Thalassemia (British English: thalassaemia) are forms of inherited autosomal recessive blood

disorders that originated in the Mediterranean region. In thalassemia, the disease is caused by the
weakening and destruction of red blood cells. 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, which results in mild or severe anemia. Thalassemia will present as microcytic anemiawhich
may be differentiated from iron deficiency anemia using the mentzer index calculation.
Thalassemia can cause significant complications, including pneumonia, iron overload, bone
deformities and cardiovascular illness. However this same inherited disease of red blood cells may
confer a degree of protection against malaria, which is or was prevalent in the regions where the trait
is common. This selective survival advantage on carriers (known as heterozygous advantage) may be
responsible for perpetuating the mutation in populations. In that respect, the various thalassemias
resemble another genetic disorder affecting hemoglobin, sickle-cell disease.[1] [2]
Contents
[hide]

1 Etymology
2 Epidemiology
3 Pathophysiology
o

3.1 Alpha () thalassemias

3.2 Beta () thalassemias

3.3 Delta () thalassemia

3.4 In combination with other hemoglobinopathies

4 Cause
5 Complications
6 Benefits
7 Treatment

7.1 Medical care

7.2 Drug treatment

7.2.1 Deferoxamine

7.2.1.1 Structure and coordination

7.2.1.2 Administration and action

7.2.1.3 Side effects

7.2.2 Deferiprone

7.2.2.1 Structure and coordination

7.2.2.2 Administration and action

7.2.2.3 Side effects

7.2.3 Deferasirox

7.2.3.1 Structure and coordination

7.2.3.2 Administration and action

7.2.3.3 Side effects

7.2.4 Indicaxanthin

7.2.4.1 Structure

7.2.4.2 Function
7.3 Carrier detection

8 Curative methods
o

8.1 Bone marrow transplant (BMT) from compatible donor

8.2 Bone marrow transplant (BMT) from haploidentical mother to child

9 References

10 External links
o

10.1 United States

10.2 United Kingdom

Etymology
The name of this condition derives from the Greek Thalassa (), sea, and haema (),
blood. The term was first used in 1932.
[edit]Epidemiology
The beta form of thalassemia is particularly prevalent among Mediterranean peoples and this
geographical association is responsible for its naming[citation needed]. In Europe, the highest concentrations
of the disease are found in Greece, coastal regions in Turkey (particularly the Aegean Region such
as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya,Adana, Mersin), in parts
of Italy, particularly Southern Italy and the lower Po valley. The major Mediterranean islands (except
the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus, andCrete are heavily affected in
particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have
high rates of thalassemia, including people from West Asia andNorth Africa. Far from the
Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16%
of the population) being in the Maldives.
Nowadays, it is found in populations living in Africa, the Americas and also, in Tharu in
the Terai region of Nepal and India.[3] It is believed to account for much lower malaria sicknesses and
deaths,[4] accounting for the historic ability of Tharus to survive in areas with heavy malaria infestation,
where others could not. Thalassemias are particularly associated with people of Mediterranean origin,
Arabs (especially Palestinians and people of Palestinian descent), and Asians. [5] The Maldives has the
highest incidence of Thalassemia in the world with a carrier rate of 18% of the population. The
estimated prevalence is 16% in people from Cyprus, 1%[6] in Thailand, and 3-8% in populations
from Bangladesh, China, India, Malaysia and Pakistan. Thalassemias also occur in descendants of
people from Latin America and Mediterranean countries (e.g. Greece, Italy, Portugal, Spain, and
others).
[edit]Pathophysiology

Normally, hemoglobin is composed of four protein chains, two and two globin chains arranged into
a heterotetramer. In thalassemia, patients have defects in either the or globin chain (unlike sicklecell disease, which produces a specific mutant form of globin), causing production of abnormal red
blood cells.
The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In
thalassemias, production of the globin chain is affected, while in thalassemia production of the
globin chain is affected.
The globin chains are encoded by a single gene on chromosome 11; globin chains are encoded
by two closely linked genes on chromosome 16. Thus, in a normal person with two copies of each
chromosome, there are two loci encoding the chain, and four loci encoding the chain. Deletion of
one of the loci has a high prevalence in people of African or Asian descent, making them more likely
to develop thalassemias. Thalassemias are not only common in Africans, but also in Greeks and
Italians.
[edit]Alpha

() thalassemias

Main article: Alpha-thalassemia

The thalassemias involve the genes HBA1[7] and HBA2,[8] inherited in a Mendelian
recessive fashion. There are two gene locii and so four alleles. It is also connected to the deletion of
the 16p chromosome. Thalassemias result in decreased alpha-globin production, therefore fewer
alpha-globin chains are produced, resulting in an excess of chains in adults and excess chains in
newborns. The excess chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta
chains), which have abnormal oxygen dissociation curves.
[edit]Beta

() thalassemias

Main article: Beta-thalassemia

Beta thalassemias are due to mutations in the HBB gene on chromosome 11, [9] also inherited in an
autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation.
Mutations are characterized as either o or thalassemia major if they prevent any formation of
chains, the most severe form of thalassemia. Also, they are characterized as + or thalassemia
intermedia if they allow some chain formation to occur. In either case, there is a relative excess of
chains, but these do not form tetramers: Rather, they bind to the red blood cellmembranes, producing
membrane damage, and at high concentrations they form toxic aggregates.
[edit]Delta

() thalassemia

Main article: Delta-thalassemia

As well as alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of
alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to
produce delta chains can occur[citation needed].
[edit]In

combination with other hemoglobinopathies

Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India; clinically

similar to thalassemia major or thalassemia intermedia.

hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically

similar to sickle cell anemia, with the additional feature of splenomegaly

hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin

o

C/ thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin

C/+ thalassemia produces a milder disease.
[edit]Cause

Cause

Thalassemia has an autosomal recessivepattern of inheritance

Both and thalassemias are often inherited in an autosomal recessive fashion, although this is not
always the case. Cases of dominantly inherited and thalassemias have been reported, the first of
which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5
bp in the -globin gene. For the autosomal recessive forms of the disease, both parents must be

carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a
25% risk with each pregnancy for an affected child. Genetic counseling and genetic testing is
recommended for families that carry a thalassemia trait.
There are an estimated 60-80 million people in the world carrying the beta thalassemia trait alone.
[citation needed]

This is a very rough estimate; the actual number of thalassemia major patients is unknown

due to the prevalence of thalassemia in less developed countries. [citation needed] Countries such as India
and Pakistan are seeing a large increase of thalassemia patients due to lack of genetic counseling
and screening.[citation needed] There is growing concern that thalassemia may become a very serious
problem in the next 50 years, one that will burden the world's blood bank supplies and the health
system in general.[citation needed] There are an estimated 1,001 people living with thalassemia major in the
United States and an unknown number of carriers.[citation needed] Because of the prevalence of the
disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis
can be difficult.[citation needed]
[edit]Complications

Iron overload: People with thalassemia can get an overload of iron in their bodies, either from
the disease itself or from frequent blood transfusions. Too much iron can result in damage to the
heart, liver and endocrine system, which includes glands that produce hormones that regulate
processes throughout the body. The damage is characterized by excessive deposits of iron.
Without adequate iron chelation therapy, almost all patients with beta-thalassemia will accumulate
potentially fatal iron levels.[10]

Infection: people with thalassemia have an increased risk of infection. This is especially true if
the spleen has been removed.

Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to
widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow
expansion also makes bones thin and brittle, increasing the risk of broken bones.

Enlarged spleen: the spleen aids in fighting infection and filters unwanted material, such as
old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large
number of red blood cells and the task of removing these cells causes the spleen to enlarge.
Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells.
Severe enlargement of the spleen may necessitate its removal.

Slowed growth rates: anemia can cause a child's growth to slow. Puberty also may be
delayed in children with thalassemia.

Heart problems: such as congestive heart failure and abnormal heart rhythms (arrhythmias),
may be associated with severe thalassemia.[11]

Benefits
Epidemiological evidence from Kenya suggests another reason: protection against severe
malarial anemia may be the advantage.[12]
People diagnosed with heterozygous (carrier) thalassemia have some protection against coronary
heart disease.[13]
[edit]Treatment
[edit]Medical

care

Mild thalassemia : patients with thalassemia traits do not require medical or follow-up care
after the initial diagnosis is made.[14] Patients with -thalassemia trait should be warned that their
condition can be misdiagnosed for the common Iron deficiency anemia. They should eschew
empirical use of Iron therapy; yet iron deficiency can develop during pregnancy or from chronic
bleeding.[15] Counseling is indicated in all persons with genetic disorders, especially when the
family is at risk of a severe form of disease that may be prevented. [16]

Severe thalassemia : Patients with severe thalassemia require medical treatment. A blood
transfusion regimen was the first measure effective in prolonging life. [14]

[edit]Drug

treatment

Patients with thalassemia gradually accumulate high levels of iron (Fe) in their bodies. This build-up of
iron may be due to the disease itself, from irregular haemoglobin not properly incorporating adequate
iron into its structure, or it may be due to the many blood transfusions received by the patient. This
overload of iron brings with it many biochemical complications.
Two key players involved in iron transport and storage in the body are ferritin and transferrin. Ferritin
is a protein present within cells that binds to Fe (II) and stores it as Fe (III), releasing it into the blood
whenever required. Transferrin is an iron-binding protein present in blood plasma; transferrin acts as a
transporter, carrying iron through blood and providing cells with the metal throughendocytosis.
Transferrin is highly specific to iron (III), and binds to it with an equilibrium constant of 1023 M-1 at a pH
of 7.4.[17]
Thalassemia results in nontransferrin-bound iron being available in blood as all the transferrin
becomes fully saturated. This free iron is toxic to the body since it catalyzes reactions that generate
free hydroxyl radicals.[18] These radicals may induce lipid peroxidation of organelles like lysosomes,

mitochondria, and sarcoplasmic membranes. The resulting lipid peroxides may interact with other
molecules to form cross links, and thus either cause these compounds to perform their functions
poorly, or render them non-functional altogether.[18] This iron overload may be treated withchelation
therapy. Deferoxamine, deferiprone and deferasirox are the three most widely used iron-chelating
agents.
[edit]Deferoxamine

Structure and coordination

The drug deferoxamine, also known as desferoxamine B and DFO-B, is a trihydroxamic acid that is
produced by the actinobacteria Streptomyces pilosus. It binds iron, decreasing the toxic reactions
catalysed by the unbound metal, and it also decreases the uptake of iron by tissues. Deferoxamine
achieves this by acting as a hexadentate iron-chelating ligand: it binds to all six coordination sites on
nontransferrin-bound iron, effectively deactivating it.[19] Deferoxamine is mostly specific to ferric iron
(Fe3+) and coordinates to Fe3+ using the oxygen atoms on its multiplehydroxyl and carbonyl groups,
forming a structure called ferrioxamine. This drug-iron complex is mostly excreted by the kidneys as it
is water-soluble.[20] Approximately one-third of ferrioxamine could also be excreted through the feces
in bile.[18]

[edit]Administration and action

Deferoxamine is administered via intravenous, intramuscular, or subcutaneous injections. Oral
administration is not possible as deferoxamine is rapidly metabolized by enzymes and is poorly
absorbed from the gastrointestinal tract. The required parenteral administration represents one of
deferoxamines downfalls as it is harder for patients to follow up with their therapy due to the financial
and emotional burdens experienced.[21] Deferoxamine was proven to cure many clinical complications
and diseases that result from iron overload. It beneficially affects cardiac disease, such as myocardial
disease which occurs as a result of iron accumulation in the heart. [22] Deferoxamine was also shown to
improve liver function by arresting the development of hepatic fibrosiswhich occurs as a result of iron
accumulation in the liver.[23] Deferoxamine also has positive effects on endocrine function and growth.
Endocrine abnormalities in thalassemic patients involve the overloaded iron interfering with the
production of insulin-like growth factor (IGF-1), as well as stimulating hypogonadism, both of which
cause poor pubertal growth. A study showed that 90% of patients who were regularly treated with
deferoxamine since childhood had normal pubertal growth, which fell to 38% for patients treated only
with low doses of deferoxamine since their teens.[18]Another endocrine abnormality that thalassemic
patients face is diabetes mellitus, which results from iron overload in the pancreas
impairing insulin secretion. Studies have shown that patients who were regularly treated with
deferoxamine have a reduced risk of developing diabetes mellitus. [24]

[edit]Side effects
Deferoxamine could lead to toxic side effects if doses greater than 50 mg/kg body weight are
administered. These side effects may include auditory and ocular abnormalities, pulmonary
toxicity,sensorimotor neurotoxicity, as well as changes in renal function.[18] Another toxic effect of
deferoxamine mostly observed in children is the failure of linear growth. This reduction in height may
occur as a result of deferoxamine chelating metals other than iron which are required for normal
growth. Deferoxamine has an affinity constant (Ka) of 1031 for Fe3+, 1014 for Cu2+ and 1010 for Zn2+, and
so may coordinate to zinc and copper when little iron is available for chelation. Zinc is needed for the
proper functioning of various metalloenzymes involved in bone formation. Zinc chelation may cause
zinc deficiency in the body, which can thus lead to a reduced growth rate, reduced collagen formation
and defective bone mineralization. Similarly, copper functions as anenzyme cofactor in bone
formation. Copper chelation may result in copper deficiency as well, leading to metaphyseal cupping
and osteoporosis. For example, abnormal collagen is formed when copper is deficient as the
enzyme lysyl oxidase, which uses copper as a cofactor and catalyzes the oxidative deamination step
that is important for cross-linking of collagen, cannot function properly. Studies have shown that even
though the blood serum of patients receiving deferoxamine was not deficient in copper and zinc,
deficiencies of the metals in the metaphyseal matrix were observed.
The toxic effect of deferoxamine on linear growth could also be due to excess deferoxamine
accumulating in tissues and interfering with iron-dependent enzymes which are involved in the
post-translational modification of collagen.[25]
Patients who receive vitamin C supplements have shown improved iron excretion by
deferoxamine. This occurs due to the expansion of the iron pool brought about by vitamin C,
which deferoxamine subsequently has access to. However, vitamin C supplementation could
also worsen iron toxicity by promoting the formation of free radicals. Therefore, only 100 mg
of vitamin C should be taken 30 minutes to one hour after deferoxamine administration. [26]
It has also been proven that combined treatment with deferoxamine and deferiprone leads to
an increased efficiency in chelation and doubles iron excretion. [27]

[edit]Deferiprone

[edit]Structure and coordination

Deferiprone

Deferiprone (DFP) is a bidentate iron-chelator. Three molecules of the drug therefore

coordinate to one iron atom, forming an orthorhombic structure.[28][29]
DFP is synthetically made and is highly selective to Fe(III). [28][30] Physical properties that allow
this compound to be effective as a drug include its water solubility, low molecular
weight (139 Da), neutral charge, and lipophilicity.[28] These physio-chemical properties allow
facile crossing of cell membranes throughout the body, including the blood-brain barrier,
facilitating removal of excess iron from within organs. [28][31]
Although the mechanism for the removal of iron by DFP is not well understood, however, a
study by Viroj Wiwanitkit in 2006 proposed a possible mechanism: the coordination to the iron
was thought to occur through the cleavage of either a C-C bond or a C-O bond in the drug.
Wiwanitkit concluded that the mechanism goes though the cleavage of the C-C bond because
this bond requires less energy to be cleaved. The total energy for the cleavage was found to
be negative, suggestingspontaneity and thermodynamic favourability of the cleavage. The
resulting structure of the product also resembled the observed tertiary structure of the drugiron complex.[29]

[edit] Deferiprone is an iron chelator that is orally active, its administration thus being much easier
than that for deferoxamine.[28] Plasma levels for the iron-drug complex climax after one hour of intake
and the drug has a half-life of 160 minutes. Most of the iron-drug complex is therefore excreted within
three to four hours following administration, the excretion occurring mostly in urine (90%).[28]
When comparing deferiprone to deferoxamine, it should be noted that they both bind iron with similar
efficiency. However, drugs with different properties are able to access different iron pools. DFP is

smaller than deferoxamine and can thus enter cells more easily. Also, at the pH of blood, the affinity of
DFP for iron is concentration dependent: at low DFP concentrations, the iron-drug complex breaks
down and the iron is donated to another competing ligand. This property accounts for the observed
tendency of DFP to redistribute iron in the body. For the same reason, DFP can shuttle intracellular
iron out to the plasma, and transfer the iron to deferoxamine which goes on to expel it from the body.
[30]

DFP was also found to be significantly more effective than deferoxamine in treating myocardial
siderosis in patients with thalassemia major[28]: DFP is thought to improve the function of mitochondria
in the heart by accessing and redistributing labile iron in cardiac cells.
Thalassemia patients may also be faced with potential oxidative damage to brain cells as the brain
has high oxygen demands, but contains relatively low levels of antioxidant agents for protection
against oxidation. The presence of excess iron in the brain may lead to higher concentrations of free
radicals. Hexadentate chelators, like deferoxamine, are large molecules, and are thus unlikely to be
able to cross the blood-brain barrier to chelate the excess iron. DFP, however, can do so and forms a
soluble, neutral iron-drug complex that can cross cell membranes by non-facilitateddiffusion. Attaching
the drug to sugars may additionally enhance the penetration of the blood-brain barrier, as the brain
uses facilitated transport for its relatively high levels of sugar intake.[32]

[edit]Side effects
DFP can be subjected to glucuronidation in the liver, which may expel as much as 85% of the drug
from the body before it has had a chance to chelate iron. DFP also has a well-known safety profile,
with agranulocytosis being the most serious side effect.[28] While agranulocytosis has been reported in
less than 2% of patients treated, it is potentially life threatening and thus requires close monitoring of
the white blood cell count.[31] Less serious side effects include gastrointestinal symptoms, which were
found in 33% of patients in the first year of administration, but fell to 3% in following years; arthralgia;
and zinc deficiency, with the latter being a problem especially for individuals with diabetes.[28]
[edit]Deferasirox

[edit]Structure and coordination

Deferasirox

Deferasirox is an N-substituted bis-hydroxyphenyl-triazole. It is capable of removing iron from the

blood through the coordination of two molecules of the deferasirox to a single iron ion, which forms
the iron chelate (Fe-[deferasirox]2).[33] Each molecule of the tridentate chelator deferasirox binds to the
iron at three sites, using one nitrogen atom and two oxygen atoms. This results in a
stable octahedral geometry around the iron centre. The ability of deferasirox to remove iron stems
directly from its relatively small size, which is what allows it to access the iron contained within the
blood and, more notably, inside tissues. Also, an important feature of deferasirox is that it has been
shown to be highly selective for iron in the +3 oxidation state, and use of the drug does not lead to a
significant decrease in the levels of other important metals in the body.[34]

Administration and action

Deferasirox-Iron (III) complex

Deferasirox is most commonly marketed under the brand name Exjade. It has one key advantage
over desferoxamine in that it can be taken orally in pill form, and so does not
require intravenous orsubcutaneous administration. With a terminal elimination half life of 8-16 hours,
the deferasirox pill can be taken just once everyday. A once-daily dose of 20mg/kg of body weight has
been found to be sufficient for most patients for the maintenance of liver iron concentration (LIC)
levels, which are usually measured as mg of iron per g of liver tissue. Larger doses may be required
for some patients in order to reduce LIC levels.[35] The ability of deferasirox to effectively reduce LIC
levels has been well documented. One study demonstrated that after 4-5 years of deferasirox
treatment the mean LIC levels of patients decreased from 17.4 10.5 to 9.6 8.0 mg Fe/g. This study
showed that long-term treatment did result in a sustainable reduction in the iron burden faced by
patients receiving blood transfusions for thalassemia.[36] An additional benefit of the use of deferasirox
instead of desferoxamine is that, unlike desferoxamine, early studies have indicated that deferasirox
does not have a significant impact on the growth and development of pediatric thalassemia patients.
In a study by Cappellini et. al. it was shown that children receiving the treatment displayed continual
near-normal growth and development over a 5-year study period. [36]

[edit]Side effects
Deferasirox can, however, have a wide variety of side effects. These may include headaches, nausea,
vomiting, and joint pains.[37] Some evidence has been shown of a link to gastrointestinal disorders
experienced by some people who have received the treatment. [36]
[edit]Indicaxanthin

Structure

Indicaxanthin, the yellow pigment of the cactus pear fruit

Indicaxanthin is a pigment derived from the cactus pear fruit and can be used as an antioxidant.
Dietary indicaxanthin has been shown to have protective effects on RBCs in people with beta
thalassemia.[38] It has a structure similar to that of amino acids, and is amphiphilic: it is able to bind to
cell membranes through charge-related interactions with polar head groups of membrane
constituents, as well through adsorption to the lipid aggregates. Upon ex vivo introduction to
thalassemic blood, indicaxanthin was shown to accumulate within RBCs. [38]

[edit]Function
Hb undergoes the following oxidation reaction during normal controlled breakdown of RBCs:
Hb Oxy-Hb Met-Hb [Perferryl-Hb] Oxoferryl further oxidation steps
This reaction is experienced by thalassemic RBCs to a greater extent because, not only are there
more oxidative radicals in thalassemic blood, but thalassemic RBCs also have limited antioxidant
defense. Indicaxanthin is able to reduce the perferryl-Hb, a reactive intermediate, back to met-Hb. The
overall effect of this step is that Hb degradation is prevented, which helps prevent accelerated
breakdown of RBCs.[38]

In addition, indicaxathin has been shown to reduce oxidative damage in cells and tissues and does so
by binding to radicals. The mechanism of its function, however, is still unknown. [38]
Indicaxanthin has high bioavailability and minimal side effects, like vomiting or diarrhea.
[edit]Carrier

detection

A screening policy exists in Cyprus to reduce the incidence of thalassemia, which since the
program's implementation in the 1970s (which also includes pre-natal screening and abortion)
has reduced the number of children born with the hereditary blood disease from 1 out of every
158 births to almost zero.[39]

In Iran as a premarital screening, the man's red cell indices are checked first, if he
has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is
tested. When both are microcytic their hemoglobin A2 concentrations are measured. If both have
a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local
designated health post for genetic counseling.[40]

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia.
The child was born from an embryo screened to be free of the disease before implantation with In
vitro fertilization. The baby's supply of immunologically compatible cord blood was saved for
transplantation to his brother. The transplantation was considered successful. [41] In 2009, a group of
doctors and specialists in Chennai and Coimbatore registered the successful treatment of
thalassemia in a child using a sibling's umbilical cord blood. [42]

Curative methods
[edit]Bone

marrow transplant (BMT) from compatible donor

It is possible to be cured, with no more need of blood transfusions, thanks to Bone Marrow
Transplantation (BMT) from compatible donor, invented in the 1980s by Prof. Guido Lucarelli. In lowrisk young patients, the thalassemia-free survival rate is 87%; the mortality risk is 3%. [43] The
drawback is that this curative method requires an HLA-matched compatible donor.
[edit]Bone

marrow transplant (BMT) from haploidentical mother to child

If the patient does not have an HLA-matched compatible donor such as the first curative method
requires, there is another curative method called Bone Marrow Transplantation(BMT) from
haploidentical mother to child (mismatched donor), in which the donor is the mother. It was invented in
2002 by Dr. Pietro Sodani. The results are these: thalassemia-free survival rate 70%, rejection 23%,
and mortality 7%. The best results are with very young patients.

[44]

References
1.

^ Weatherall David J, "Chapter 47. The Thalassemias: Disorders of Globin Synthesis"

(Chapter). Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal, JT: Williams Hematology,
8e: http://www.accessmedicine.com/content.aspx?aID=6123722.

2.

^ Mayoclinichttp://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=complication
s. Retrieved 20 September 2011.

3.

^ Modiano, G. et al. (1991). "Protection against malaria morbidity: Near-fixation of the thalassemia gene in a Nepalese population". American Journal of Human Genetics 48 (2): 390
397. PMC 1683029. PMID 1990845.

4.

^ Terrenato, L. et al. (1988). "Decreased Malaria Morbidity in the Tharu People Compared to
Sympatric Populations in Nepal". Annals of Tropical Medicine and Parasitology 82 (1): 1
11.PMID 3041928.

5.

^ E. Goljan, Pathology, 2nd ed. Mosby Elsevier, Rapid Review Series.

6.

^ http://www.dmsc.moph.go.th/webrOOt/ri/Npublic/p04.htm

7.

^ Online 'Mendelian Inheritance in Man' (OMIM) 141800

8.

^ Online 'Mendelian Inheritance in Man' (OMIM) 141850

9.

^ Online 'Mendelian Inheritance in Man' (OMIM) 141900

10.

^ Cianciulli P (October 2008). "Treatment of iron overload in thalassemia". Pediatr Endocrinol

Rev. 6 Suppl 1: 20813. PMID 19337180.

11.

^ "Thalassemia Complications". Thalassemia. Open Publishing. Retrieved 27 September 2011.

12.

^ Wambua S, Mwangi TW, Kortok M et al. (May 2006). "The Effect of +-Thalassaemia on the
Incidence of Malaria and Other Diseases in Children Living on the Coast of Kenya". PLoS
Medicine 3 (5): e158. doi:10.1371/journal.pmed.0030158. PMC 1435778.PMID 16605300.

13.

^ Tassiopoulos S, Deftereos S, Konstantopoulos K et al. (2005). "Does heterozygous betathalassemia confer a protection against coronary artery disease?". Annals of the New York Academy of
Sciences 1054: 46770. doi:10.1196/annals.1345.068. PMID 16339699.

^ a b "Pediatric Thalassemia Treatment & Management". Medical Care. Open Publishing. 30

14.

April 2010. Retrieved 27 September 2011.

15.

^ Claude Owen Burdick. "Separating Thalassemia Trait and Iron Deficiency by Simple
Inspection". American Society for Clinical Pathology. Retrieved 27 September 2011.

16.

^ * Harrison's Principles of Internal Medicine 17th Edition. McGraw-Hill medical. September

2008. p. 776. ISBN 0-07-164114-9.

17.

^ Aisen P, Leibman A, Zweier J (March 1978). "Stoichiometric and site characteristics of the
binding of iron to human transferrin". J. Biol. Chem. 253 (6): 19307. PMID 204636.
^ a b c d e >Brittenham, Gary M; Olivieri, Nancy F (1997). "Iron-chelating therapy and the

18.

treatment of thalassemia". Journal of the American Society of Hematology 89: 739761. Retrieved 28
February 2013.
19.

^ Griffith, Patricia M. (1994). "Efficacy of deferoxamine in preventing complications of iron

overload in patients with thalassemia major.". The New England Journal of Medicine 331: 567573.
Retrieved March 5, 2013.

20.

^ Cozar, O.; et al. (2006). "IR, Raman and surface-enhanced Raman study of desferrioxamine
B and its Fe(III) complex, ferrioxamine B.". Journal of Molecular Structure 788: 16. Retrieved March 1,
2013.

21.

^ Cohen, Alen; et al. (1981). "Response to long-term deferoxamine therapy in

thalassemia.".The Journal of Pediatrics 99: 689694. Retrieved March 2, 2013.

22.

^ Wonke, Beatrix; et al (2005). "Randomized controlled trial of deferiprone or deferoxamine in

beta-thalassemia major patients with asymptomatic myocardial siderosis.". Journal of the American
Society of Hematology 107: 37383744. Retrieved March 2, 2013.

23.

^ Sakaida, Isao; et al. (2007). "The iron chelator deferoxamine causes activated hepatic
stellate cells to become quiescent and to undergo apoptosis.". Journal of Gastroenterology 42: 475
484. Retrieved March 3, 2013.

24.

^ Kye, T. B.; et al. (1993). "Non-insulin-dependent diabetes mellitus and elevated serum ferritin
level.". Journal of Diabetes and its Complications 7: 246. Retrieved March 5, 2013.

25.

^ Templeton, D. M.; et al. (1992). "Growth failure and bony changes induced by
deferoxamine.". American Journal of Pediatric Hematology/Oncology 14: 4856. Retrieved March 5,
2013.

26.

^ Rhoades, E. D.; et al. (1982). "Effect of subcutaneous deferoxamine and oral vitamin C on
iron excretion in congenital hypoplastic anemia and refractory anemia associated with the 5qsyndrome.". The American Journal of Pediatric Hematology/Oncology 4: 115. Retrieved March 10,
2013.

27.

^ Kattamis, Antonis (2005). "Combined therapy with deferoxamine and deferiprone.". Annals of
the New York Academy of Sciences 1054: 175182. Retrieved March 10, 2013.
^ a b c d e f g h i Berdoukas, V.; et al. (2012). "Treating Thalassemia Major-Related Iron Overload:

28.

The Role of Deferiprone.". Journal of Blood Medicine: 119129.

^ a b Wiwanitkit, Viroj (2006). "Quantum Chemical Analysis of the Deferiprone-Iron Binding

29.

Reaction". International journal of nanomedicine 1: 111113.

^ a b Olivieri, N. F.; Brittenham, G. M. (1997). "Iron-Chelating Therapy and the Treatment of

30.

Thalassemia". Blood 89 (3): 739.

^ a b Galanello, R.; Campus, S. (2009). "Deferiprone Chelation Therapy for Thalassemia

31.

Major".Acta Haematologica 122: 155.

32.

^ Heli, H.; Mirtorabi, S. and Karimian, K (2011). "Advances in iron chelation: an update". Expert
Opinion on Therapeutic Patents 21 (6): 819856.

33.

^ Cappellini; et al. (2006). "Aphase 3 study of deferasirox (ICL670), a once-daily oral iron
chelator, in patients with -thalassemia". Blood 107: 3455 3462.

34.

^ Galanello et. al. (2006). "Phase II clinical evaluation of deferasirox, a once-daily oral
chelating agent, in pediatric patients with -thalassemia major". Haematologica 91: 13431351.

35.

^ Nisbet-Brown, E.; Olivieri, N.F., Giardina, P.J., et al. (2003). "Effectiveness and safety of
ICL670 in iron-loaded patients with thalassemia: a randomised, doubleblind, placebo-

1.

controlled, dose-escalation trial". Lancet 361: 15971602.

2.

^ a b c Cappellini; et. al. (31). "Iron chelation with deferasirox in adult and pediatric patients with
thalassemia major: efficacy and safety during 5 years' follow-up". Blood.

3.

^ "How Are Thalassemias Treated?". National Heat, Lung and Blood institute. Retrieved March
2, 2013.

^ a b c d Tesoriere, L.; Allegra, M., Butera, D., Gentile, C. & Livrea, M.A. (July 2006).

4.

"Cytoprotective effects of the antioxidant phytochemical indicaxanthin in beta-thalassemia red blood

cells". Free Radical Research 40 (7): 753761.
5.

^ Leung TN, Lau TK, Chung TKh (April 2005). "Thalassaemia screening in pregnancy". Current
Opinion in Obstetrics & Gynecology 17 (2): 129
34.doi:10.1097/01.gco.0000162180.22984.a3. PMID 15758603.

6.

^ Samavat A, Modell B (November 2004). "Iranian national thalassaemia screening

programme". BMJ (Clinical Research Ed.) 329 (7475): 1134
7.doi:10.1136/bmj.329.7475.1134. PMC 527686. PMID 15539666.

7.

^ Spanish Baby Engineered To Cure Brother

8.

^ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 2009

9.

^ HLA-matched sibling bone marrow transplantation for -thalassemia major, Blood Journal, 3
February 2011

10.

^ T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients.,

Pediatric Reports , 22 June 2011

[edit]External

links

List of hematologic conditions

[edit]United

States

GeneReviews/NCBI/NIH/UW entry on Alpha-Thalassemia

OMIM etries on Alpha-Thalassemia

Thalassemia at the Open Directory Project

Cooley's Anemia Foundation

Information on Thalassemia

Learning About Thalassemia published by the National Human Genome Research Institute.

ThalPal.com- A patients' help group and support forum

Northern California's Comprehensive Thalassemia Center

Thalassemia Community Forum

FerriScan - MRI-based test to measure iron overload

[edit]United

Kingdom

United Kingdom Thalassaemia Society

Thalassaemia Support Group for newly diagnosed patients and their parents and carers

Cardiff Sickle Cell & Thalassaemia Centre

Thalassemia is a blood disorder passed down through families (inherited) in which the body makes an
abnormal form of hemoglobin, the protein in red blood cells that carries oxygen. The disorder results
in excessive destruction of red blood cells, which leads to anemia.
See also:

Hemolytic anemia

Sickle cell disease

Causes

Hemoglobin is made of two proteins: Alpha globin and beta globin. Thalassemia occurs when there is
a defect in a gene that helps control production of one of these proteins.
There are two main types of thalassemia:

Alpha thalassemia occurs when a gene or genes related to the alpha globin protein are
missing or changed (mutated).

Beta thalassemia occurs when similar gene defects affect production of the beta globin
protein.

Alpha thalassemias occur most commonly in persons from southeast Asia, the Middle East, China,
and in those of African descent.
Beta thalassemias occur in persons of Mediterranean origin, and to a lesser extent, Chinese, other
Asians, and African Americans.
There are many forms of thalassemia. Each type has many different subtypes. Both alpha and beta
thalassemia include the following two forms:

Thalassemia major

Thalassemia minor

You must inherit the defective gene from both parents to develop thalassemia major.
Thalassemia minor occurs if you receive the defective gene from only one parent. Persons with this
form of the disorder are carriers of the disease and usually do not have symptoms.
Beta thalassemia major is also called Cooley's anemia.
Risk factors for thalassemia include:

Asian, Chinese, Mediterranean, or African American ethnicity

Family history of the disorder

Symptoms
The most severe form of alpha thalassemia major causes stillbirth (death of the unborn baby during
birth or the late stages of pregnancy).
Children born with thalessemia major (Cooley's anemia) are normal at birth, but develop
severe anemia during the first year of life.
Other symptoms can include:

Bone deformities in the face

Fatigue

Growth failure

Shortness of breath

Yellow skin (jaundice)

Persons with the minor form of alpha and beta thalassemia have small red blood cells (which are
identified by looking at their red blood cells under a microscope), but no symptoms.
Exams and Tests
A physical exam may reveal a swollen (enlarged) spleen.
A blood sample will be taken and sent to a laboratory for examination.

Red blood cells will appear small and abnormally shaped when looked at under a microscope.

A complete blood count (CBC) reveals anemia.

A test called hemoglobin electrophoresis shows the presence of an abnormal form of

hemoglobin.

A test called mutational analysis can help detect alpha thalassemia that cannot be seen
with hemoglobin electrophoresis.
Treatment
Treatment for thalassemia major often involves regular blood transfusions and folate supplements.
If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high
amount of iron to build up in the body, which can be harmful.
Persons who receive significant numbers of blood transfusions need a treatment called chelation
therapy to remove excess iron from the body.
A bone marrow transplant may help treat the disease in some patients, especially children.
Outlook (Prognosis)
Severe thalassemia can cause early death due to heart failure, usually between ages 20 and
30. Getting regular blood transfusions and therapy to remove iron from the body helps improve the
outcome.
Less severe forms of thalassemia usually do not shorten lifespan.
Genetic counseling and prenatal screening may help people with a family history of this condition who
are planning to have children.

Possible Complications

Untreated, thalassemia major leads to heart failure and liver problems, and makes a person more
likely to develop infections.
Blood transfusions can help control some symptoms. However, they may result in too much iron,
which can damage the heart, liver, and endocrine system.
When to Contact a Medical Professional
Call for an appointment with your health care provider if:

You or your child has symptoms of thalassemia

You are being treated for the disorder and new symptoms develop

Alternative Names
Mediterranean anemia; Cooley's anemia; Beta thalassemia; Alpha thalassemia
References
Giardina PJ, Forget BG. Thalassemia syndromes. In: Hoffman R, Benz EJ, Shattil SS, et al.,
eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, Pa: Elsevier Churchill
Livingstone; 2008:chap 41.
DeBaun MR, Frei-Jones M, Vichinsky E. Hemoglobinopathies. In: Kliegman RM, Behrman RE,
Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, Pa: Saunders
Elsevier; 2011:chap 456.
Update Date: 2/7/2012
Updated by: Yi-Bin Chen, MD, Leukemia/Bone Marrow Transplant Program, Massachusetts General
Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M. Health Solutions, Ebix,
Inc.
Browse the Encyclopedia

halassaemia is the name we give to a group of related conditions. These conditions affect
haemoglobin - the substance in our blood that carries oxygen around our body.
Some conditions are more serious than others. The most serious forms are called beta
thalassaemia major and alpha thalassaemia major. Although it is possible to live with treatment
for beta thalassaemia major, alpha thalassaemia major is not compatible with life.
The two other most common forms of thalassaemia are beta thalassaemia intermediate which
usually has less serious effects and a mild form of alpha thalassaemia, called Hb H Disease.
These conditions do not usually require treatment on a regular basis.
The information below is about beta thalassaemia major. However, you can find out more about
the different types of thalassaemia at NHS Choices.
Beta thalassaemia major affects the body's ability to create red blood cells. This is important
because red blood cells contain haemoglobin - the substance that carries oxygen around our
bodies.
If your body does not receive enough oxygen, you will feel tired, breathless, lethargic and faint.
This condition is known as anaemia. Beta thalassaemia major can also cause other
complications including organ damage, restricted growth, liver disease, heart failure and death.
People with Beta Thalassaemia Major will need to receive blood - called a blood transfusion - all
their lives. Most people will need a blood transfusion about every 3-4 weeks. They will also need
medication to help their bodies manage the extra iron in the body which they get from blood they
receive.
The only known cures for beta thalassaemia major are bone-marrow transplant and cord blood
transplantations (using blood cells taken from a fetus related to the affected child). These
procedures can cause other complications and are not suitable for everyone.