes that form in thalassemia have abnormalities in
membrane structure and permeability that can be easily damaged. Erythrocytes in thalassemia
have a less amount of HbA so that other types of hemoglobin are formed. Other types of
hemoglobin are more susceptible to oxidative stress and easily form precipitates to form
inclusion bodies , Heinz bodies , and Howell Jolly bodies . When erythrocytes are damaged,
yellow symptoms and enlarged spleen occur. Erythropoiesis that occurs also cannot occur
properly so it needs to be done excessively and cause abnormalities and bone hyperoplasia.

Alpha Thalassemia
Alpha thalassemia is a group of hereditary anemia syndromes caused by the lack or
absence of production from 1 or more alpha globin chains. Abnormal production of alpha globin
chains causes the relative excess of the gamma globin chain in fetuses and newborns, and beta
globin chains in adults. The globin chains can combine to become tetramers. The combination of
4 beta globin chains (β4) is called Hemoglobin H (HbH) and the combination of 4 gamma globin
chains (γ4) is called Hemoglobin Barts. HbH is unstable and can form precipitates so that they
will be damaged in the previous time.

There are 4 copies of the alpha chain gene in each pair of homologous chromosomes 16.
The majority of genetic abnormalities found in alpha globin chain genes cause deletions. Alpha
hemoglobin is needed in the formation of HbA and HbF. Hb Barts and HbH are only the types of
hemoglobin that can form. This condition is known as fetal hydrops, thalassemia alpha major, or
Barts hemoglobin. A fetus that experiences this condition will usually die in the womb or shortly
after birth.
 A person with alpha career thalassemia has only deletions in 1 alpha chain globin gene.
Patients with alpha career thalassemia do not have any clinical abnormalities and can have
normal blood output or a slight decrease in mean corpuscular volume (MCV) and mean
corpuscular hemoglobin (MCH).
Deletion of 2 alpha globin genes in heterozygous (- / αα) or homozygous (α- / α-) causes
alpha trait thalassemia. A person with alpha trait thalassemia is often clinically normal but can
have minimal anemia and rather low MCV and MCHC values. The RBC value usually increases
slightly.
In hemoglobin H (HbH) or thalassemia intermedia, there are only 1 in 4 alpha globin
chain genes. Because of the loss of 3 alpha globin chain genes, a lot of HbH is formed. HbH has
a high affinity for oxygen and is therefore an ineffective provider of oxygen in tissues. It can also
be seen that in the 4 alpha globin chain genes, two of them can only produce 25% of the alpha
globin chain and two to 75% so that the severity of the disease can vary greatly.

Beta Thalassemia
In contrast to alpha thalassemia, the gene for the beta globin chain is only 2. Beta
thalassemia can be heavier than alpha thalassemia because the gene is only 2. Because of the
lack of a beta globin chain, alpha hemoglobin (HbA2) can be formed consisting of α2 β2 and
fetal hemoglobin (HbF) α2 β2.

Gene abnormalities that occur on chromosome 11 in beta thalassemia are not only
deletical as in alpha thalassemia. Mutations that occur can cover all aspects of the production of
beta globin chains from transcription, translation, and stability from production. Eventually, the
molecular defects present in beta thalassemia end in a reduced or nonexistent number of beta
globin chains. The amount of excess alpha globin chains is unstable and causes structural
abnormalities in erythrocytes so that they are shortened. The process of erythropoiesis is also
hampered.

Beta thalassemia is divided into 3 types namely thalassemia major ( Cooley anemia ),
beta minor thalassemia (career / trait), and thalassemia beta intermedia. In beta major
thalassemia, sufferers have homozygous or compound heterozygous genes for gene mutations in
the beta thalassemia gene so that the phenotype represents a severe anemia that requires chronic
transfusion and iron chelation agents. In beta minor thalassemia, there is a heterozygous gene
where there is only an abnormality in 1 beta globin chain gene so that the patient can be
asymptomatic and the lab results can be only slightly abnormal. In beta intermedia thalassemia,
phenotypes experienced by patients are between the major and minor types, beta globin chains
can still be formed. In rare cases there are conditions where mutations occur in beta and alpha
globin chain genes.

Thalassemia Hemoglobin E
Thalassemia hemoglobin E (HbE) is a variant of the structure of hemoglobin which
involves a mutation in the gene for the beta globin chain. Therefore Hal thalassemia is also often
known as beta thalassemia E. Mutations that occur in HbE thalassemia occur specifically in
codon 26 in the beta globin chain gene and in heterozygous cases can cause a mild beta
thalassemia picture. Thalassemia beta E by itself if it occurs homozygous includes 50% of the
genotype in severe cases of beta thalassemia. Thalassemia HbE is considered a very
heterogeneous disease because the mutations that occur often overlap with other types of alpha
or beta thalassemia.

The symptoms

Thalassemia sufferers have symptoms that vary depending on the type of amino acid
chain lost and the amount of loss. Most sufferers experience mild anemia, especially hemolytic
anemia (Tamam.M. 2009). Severe circumstances in beta-thalassemia major will experience
anemia due to failure of blood cell formation, patients appear pale due to lack of hemoglobin.
Stomach looks distended due to hepatomegaly and splenomegaly as a result of the accumulation
of Fe, black skin resulting from increased Fe production, also occurs jaundice due to increased
production of bilirubin. Heart failure is caused by iron buildup in the heart muscle, facial bone
deformity, growth retraction, premature aging (Herdata.NH 2008 and Tamam. M. 2009).
Physical examination

As a first step to the examination, the doctor will ask about the symptoms experienced by
the patient. Then the doctor will do a physical examination to see signs of anemia and enlarged
organs of the spleen and liver.

The doctor will also do a blood test to diagnose thalassemia. Some types of blood tests that will
be carried out are:

 Complete blood cell count .

 Preparations remove peripheral blood, by looking at the picture of blood cells under a
microscope.

 Analysis of hemoglobin or red blood cell protein.

 Amount of iron.

 Examination of genes or DNA.

From all of these examinations, the doctor will determine whether the child has thalassemia or
not, as well as the type of thalassemia he has.

Supporting investigation
There are many investigations that can be done for thalassemia. However definite
diagnosis can only be found by genetic examination .

Clinicians can lead to investigations according to the needs of patients. In general, when
thalassemia is suspected, patients can be examined for a complete blood count and peripheral
blood smears. Bilirubin and reticulocytes can also be examined if there is suspected hemolytic
anemia and iron studies can be done to rule out iron deficiency anemia.

PCR genetic examination can then be done to re-confirm the diagnosis of thalassemia
after Hb electrophoresis or to diagnose thalassemia that is not so clinically visible or the results
of Hb electrophoresis.
Hematology examination

A complete blood test can be done as a first supporting examination performed by the clinician
and can establish a diagnosis of anemia.

Bilirubin values, especially direct bilirubin and increased reticulocytes can lead to a diagnosis of
hemolytic anemia.

Peripheral blood smears are standard examinations carried out with complete blood tests and can
direct the diagnosis in thalassemia if hypochromic microcytic erythrocytes are found.

Iron Studies

Iron studies can be done to rule out a differential diagnosis of iron deficiency anemia and to
monitor for the side effects of iron overload.

Hemoglobin (Hb) Electrophoresis

Hb electrophoresis is a mandatory examination for patients suspected of thalassemia to assess the

percentage of hemoglobin in the blood.

Genetic Examination

PCR genetic examination can be done to truly confirm the diagnosis of thalassemia after Hb
electrophoresis.

Bone Marrow Aspiration

Bone marrow aspiration to rule out a differential diagnosis at the beginning of a disease
investigation.
Imaging

X-ray of the bone to see the fracture and deformity in severe thalassemia cases that are not given
therapy but should not be done.

Examination of the Heart and Liver

Examination of the heart and liver to see iron levels in the body to see complications from
chronic transfusion. The checks that need to be carried out are as follows:

 CT scan and MRI

 ECG and echocardiography

 Liver biopsy if necessary

General check Hb
up Blood smear Reticulocytes electrophoresis

Mild anemia
Hematocrit 28-
Erythrocytes,
48%
microcytes,
Thalassemia hypochromes, target
MCV 60-75 fl
alpha trait cells, acetosis Normal Normal

Anemia
Hematocrit 22-
32% The picture is a
little abnormal.
MCV 60-70 fl
Hypochromic
erythrocytes,
Erythrocytes
microcytosis, target
increase
HbH disease cells, poikilositosis Increase HbH 10-40%

Thalassemia Anemia The picture is a Normal or HbA 2 4-8%

beta minor Hematocrit 28- little abnormal. increased HbF 1-5%
40% Erythrocyte
hypochromia,
MCV 55-75 fl
microcytosis, target
cells, and asophilic
Erythrocytes are
stippling.
normal or
increased

Anemia
Hematocrit 17-
33%
Abnormal.
MCV 55-75 fl
Erythrocyte
hypochromia,
Normal or
Thalassemia microcytosis, target
increased HbA 2 10%
beta cells, and asophilic
erythrocytes HbF 6-10%
intermedia stippling. Increase

Very abnormal
results.
Poikilositosis,
hypochromia,
microcytosis, target
Severe anemia
cells, basophilic
Hematocrit <10%
stippling and
without
Thalassemia nucleated There is almost
transfusion
beta major erythrocytes. Increase no HbA

Table 2. Results of thalassemia lab tests. Source: author's personal work.

Management

The main management for patients with severe thalassemia is routine transfusion and iron
chelation therapy.

Patients with mild thalassemia (alpha trait thalassemia and beta minor thalassemia) do not
require special therapy.

Complications

1. Bone disorders

Thalassemia sufferers' bones become thin and brittle ( osteoporosis ), so that sufferers are
at risk for fractures. This condition occurs due to the bone marrow working hard to
produce blood cells, so that the bone marrow cavity widens.

2. Enlarged spleen

Damage to red blood cells due to thalassemia can cause the spleen to have to work harder
to destroy damaged blood cells. This results in enlarged spleen organs. If the spleen
enlarges, not only damaged blood cells will be destroyed, but also healthy blood from the
donor.

3. Heart problems

Severe thalassemia can also cause heart problems, such as heart rhythm disorders
(arrhythmias) and heart failure.
 4. Growth in children becomes stunted

Thalassemia can cause a child's growth to be slow. In addition, children will also
experience puberty late.

Prognosis

Thalassemia minor has a very good prognosis, but in cases of severe thalassemia, the
patient's final outcome is very dependent on transfusion therapy and iron chelation obtained.