β – THALASSEMIA

-PRANJALI BHANAGE (18BBT0128)

TEJAS PAWAR (18BBT0126)
AHMED MOHAMMED NAVEED (18BBT0121)

ABSTRACT
Thalassemia is the most common haematological disorder that affects millions
of people in the world and kills thousands of patients each year. Thalassemia is
a chronic genetic disorder that requires awareness and education to prevent its
further spreading. People must know about developing facilities for gene
therapy and foetal diagnosis. Gene therapy is in the experimental phase and is
emerging as a powerful approach of treatment but has few drawbacks. Stem cell
transplantation can also be a cure for thalassemia. It has gone through major
developments that made it less toxic, more successful and feasible for patients.
Patients with Thalassemia often complaint of pain, fatigue, reduced muscle
mass and they are of higher risks for osteoporosis. It is essential to discuss the
reasons of heterogeneity and history so that an effective method for control and
management of thalassemia can be established. These treatment measures
should be cost effective and it should improve quality of life of the patient. This
review will inculcate knowledge about thalassemia, its distribution, cause,
symptoms, prevention; including the use of gene therapy as a possible cure.

Keyword: Thalassemia, Gene therapy, Haematological disorder, Osteoporosis,

Foetal diagnosis, Transplantation, Heterogeneity
INTRODUCTION
The word thalassemia originates from a Greek word “THALASSA” which
means “The Sea”. Thalassemia is heredity anaemia which was first recognized
among the Greek people living around the Mediterranean Sea.
Thalassemia is inherited blood disorder due to abnormal haemoglobin
production. It is considered chronic haemolytic anaemia. There are two main
types of thalassemia alpha and beta. Beta thalassemia is most common type. It
is autosomal recessive disorder and is inherited to a victim from both the
parents. Symptoms depend on type and vary from none to severe anaemia. Slow
growth may occur in children. It is considered world’s most widely spread
genetic disease.
Haemoglobin is a tetramer with a molecular weight of 64.5 kDa. It consists of
two alpha and two non-alpha globin polypeptide chain, which are covalently
bound to heme group. Each of four heme group is made up of iron atom bound
with a protoporphyrin IX ring. In thalassemia, part of the haemoglobin is faulty-
either alpha chain or beta chain. This means that some of haemoglobin doesn’t
work properly, as a result there is not enough normal haemoglobin and the
RBC’s break down easily. This makes the person anaemic with symptoms such
as tiredness, fatigue, delayed growth, dark urine and pale skin. As body tries to
make more haemoglobin and RBCs, the blood system goes into overproduction
mode which can cause more symptoms and complications.
Every year approximately 1,00,000 children with Thalassemia Major are born
world over, of which 10,000 are born in India. It is estimated that there are
about 65,000 to 67,000 β-thalassemia patients in our country. On an average, 3
in 100 of the world’s population have a thalassemia gene. It is more common in
people whose origins are Mediterranean, Asian or African.
Those who have minor degrees of thalassemia similar to those with sickle cell
traits have some protection against malaria. This explains why they are more
common in regions of the world where malaria exists.

Overview
Thalassemia is caused by mutations in the DNA of cells that make haemoglobin
chain (a protein in red blood cells that carries oxygen throughout body). The
mutations associated with thalassemia are passed from parents to children.
Thalassemia disrupts the normal production of haemoglobin and healthy red
blood cells. This causes anaemia. With anaemia, blood doesn't have enough red
blood cells to carry oxygen to tissues leaving body fatigued. Meanwhile, the
body tries to make more haemoglobin and more red blood cells. So, the blood
system goes into overproduction mode, which can cause more symptoms and
complications. β-Thalassemia occurs when body can’t produce β-globin chain.
Two genes, one from each parent, are inherited to make beta globin. This type
of thalassemia comes in two serious subtypes: thalassemia major (Cooley’s
anaemia) and thalassemia intermedia. [1]. Depending on the type of beta
thalassemia, the amount of abnormal hemoglobin varies. It can be most of the
body's hemoglobin, or only a small proportion. This is mainly what determines
how severe the thalassemia is. There are also other individual factors involved.
So, two people with the same type of thalassemia may have a different severity
of illness from the same condition.
When a person having the beta thalassemia trait (carrier of β-thalassemia gene)
marries another beta thalassemia trait there is 1 in 4 chance of the foetus being
affected, 1:2 chance of the foetus having the trait and 1 in 4 chance of being
properly normal. Thus for each pregnancy there is a 25% chance for baby being
affected with thalassemia major. [25]

Beta Thalassemia in India

β-Thalassemia disorder has significant health burden in India. ‘PROJECT
RAINBOW’ was introduced in India aiming at tackling thalassemia in Punjab.
Bone marrow transplantation was first performed in 1983 in India at Christian
Medical College (CMC Vellore). [7]
In India, around 1,00,000 patients are suffering with β-thalassemia syndrome. 3-
4% of India’s population is carrier for β-thalassemia gene which means 35-45
million carriers in 1.21 billion people of our country according to 2011 Census
of India. Maximum prevalence of this syndrome was found in Vasava,
Chaudhry, Gamit and Konkana tribes from Surat, south Gujrat i.e. (12-15%). [8]
Studies show that population of rural areas had not heard about thalassemia and
aetiology of this syndrome. According to their orthodox believes, this syndrome
is caused by sins committed by parents. More than 50% of individuals from
urban areas are not willing for pre-marital screening of β-thalassemia. This
emphasises need for education and awareness programmes in different regions.
The Nation Health Portal of Ministry of Health and Family welfare, GOI
provide information on thalassemia for the public and professionals. Since
around five decades, different Institutions, NGO’s and Social organisation in
India like Rotatory clubs, Lions club etc are conducting education and
awareness programmes. [26]
Yet, there is no formal education in curriculum for higher secondary school.
Mass media is powerful tool to spread awareness. Short clip on β-thalassemia
by any personality during prime television time would give significant impact
on large population. [8]

TYPES OF BETA THALASSEMIA

Beta thalassemia can be classified into:
 Beta-thalassemia trait: This means the patient have one abnormal beta-
haemoglobin gene (out of the normal two beta genes). It doesn't’t make
the patient ill, but if the partner also has beta-thalassemia trait, then their
children could inherit BTM or BTI. Sometimes however, it can result in a
mild asymptomatic anaemia usually picked up on routine complete blood
count. [1]
 Beta-Thalassemia Intermedia (BTI): This type is less severe than
BTM. There are two beta-thalassemia genes but can make some
hemoglobin, which works reasonably well. This may be because the
patient’s particular combination of thalassemia genes is (in effect) less
severe, or because of some other protective factor. Although less severe
than thalassemia major, thalassemia intermedia does need regular
monitoring for life and often needs some treatment to prevent
complications. People with BTI can get iron overload, similar to patients
with BTM, although it may be less severe. This can happen, even if they
did not have transfusions, because the thalassemia causes extra iron to be
absorbed from food. [32]

 Beta-Thalassemia Major (BTM): A person with BTM has two beta-

thalassemia genes. Most of their hemoglobin is abnormal and does not
work. This causes severe anemia starting around the age of 4-6 months.
Before that, the baby is not affected. This is because until age 3-6 months
the baby makes a different type of hemoglobin, called fetal hemoglobin,
which is not affected by the thalassemia gene. With BTM, the patient
needs regular blood transfusions, plus other treatment like chelation
treatment to prevent complications. [33] [34]

SYMPTOMS
The signs and symptoms of beta thalassemia vary depending on the type that a
child has. Most children with beta thalassemia trait have no symptoms. Those
with β thalassemia major and intermedia may not show any symptoms at birth,
but usually develop them in the first 2 years of life.

While people with Beta thalassemia intermedia have less severe symptoms than
those with BTM, they can get complications such as:

 Bone and growth problems (similar to BTM, because the bone marrow
over-expands).
 Swellings near the spine (which don't usually cause problems, but
sometimes press on a nerve and need treatment).
 Gallstones.
 blood may be more prone to forming clots.
 Pulmonary hypertension.

For BTM , if diagnosed and treated early , can prevent symptoms and reduce
complications. So with good care, there may be few symptoms. BTM start at
around age 4-6 months. Symptoms come on gradually and are:

 Anaemia: Almost everyone with thalassemia major or other serious types

will develop anemia, which can be life threatening in severe cases. In
anemia there are low levels of hemoglobin in the blood, which typically
causes tiredness (fatigue) and lack of energy, shortness of breath,
noticeably pounding, fluttering or irregular heartbeats (palpitations), pale
skin, yellowing of the skin and eyes (jaundice).
Frequent blood transfusions will be needed for life to stop anemia
becoming severe.

 Bone symptoms: the body tries to produce more red blood cells. This is a
natural reaction to anemia. However, it does not help thalassemia much
because most of the hemoglobin that is produced is abnormal. The result
is over-expansion of the bone marrow, which is the body's blood cell
factory. This affects bone growth including the face and jawbones,
making the forehead and upper jaw very prominent.

Without treatment, symptoms of BTM get gradually worse. Untreated, children

with BTM usually die from infection or heart failure in childhood. It can also
lead to complications such as:

 Infections: People with BTM can be more prone to serious

bacterial infections (for various reasons). Certain types of infection
 (from species of germs (bacteria) called Yersinia and Klebsiella)
are more common than usual, due to iron overload or chelation
treatment. Yersinia causes tummy (abdominal) pain, diarrhoea and
fever. Sometimes, this can mimic appendicitis. Klebsiella causes
fever and severe illness.

 Complications of anaemia and transfusions: Untreated anemia can

affect growth and bone development because the bone marrow
expands to try to make more blood cells. Anemia can also cause an
enlarged spleen (the spleen is an organ in the tummy which is part
of the immune system). A large spleen can make anemia worse,
Once the spleen is removed, the patient will need extra
immunizations and daily penicillin, to protect against certain
infections (pneumococcal infection and meningitis).

Transfusions can cause blood reactions. These are less likely if the
blood is very carefully matched to be as close as possible to
patient’s blood type. Infections such as hepatitis B and C can be
transmitted by transfusion. This is less likely in the UK and
countries where donor blood is tested for infections. Hepatitis B
immunization is therefore recommended.

 Complication of iron overload: Most people with thalassemia

major will be at risk of developing a range of problems caused by
build-up of iron in the body. It is usually a side effect of repeated
blood transfusions. This can cause:

o heart problems – including problems affecting the heart muscle

(cardiomyopathy), an irregular heartbeat and heart failure
o swelling and scarring of the liver (cirrhosis)
o delayed puberty
o low levels of oestrogen (in female) or testosterone (in male)
o diabetes
o problems with the thyroid gland (hypothyroidism) and
parathyroid glands (hypoparathyroidism) [4]

HOW IS BETA THALASSEMIA DIAGNOSED?

In general, β thalassemia is detected by new-born screen. In this test,
identification of haemoglobin F is only done, not haemoglobin A. Some
severely affected beta thalassemia intermedia patients are also identified in this
way.
Mildly affected patients are identified on routine complete blood count. The
CBC will reveal a mild to moderate anaemia with very small red blood cells.
This can be confused with iron deficiency anaemia. Diagnosis is confirmed by a
haemoglobin profile also called electrophoresis. In beta thalassemia intermedia
and trait, this test reveals elevation in haemoglobin A2 (a 2nd form of adult
haemoglobin) and sometimes F (fatal). [5]
Most persons with thalassemia trait are found incidentally when their complete
blood count shows a mild microcytic anaemia. Microcytic anaemia can be
caused by iron deficiency, thalassemia, lead poisoning, sideroblastic anaemia,
or anaemia of chronic disease. The mean corpuscular volume (MCV), red blood
cell distribution width (RDW), and the patient's history can exclude some of
these etiologies. The MCV is usually less than 75 Fl with thalassemia and rarely
less than 80 Fl in iron deficiency until the haematocrit is less than 30 %.
For children, the Mentzer index (MCV/red blood cell count) can help
distinguish between iron deficiency and thalassemia. In iron deficiency, the
ratio is usually greater than 13, whereas thalassemia yields value less than 13. A
ratio of 13 would be considered uncertain.
The RDW may assist in differentiating iron deficiency and sideroblastic
anaemia from thalassemia. The RDW will be elevated in more than 90 percent
of persons with iron deficiency, but in only 50 percent of persons with
thalassemia. The RDW is usually elevated in sideroblastic anaemia. Therefore,
although a microcytic anaemia with a normal RDW will almost always be
because of thalassemia, persons with an elevated RDW will require additional
test [6]
 IRON BETA
TEST DEFICIENCY THALASSEMIA

MCV (abnormal if < 80 Fl in Low Low

adults; < 70 Fl in children six
months to six years of age; and <
76 Fl in children seven to 12 years
of age)

Red blood cell distribution width High Normal; occasionally

high

Ferritin Low Normal

Mentzer index for children > 13 < 13

(MCV/red blood cell count)

Hb electrophoresis Normal (may Increased HbA2,

have reduced reduced HbA, and
HbA2) probably increased
HbF

COMPLICATIONS OF THALASSEMIA
Growth impairment: Children with thalassemia are at high risk for growth
failure from chronic anaemia. Nutritional deficiencies, chelation toxicity, iron
induced endocrinopathies also lead to impaired linear growth and weight gain.
Pubertal development is delayed due to iron loading and severe anaemia. [18]
FOETAL CHOLELITHIASIS IN CHASE OF β-THALASSEMIA : Foetal
cholelithiasis (it is decrease in bile flow due to impaired secretion by
hepatocytes) is reported in foetal gallbladder in third trimester of pregnancy.
Potential risk factors for mother are; abruption placentae, increased oestrogen
levels, dehydration, diabetes, sepsis etc. foetal risk factors include haemolytic
anaemia, ABO or Rh incompatibility, down’s syndrome, congenital infections
and biliary cholestasis. Association of foetal cholelithiasis with β-thalassemia is
rare. It is detected during routine ultrasonography after gestation. The gallstones
persisted after neonatal period and infant was later diagnosed as β-thalassemia
major. [19] [31]
BONE DISEASE AND SKELETAL COMPLICATIONS: Osteoporosis in
patient population results from a variety of genetic and acquired factors.
Fracture prevalence in β-thalassemia major occurs in teenage and it is related to
Vitamin D deficiency and low bone mineral density. Bone, joint pain and spinal
deformity are common in patients. Intervertebral disc changes are in patients
who are chelated with deferoxamine. [20]

TREATMENT OF β-THALASSEMIA
There are different options for treating Beta-Thalassemia including:
CONVENTIONAL THERAPIES:
Conventional treatment of patients with β-Thalassemia resulted in
improvement of survival, physiological development and acceptable
levels of social adaptations and quality of life. [9]
Conventional therapies include regular RBC transfusion, splenectomy
and iron chelation with injectable Deferoxamine or oral Deferiprone
drugs. Patients receive excess iron through RBC transfusions. This excess
iron may cause damage to organs like heart. Iron chelation helps body to
remove iron. These can be given as an oral medication or an infusion
under skin. Patients with β-Thalassemia may develop iron overload even
in absence of blood transfusions secondary to increased absorption of iron
in small intestine. [10] [36]
There are many drawbacks of this therapy.
 High cost which can reach up to 2 lakh USD from birth to early
adulthood life making it unaffordable in most developing countries.
 Lack of human resource and blood banking facilities.
 Infections may also be a threat causing HCV, HBV, CMV and HIV
which is caused by blood transfusion.
 Transfusion reactions [11]

PHARMACOLOGICAL THERAPIES:
Very small amounts of foetal haemoglobin (HbF) is present in adult. It is
less than 1% of total Hb. Therapeutic approaches concentrate on
reactivating HbF and increasing its concentration. HbF levels can be
increased by using regulatory transcription factors involved in gamma-
globin gene regulation and survival. But it is difficult to modulate
function modulate the functions of factors (except enzymes) by disrupting
DNA-protein and Protein-protein interactions. Interfering with erythroid
transcription may result in disruption of erythropoiesis (formation of
RBCs).
STEM CELL TRANSPLANTATATION:
Conventional therapies improve quality of life and survival of patients but
allogenic hematopoietic stem cell transplantation (HSCT) is cure for β-
thalassemia.[4] The concept of this process is replacement of
hematopoietic stem cells (HSC) from a donor to a recipient resulting in a
new donor derived hematopoietic system in recipient. Following the
intense course of chemotherapy (and sometimes radiotherapy), the
solution containing stem cells is given into one of the veins via a drip.
The stem cells travel through the bloodstream and end up in the bone
marrow. Here they start to make blood cells.
It can take several weeks for the bone marrow to recover, to take up the
transplanted stem cells, and to make enough new blood cells. During this
treatment the patient will need to be in hospital and be closely monitored.
several blood transfusions may be needed during this time until enough
blood cells are made . Antibiotic medicines are given to minimize the risk
of infection. Also, medicines are given to help the stem cells to multiply
as quickly as possible.
There is a great need for effective transplantation programmes. Absence
of suitable donors, treatment cost and lack of enough centres for this
therapy are a few challenges as a hinderance for preventing wider use of
this therapy. More experience is required with transplants before they can
be standard for cure. [12]

GENE THERAPY
Gene therapy refers to the introduction of normal genes into cells in place
of missing or defective ones in order to correct genetic disorders. The
concept of gene therapy was known from 1978 at University of California
at Los Angeles. This goal was made possible by characterisation,
isolation, size reduction and blending of β-globin locus regulatory
elements and lentiviral vectors were used to transfer complex sequences
into hematopoietic stem cells. [10] For patients who are not having donor,
gene therapy is alternative as it is not limited by histocompatibility barrier
and doesn’t require immunosuppressant. The development of lentiviral
vectors and optimisation of hematopoietic stem cells transduction have
given significant contributions to treatment. [13]
The efficient LV-mediated β-globin gene transfer in CD34+ cells from
thalassaemic patients leads to correction of some biological features.
Analysis of specific globin chains proportion and contribution to
phenotype correction is still under evaluation. [14] [27]

BONE MARROW TRANSPLANTATION

Bone marrow transplantation relies on high dose chemotherapy to
eliminate thalassemia producing cells in the marrow and replaces them
with healthy donor cells from bone marrow. Decision to perform BMT is
considered appropriate for those patients who have fully HLA-matched
donor. According to recent study, incidence of hypothyroidism,
hypogonadism and cardiomyopathy was higher in conventionally treated
patients whereas growth impairment was found in those who had done
BMT. [15] [35]
Despite considerable progress of gene BMT; may few individuals with
thalassemia major are treated. This is due to:
 transplantation process is numerous, complex and expensive
procedure.
 It is also not available in all regions of the world where
thalassemia is endemic. Transplant services are also not provided
via governmental or non-governmental organisations.
  Some argue that BMT may cause impairments in quality of life
thus leading to replacement of one chronic health condition to
other. [16]
 Generally, not affordable
 Awareness of this technology is not there in medical societies and
public.

CLINICAL MANAGEMENT OF β-THALASSEMIA MAJOR

Management of patients with β-thalassemia is based on:
 Prevention of iron overload: It causes multiple endocrinopathies,
osteoporosis and it causes cardiac diseases.
 Adequate and safe blood transfusions: Blood which is free of transfusion
transmitted diseases
Treatment is complex, expensive and require multidisciplinary approach. [21]
β-thalassemia patients should have regular visits to doctor to evaluate the
common and important problems. In addition; reticulocyte counts, age
appropriate lab studies should be performed to evaluate endocrine function,
chelation related toxicities and nutritional deficiencies. Bone density
measurements and non-invasive imaging of tissue iron burden provide
important information of the patient. [22] [37]

PREVENTION
Screening:
It is advisable that all prospective couples who wish to get married and who
come from countries where there is a high incidence of beta-thalassemia should
be screened for the detection of beta thalassemia trait. . A simple blood test will
indicate whether the person is a thalassemia trait or not. The results are
confidential and are available within a few days. [28] [29]
Prenatal Diagnosis
This technique can be used to determine the status of the fetus. It involves
aspirating a small fetal tissue from the placenta. The DNA is then extracted and
the genetic status of the fetus is determined through DNA technology. .
Molecular defect in disease gene is known, direct DNA analysis using PCR or
RFLP probe is possible. Through DNA sequencing, a point mutation is
identified. Analysis indicates if foetus has indicated parental β-thalassemia
mutation from parents or not. [24]
Prenatal diagnosis should be offered to couples at risk for having children with
severe thalassemia. Synthesis of defected β-chain is detected foetuses as young
as 8 to 10 weeks.[17]

Prenatal Diagnosis is the most effective method of preventing the birth of

thalassemic children and has been extremely successful in many countries
including Cyprus, Greece, Turkey, Italy, Scandinavia, Thailand and India.
Pre-implantation genetic diagnosis (PGD) is another possible option for couples
who do not want to have a child with thalassemia disease yet feel, for whatever
reason that they are unable to consider termination of an affected pregnancy.
This option is now available in many countries (including UAE) for those
parents who are at risk of having a child with thalassemia disease.

OUTLOOK FOR BETA-THALASSEMIA

Untreated, Beta thalassemia, especially BTM can cause severe illness with
worsening anemia, infections and heart failure, which will usually lead to death
by the age of 5 years. With treatment, the outlook is good because anemia and
complications can be controlled by transfusions and chelation treatment.
Nowadays, treatment of thalassemia is usually successful, with patients living
into adulthood and generally able to have careers, relationships and children.
The long-term outlook depends on how well complications can be prevented,
particularly the iron overload. Early deaths can still occur, and children
sometimes develop complications such as poor growth. What makes the most
difference to the outlook is good chelation treatment. Also, patients treated at
specialist centers have had better outcomes
With advancements in medicines and new treatment techniques, as well as
recent progress in chelation treatment, the outlook will likely continue to
improve.

CONCLUSION
Over the years, increase in understanding and molecular mechanisms of
thalassemia has caused improvement in diagnosis and treatments of the
syndrome. Improved knowledge of pathophysiology and disease burden in
patients has helped in management and development of new therapeutics.
Moreover, in future focus will always be there in improving quality of life of
the patients. [23]
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