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 (α) thalassemias

o 3.2 Beta (β) thalassemias

o 3.3 Delta (δ) thalassemia

o 3.4 In combination with other hemoglobinopathies

4 Cause

5 Complications

6 Benefits

7 Treatment

o 7.1 Medical care

o 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

o 7.3 Carrier detection

8 Curative methods

o 8.1 Bone marrow transplant (BMT) from compatible donor

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

9 References

10 External links

o 10.1 United States

o 10.2 United Kingdom

Etymology

The name of this condition derives from the Greek Thalassa (θάλασσα), sea, and haema (αἷμα),

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 α and two β globin chains arranged into

a heterotetramer. In thalassemia, patients have defects in either the α or β globin chain (unlike sickle-

cell disease, which produces a specific mutant form of β globin), causing production of abnormal red

blood cells.

The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In

α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β

globin chain is affected.

The β globin chains are encoded by a single gene on chromosome 11; α 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 β chain, and four loci encoding the α chain. Deletion of

one of the α loci has a high prevalence in people of African or Asian descent, making them more likely

to develop α thalassemias. β Thalassemias are not only common in Africans, but also in Greeks and

Italians.

[edit]Alpha (α) thalassemias

Main article: Alpha-thalassemia

The α 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. α Thalassemias result in decreased alpha-globin production, therefore fewer

alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in

newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta

chains), which have abnormal oxygen dissociation curves.

[edit]Beta (β) 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 βo or β thalassemia major if they prevent any formation of β

chains, the most severe form of β thalassemia. Also, they are characterized as β+ or β thalassemia

intermedia if they allow some β chain formation to occur. In either case, there is a relative excess of α

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 (δ) 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 β 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

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

C/β+ thalassemia produces a milder disease.

[edit]Cause

Cause

Thalassemia has an autosomal recessivepattern of inheritance

Both α and β thalassemias are often inherited in an autosomal recessive fashion, although this is not

always the case. Cases of dominantly inherited α and β 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 β-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) β 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 β-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

deferoxamine’s 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 drug-

iron 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 1980′s by Prof. Guido Lucarelli. In low-

risk 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=complications.

Retrieved 20 September 2011.

3. ̂  Modiano, G. et al. (1991). "Protection against malaria morbidity: Near-fixation of the α-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: 208–13. 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 α +-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 beta-thalassemia

confer a protection against coronary artery disease?". Annals of the New York Academy of

Sciences 1054: 467–70. doi:10.1196/annals.1345.068. PMID 16339699.

14. ^ a b "Pediatric Thalassemia Treatment & Management". Medical Care. Open Publishing. 30 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): 1930–7. PMID 204636.

18. ^ a b c d e >Brittenham, Gary M; Olivieri, Nancy F (1997). "Iron-chelating therapy and the treatment of

thalassemia". Journal of the American Society of Hematology 89: 739–761. 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: 567–573. 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: 1–6. Retrieved March 1, 2013.

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

Journal of Pediatrics 99: 689–694. 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: 3738–3744. 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: 48–56. 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 5q-

syndrome.". 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: 175–182. Retrieved March 10, 2013.

28. ^ a b c d e f g h i Berdoukas, V.; et al. (2012). "Treating Thalassemia Major-Related Iron Overload: The

Role of Deferiprone.". Journal of Blood Medicine: 119–129.

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

Reaction". International journal of nanomedicine 1: 111–113.

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

Thalassemia". Blood 89 (3): 739.

31. ^ a b Galanello, R.; Campus, S. (2009). "Deferiprone Chelation Therapy for Thalassemia 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): 819–856.

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 β-thalassemia major". Haematologica 91: 1343–1351.

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: 1597–1602.

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.

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

effects of the antioxidant phytochemical indicaxanthin in beta-thalassemia red blood cells". Free

Radical Research 40 (7): 753–761.

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 β-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.