Thalassemia

Silvanus Chakra Puspita

Etiology & Epidemiology

Types & Overview

Alpha Thalassemia

Beta Thalassemia

Summary
Etiology &
Epidemilogy
Hemoglobin Review
• Heritable, hypochromic anemias-varying degrees of severity
• Genetic defects result in decreased or absent production of
mRNA and globin chain synthesis
• At least 100 distinct mutations
• Each complex consists of :
• Four polypeptide chains, non-covalently bound
• Four heme complexes with iron bound
• Four O2 binding sites
 Globin Chains
• Alpha Globin
• 141 amino acids
• Coded for on Chromosome 16
• Found in normal adult hemoglobin, A1 and A2
• Beta Globin
• 146 amino acids
• Coded for on Chromosome 11, found in Hgb A1
• Delta Globin
• Found in Hemoglobin A2--small amounts in all adults
• Gamma Globin
• Found in Fetal Hemoglobin
• Zeta Globin
• Found in embryonic hemoglobin
Hemoglobin Types

Hemoglobin Type Globin Chains

• Hgb A1—92%--------- a2b2
• Hgb A2—2.5%-------- a2d2
• Hgb F — <1%--------- a2g2
• Hgb H ------------------ b4
• Bart’s Hgb-------------- g4
gluval
• Hgb S-------------------- a226
b26
• Hgb C------------------- a226
b26 glulys
Genetics
• Alpha globins are coded on chromosome 16
• Two genes on each chromosome
• Four genes in each diploid cell
• Gene deletions result in Alpha-Thalassemias
• Also on chromosome 16 are Zeta globin genes—Gower’s
hemoglobin (embryonic)
• Beta globins are coded on chromosome 11
• One gene on each chromosome
• Two genes in each diploid cell
• Point mutations result in Beta-Thalassemias
• Also on chromosome 11 are Delta (Hgb A2) and Gamma (Hgb
F) and Epsilon (Embryonic)
Epidemiology
• Thalassemia is found throughout the world, most of the countries included
in the Thalassemia Belt (Southeast Asia, the Middle East, Sub-Saharan
Africa and the Mediterranean), including Indonesia.
• High incidence in Asia, Africa, Mideast, and Mediterrenean countries
• The prevalence of the world's population who have a hemoglobin gene
abnormality is around 7-8%, so in Indonesia around 20 million Indonesians
carry this gene disorder.
• Until 2016 there were only 9,121 thalassemia major patients in Indonesia,
but there are still many that have not been verified and received optimal
treatment.
Types &
Overview
THALASSEMIA
• Thalassemia is an inherited blood disorder in which the body
produces an abnormal form of hemoglobin which results in excessive
destruction of red blood cells and further leads to anemia.
• Alpha thalassaemias result from insufficient alpha-globin chain
synthesis. Beta-thalassaemias result from inadequate beta-
globin chain synthesis.

TYPES OF THALASSEMIA:

ALPHA THALASSEMIA BETA THALASSEMIA

Alpha
Thalassemia
Alpha Thalassemia

Alpha thalassemia is the result of changes in

the genes for the alpha globin component of
hemoglobin.
ETIOLOGY

Mutation in the DNA of cells that produce

hemoglobin

Inheritance
Pathophysiology

Alpha thalassemia results when there is disturbance in production of α-

globin from any or all four of the α- globin genes.
 Genes are responsible for regulating the synthesis and structure of
different globins which are divided into 2 clusters.
 The α-globin genes are encoded on chromosome 16 and the γ, δ, and
β-globin genes are encoded on chromosome 11
 A normal person carries a linked pair of alpha globin genes, 2 each
from maternal and paternal chromosome.
Pathophysiology

 Therefore, alpha thalassemia occurs when

there is a disturbance in production of α-globin from any or all
four of the α-globin genes.
 When functional point mutations, frame shift mutations,
nonsense mutations, and chain termination mutations occur
within or around the coding sequences of the alpha-globin
gene cluster hemoglobin is impaired.
 When that occurs, protein synthesis may be inhibited.
Pathophysiology
 Normal production of alpha chains is absent which results in excess production
of gamma- globin chains in the fetus and newborn or beta- globin chains in
children and adults.
 The β-globin chains are capable of forming soluble tetramers (beta-4, or HbH)
 This form of hemoglobin is still unstable and precipitates within the cell,
forming insoluble inclusions called Heinz bodies
 These Heinz bodies damage the red blood cells.
 This further results in damage to erythrocyte precursors and ineffective
erythropoiesis in the bone marrow, hypochromia and microcytosis of circulating
red blood cells
 Mutated Thalassemia
 Alpha (0) thalassemia – More than 20 mutations have been
found.
 Those that result in the functional depletion of both pair of α
-globin genes
 Individuals with this disorder are not able to produce any functional
α -globin and thus are unable to make any functional hemoglobin
A, F, or A2.
 This leads to the development of hydrops fetalis or hemoglobin
Bart (excess buildup of fluid before birth)
Mutated Thalassemia
 Alpha (+) thalassemia –More than 15 different genetic mutations that
result in decreased production of α -globin usually due to the
functional deletion of 1 of the 4 alpha globin genes.
 Further classification of Alpha (+) thalassemia: A- Thalassemia
(-α/α α)
 Characterized by inheritance of 3 normal α-genes.
 Patients clinically known as silent carriers of alpha thalassemia.
 Also known as alpha thalassemia minima, alpha thalassemia-2 trait,
and heterozygosity for alpha (+) thalassemia minor
Clinical Presentation
 Shortage of red blood cells- Anemia
 Pale skin
 Weakness
 Fatigue
 Enlarged liver and spleen- hepatosplenomegaly
Clinical Presentation

Heart defects
 Abnormalities of the urinary system or genitalia
 Hb Bart syndrome can cause complications in pregnancy such as
• High blood pressure
• Premature delivery
• Abnormal bleeding
• Jaundice
Treatment of Alpha Thalassemia

• Treatment for thalassemia 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.
• Bone marrow transplant may help treat the disease in some patients, especially
children.
Surgical Treatment

– Perform splenectomy if transfusion requirements are increasing.

– Surgical or orthodontic correction may be necessary to correct
skeletal deformities of the skull and maxilla caused by erythroid
hyperplasia.
Medications

• FOLIC ACID- ORAL

• FOLIC ACID - INJECTION
• DEFEROXAMINE - INJECTION
FOLIC ACID - ORAL
• USES
– Folic acid is the man-made form of
folate which is a B6- vitamin naturally
found in some foods.
– It is needed to form healthy cells,
especially red blood cells.
– Active forms of folic acid are: L-
methylfolate and levomefolate
– Folic acid supplements are used to
treat or prevent low folate levels.
Dosage

• Taken orally with or without food once daily.

• However, recommended dose for deficiency states is 250-
1000 mcg (micrograms) per day
SIDE EFFECTS

– Folic acid usually has very few side effects

– Possible side effects include:
• Serious allergic reaction, including: rash,
itching/swelling (especially of the face/tongue/throat),
dizziness, trouble breathing
• Folic acid is safe to take during pregnancy when used as directed. It is
included in prenatal vitamin products.
• Certain spinal cord birth defects may be prevented by taking adequate
amounts of folic acid during pregnancy.
DRUG INTERACTIONS

– Fosphenytoin
Taking folic acid along with fosphenytoin might decrease the effectiveness of the
drug for preventing seizures since folic acid increase the breakdown of the drug.

– Methotrexate
Folic acid decrease the effectiveness of methotrexate.

- Phenobarbital
Taking folic acid can decrease how well phenobarbital works for preventing seizures.
DRUG INTERACTIONS

– Primidone
Folic acid can decrease the effectiveness of primidone for preventing
seizures.

– Pyrimethamine
It is used to treat parasite infections. Folic acid might decrease the
effectiveness of pyrimethamine (Daraprim)
 FOLIC ACID - INJECTION

• USES: Folic acid is used to treat or prevent

– certain anemias caused by poor diet,
– pregnancy,
– alcoholism,
– Liver disease,
– certain stomach/intestinal problems,
– kidney dialysis, or
– relieve symptoms such as unusual tiredness and diarrhea

• ADMINISTRATION: This medication is given by IM, IV OR SC usually once a day.

• DOSAGE:- 1-5 mg/day
DRUG INTERACTIONS
• Chloramphenicol-cause depletion of folic acid.
• Folic acid does not correct folate deficiency due to dihydrofolate reductase
inhibitor such as methotrexate. Methotrexate, trimethoprim, and pyrimethamine
prevent the reduction of folic acid to tetrahydrofolate.
• Sulphasalazine depresses folic acid absorption.
• Folic acid is incompatible with oxidising and reducing agents
and ions with heavy metals.
• Folic acid may affect certain laboratory tests for vitamin B12 deficiency, resulting
in false test results. Untreated vitamin B12 deficiency may result in serious nerve
problems (e.g., peripheral neuropathy with numbness/tingling symptoms).
DEFEROXAMINE - INJECTION
• Deferoxamine is an iron-binding agent that belongs to a
class of drugs known as heavy metal antagonists. It
works by helping the kidneys and gallbladder get rid of
the extra iron.

Mechanism of Action
• Deferoxamine works in treating iron toxicity by
binding trivalent (ferric) iron (for which it has a strong
affinity), forming ferrioxamine, a stable complex
which is eliminated via the kidneys.
Uses
• This medication is used along with other treatments (such as syrup of ipecac) to
treat sudden iron poisoning.
• It is most effective when given as soon as possible after the iron was eaten.
• This medication can also be used to help get rid of iron in patients with high iron
levels due to many blood transfusions.
• This medication is not recommended for use in children less than 3 years old
• This drug may also be used to treat high levels of aluminum in dialysis patients and
people with aluminum poisoning.
ADMINISTRATION & DOSAGE
• This medication is administered via IM, IV or SC.

• Intramuscular Administration: A dose of 1000 mg should be administered

initially. This may be followed by 500 mg every 4 hours for two doses. Depending
upon the clinical response, subsequent doses of 500 mg may be administered every
4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours.
ADMINISTRATION & DOSAGE

• Subcutaneous Administration: A daily dose of 1000-2000

mg/day should be administered over 8-24 hours, utilizing a
small portable pump capable of providing continuous mini-
infusion. The duration of infusion must be individualized. In
some patients, as much iron will be excreted after a short
infusion of 8-12 hours as with the same dose given over 24
hours.
ADMINISTRATION & DOSAGE
• Intravenous Administration
• THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF
CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION BECAUSE
DEFEROXAMINE CAN CAUSE HEART PROBLEMS.
• THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000
MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A
SLOWER RATE, NOT TO EXCEED 125 MG/HR.
• This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical
response, subsequent doses of 500 mg may be administered over 4-12 hours. The total amount
administered should not exceed 6000 mg in 24 hours.
• As soon as the clinical condition of the patient permits, intravenous administration should be
discontinued and the drug should be administered intramuscularly.
SIDE EFFECTS

– fast heartbeats;
– blue lips, skin, or fingernails;
– severe, watery, bloody diarrhea with cramping;
– cough, wheezing, gasping, or other breathing problems;
– stuffy nose, fever, redness or swelling around your nose and eyes, scabbing inside your
nose;
– stomach or back pain, coughing up blood;
– easy bruising or bleeding, unusual weakness;
– urinating less than usual or not at all;
– vision or hearing problems; or
– leg cramps, bone problems, or growth changes (in a child using this medication).
SIDE EFFECTS
• Less serious side effects:
– numbness or burning pain anywhere in the body;
– warmth, redness, or tingly feeling under the skin;
– mild itching or skin rash;
– mild diarrhea, nausea, or upset stomach;
– dizziness;
– reddish colored urine; or
– pain, burning, swelling, redness, irritation, or a hard lump where the medicine
was injected.
 PRECAUTIONS

• Before using this medication, confirm with a health professional if you

have kidney problems, rheumatoid arthritis, diabetes, or any fungal
infection.
• If you are using this medication for aluminum poisoning, consult a
doctor if you experience symptoms such as seizures, decreased calcium
levels in the blood, hyperparathyroidism.
• This drug may make you dizzy or cause blurred vision. Do not drive, use
machinery, or do any activity that requires alertness or clear vision until
you are sure you can perform such activities safely.
PRECAUTIONS
• Limit intake alcoholic beverages.
• Children (especially those younger than 3 years of age) may be more
sensitive to the side effects of this drug, especially the effects on bone
growth.
• Older adults may be more sensitive to the side effects of this drug,
especially vision/hearing problems.
• During pregnancy, this medication should be used only when
clearly needed
 DRUG INTERACTIONS
• Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes
the vitamin. Vitamin C increases availability of iron for chelation. As an addidtive to iron chelation therapy,
vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of
regular treatment with Desferal. In general, 50 mg daily suffices for children under 10 years old and 100 mg
daily for older children.

• Prochlorperazine: Concurrent treatment with Desferal (deferoxamine) and prochlorperazine, a phenothiazine

derivative, may lead to temporary impairment of consciousness.

• Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of Desferal
(deferoxamine) bound gallium-67. Discontinuation of Desferal (deferoxamine) 48 hours prior to
scintigraphy is advisable.
Beta
Thalassemia
Beta Thalassemia

• Beta thalassemia is a genetic blood

disorder that reduces the production of
hemoglobin.

• Specifically, it is characterized by a genetic

deficiency in the synthesis of beta- globin
chains.

• Beta-globin is a component
(subunit) of hemoglobin.
Types

Thalassemia Major
(Cooley's anemia)
Thalassemia Minor
-severe form of beta
thalassemia - presence of one normal gene
and one with a mutation
- presence of two abnormal
genes that cause either a - causes mild to
severe decrease or complete moderate mild
lack of beta globin anemia.
production.
Etiology

• Beta thalassemia is caused by a deficiency of Beta

globin inherited in an autosomal recessive pattern,
which means both copies of the HBB(Hemoglobin
beta) gene in each cell have mutations.
• The parents of an individual with an autosomal
recessive condition each carry one copy of the
mutated gene, but they typically do not show signs
and symptoms of the condition.
Etiology-cont’d

• The HBB gene provides instructions for making a protein called

beta-globin.
• When there is a mutations in the HBB gene, it prevents the
production of any beta-globin.
• The absence of beta-globin is referred to as beta- zero (B0)
thalassemia.
• Other HBB gene mutations allow some beta-globin to be produced
but in reduced amounts. A reduced amount of beta-globin is called
beta-plus (B+) thalassemia.
Etiology-cont’d

• A lack of beta-globin leads to a reduced amount of functional

hemoglobin. Without sufficient hemoglobin, red blood cells do not
develop normally, causing a shortage of mature red blood cells.

• The low number of mature red blood cells leads to anemia and
other associated health problems in people with beta thalassemia.
Clinical Presentations
Thalassemia minor- characterized by mild anemia
Symptoms of beta thalassemia major appear in the first two years of life.
• Fatigue and weakness
• Pale skin or jaundice (yellowing of the skin)
• Protruding abdomen with enlarged spleen and liver
 Clinical Presentations
• Dark urine
• Abnormal facial bones and poor growth
• A poor appetite.
• Adolescents with the severe form of beta thalassemia
may experience delayed puberty.
 Pathophysiology
• In Beta thalassemia major, patients have severe anemia, ineffective erythropoiesis,
extramedullary hematopoiesis, and iron overload resulting from transfusion and
increased iron absorption.

• The skin may show pallor from anemia and jaundice from hyperbilirubinemia.

• The skull and other bones may be deformed secondary to erythroid hyperplasia with
intramedullary expansion and cortical bone thinning.

• Heart examination may reveal findings of cardiac failure and

arrhythmia, related to either severe anemia or iron overload.
Pathophysiology- Cont’d
• Abdominal examination may reveal changes in the liver, gallbladder, and
spleen.

• Patients who have received blood transfusions may have hepatomegaly or

chronic hepatitis due to iron overload.

• The gallbladder may contain bilirubin stones formed as a result of the patient's
lifelong hemolytic state.
 Pathophysiology- Cont’d

• Splenomegaly typically is observed as part of the extramedullary hematopoiesis

or as a hypertrophic response related to the extravascular hemolysis.

• In addition to cardiac dysfunction, hepatomegaly, and hepatitis, iron overload can

also cause endocrine dysfunction, especially affecting the pancreas, testes, and
thyroid.

• Transfusion-associated viral hepatitis resulting in cirrhosis or portal

hypertension also may be seen.
Surgical Treatment

• Splenectomy- decrease transfusion requirements

• Cholecystectomy- Patients with thalassemia minor may have
bilirubin stones in their gallbladder and, if symptomatic,
may require treatment. Perform a cholecystectomy using a
laparoscope or carry out the procedure at the same time as
the splenectomy.
 Treatment

Treatment for beta thalassemia involves iron chelation.

1. Deferoxamine
2. Deferasirox

Deferoxamine is an intravenously administered chelation agent.

Deferoxamine chelates iron by forming a stable complex that prevents the iron from
entering into further chemical reactions. It readily chelates iron from ferritin and
hemosiderin but not readily from transferrin; it does not combine with the iron from
cytochromes and hemoglobin. It does not cause any demonstrable increase in the
excretion of electrolytes or trace metals.
Adverse Effects
• Hypotension (with too rapid IV infusion)
• Pulmonary edema with over 24 hr IV infusion
• Anaphylaxis (rare)
• Renal failure
• Hepatic dysfunction
• Yersinia enterocolitica, Y. pseudotuberculosis, and fungal infections
Cautions
• In acute iron toxicity, give IV only to patients with cardiovascular collapse or in shock
• Do NOT administer by rapid IV
• Increased serum creatinine (possibly dose related); acute renal failure and renal tubular disorder reported
• NOT a substitute for standard measures generally used in iron toxicity (eg, induced emesis, gastric lavage)
• Risk of potentially fatal infections
 Drug Interactions
There are a number of drug interactions that should be monitored closely when giving Deferoxamine e.g.:
• ascorbic acid
• calcium carbonate calcium carbonate
• ferric carboxymaltose
• ferric gluconate
• ferrous fumarate
• polysaccharide iron
• prochlorperazine
• sodium bicarbonate
• sodium bicarbonate

• aluminum hydroxide- deferoxamine decreases levels of aluminum hydroxide by inhibition of GI

absorption. Applies only to oral form of both agents.
• sodium citrate/citric acid- deferoxamine decreases levels of sodium citrate/citric acid by inhibition of
GI absorption. Applies only to oral form of both agents.
Dosing Forms & Strengths
Powder for injection
• 500mg/vial
• 2g/vial

Acute Iron Poisoning

• Initial 1 g IM (ALL patients not in shock) or slow IV infusion (ONLY
patients with cardiovascular collapse or shock), THEN;
• 500 mg IM/IV q4hr x2, THEN;
• Depending on clinical circumstance, may administer additional doses of 500 mg IM/IV q4-12hr
PRN;
• IV infusion rate: initial 1 g at 15 mg/kg/hr, all subsequent doses no more than 125 mg/hr;
• No more than 6 g/day (IM or IV), but in severe cases should continue infusion up to 24 hours
Dosing Forms & Strengths

Chronic Iron Overload

• 500-1000 mg IM everyday, PLUS
• 2000 mg IV infusion at no more than 15 mg/kg/hr with (but separately) each
unit of blood transfused
• No more than 1 g/day (without transfusion); 6 g/day (with transfusion)
• Alternatively, 1-2 g/day SC infusion over 8-24 hours
Deferasirox- Exjade

Mechanism of Action

• Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+).
It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although
deferasirox has very low affinity for zinc and copper there are variable decreases in
the serum concentration of these trace metals after the administration of deferasirox.
Adverse Effects
• Serum creatinine increase (dose related)
• Proteinuria
• Pyrexia
• Cough
• Influenza
• Rash
• Respiratory tract infection
• Bronchitis
• ALT increased
• Acute tonsillitis
• Rhinitis
• Anaphylaxis
• Angioedema
• Cytopenias, including agranulocytosis, neutropenia and thrombocytopenia; leukocytoclastic
vasculitis
Precautions

• Do not take with aluminum-containing antacids

• Concomitant cholestyramine -Coadministration with a single dose of
cholestyramine decreases deferasirox AUC by 45%; avoid concomitant
use. If coadministration is necessary, consider increasing initial
deferasirox dose to 30 mg/kg and monitor serum ferritin levels and
clinical responses for further dose modification.
• Risk of hepatic failure, some with fatal outcome; most occurred
with age >55 yr and with comorbid conditions (eg, liver cirrhosis,
multiorgan failure)
Summary Thalassemia

The thalassaemias are an inherited group of conditions that result from an

imbalance in globin synthesis of the haemoglobin molecule, causing varying
degrees of haemolytic anaemia and expansion of the bone marrow. Alpha
thalassaemias result from insufficient alpha-globin chain synthesis. Beta-
thalassaemias result from inadequate beta-globin chain synthesis.

Anaemia which results mainly from a combination of ineffective red cell

synthesis and reduced red cell survival (haemolysis). Severe forms require
regular transfusions of 2-4 units/month. Iron overload which results from
transfused blood (RBCs breakdown) and to a much lesser extent from
increased dietary iron absorption (the latter being the main cause of iron load
in patients with TI).

Heterozygotes or carriers require no treatment but β-thalassaemia carriers in

particular do require genetic counselling, in order to allow them to make
informed choices when in an ‘at risk’ partnership (i.e. with another carrier).
Blood Transfusion and Iron Chelation are the most common treatment
1.Complete Blood Count
(CBC)
2. Tes Hemoglobin
3. Prenatal test:
• Chorionic Villus
Sampling
( 11 week gestation,
placenta sampling)
• Amniocentesis
Amnion test week 16
gestation
• Electroforesis
Hemoglobin
 References
• American College of Obstetricians and Gynecologists (ACOG). Hemoglobinopathies in Pregnancy. ACOG Practice Bulletin, number
78, January 2007.
• Beta Thalassemia. (Sept 2, 2011). Retrieved from http://emedicine.medscape.com/article/206490-overview
• Bleibel, S. et al. Thalassemia, Alpha. Retrieved: 29 September, 2011 from
http://emedicine.medscape.com/article/206397-overview#a0104
• Cohen, A.R., et al. Thalassemia. Hematology 2004, American Society of Hematology, pages 14-34.
• Cooley’s Anemia Foundation. About Thalassemia. Updated 2007.
• Cunningham, M.J. Update on Thalassemia: Clinical Care and Complications. Pediatric Clinics of North America, volume 55, April
2008, pages 447-460.
• Deferoxamine [Pharm GKB]. (n.d.). Retrieved from
http://www.pharmgkb.org/do/serve?objId=PA164746490&objCls=Drug#tabview=tab1
• Di Bartolomeo, P., et al. Long-term Results of Survival in Patients with Thalassemia Major Treated with Bone Marrow Transplantation.
American Journal of Hematology, February 13, 2008 (Epub ahead of print).
• Exjade (Deferasirox) Drug Information… (Aug 19, 2011). Retrieved from http://www.rxlist.com/exjade- drug.htm
• Food and Drug Administration (FDA). FDA Approves First Oral Drug for Chronic Iron Overload. FDA News, November 9, 2005
• Food and Drug Administration (FDA). FDA Approves First Oral Drug for Chronic Iron Overload. FDA
News, November 9, 2005.
• Linda J. Vorvick, MD, Medical Director, MEDEX Northwest Division of Physician Assistant Studies,
University of Washington, School of Medicine; and Yi-Bin Chen, MD, Leukemia/Bone Marrow Transplant Program, Massachusetts
General Hospital; and David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc., Review Date: 1/31/2010,Thalassemia, retrieved on 2011-
09-30, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001613/
• Lucile Packard Children’s Hospital at Standford. 2011. Alpha Thalassemia. Retrieved: 29 September, 2011 from
http://www.lpch.org/DiseaseHealthInfo/HealthLibrary/hematology/thalapth.htmlth
• National Heart, Lung and Blood Institute. Thalassemias. Posted 1/08.
• New York Academy of Sciences. Cooley’s Anemia Eighth Symposium. Posted 7/22/05, accessed 5/2/08.
• Northern California Comprehensive Thalassemia Center. Alpha Thalassemia. Accessed 5/2/08.
• Mayo Clinic Staff. February 04th, 2011. Retrieved: 29 September, 2011 from
http://www.mayoclinic.com/health/thalassemia/DS00905/DSECTION=causes
• Medicinenet.com. 1996- 2011.Alpha Thalassemia. Retrieved: 29 September, 2011 from
http://www.medicinenet.com/alpha_thalassemia/article.htm
• Rund, D. and Rachmilewitz, E. Medical Progress: Beta-Thalassemia. New England Journal of Medicine, volume 353, number
11, September 15, 2005, pages 1135-1146.
• The Free Dictionary By Farlex. 2011. Retrieved: 29 September, 2011. http://medical-
dictionary.thefreedictionary.com/Alpha+Thalassemia
• WebMD, ©2005-2011, FOLIC ACID, retrieved on 2011-09-30,
http://www.webmd.com/vitamins- supplements/ingredientmono-1017- FOLIC%20ACID.aspx?activeIngredientId=1017&activeIngr
edientName=FOLIC%20ACID
• What are thalassemias? National Heart, Lung, and Blood Institute. Retrieved: 29 September, 2011 from http://www.nhlbi.nih.g
ov/health/dci/Diseases/Thalassemia/Thttp://medical- dictionary.thefreedictionary.com/Alpha+Thalassemiahttp://medical-
dictionary.thefreedictionary.com/Alpha+Thalassemiahalassemia_All.html. linic