THALASSEMIA

WORLD THALASSEMIA DAY-MAY 8

Dr. VENKATESH

OBJECTIVES

To know :

• Basic features of thalassemia syndromes

• Transfusion protocols in thalassemia

• Chelation therapy in thalassemia

• Supportive care in thalassemic patients

• Follow-up guidelines

• Hemtopoitic Stem cell transplantation

• Future aspects.

DEFINITION

Thalassemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent one or more of the globin chains of adult hemoglobin.

They characterised by varying degrees of ineffective hematopoiesis and increased hemolysis

ICD classification: D-56

HEMOGLOBIN A

Fetal Hemoglobin (2 alpha, 2 gamma)

Hemoglobin A2 (2 alpha, 2 delta)

Small amounts in body

α

αβ

β

Copyright ©1997 BMJ Publishing Group Ltd.

NORMAL HUMAN HAEMOGLOBINS

Haemoglobin Structural formula

Adult Hb-A 2 2 97%

Hb-A2 2 2 1.5-3.2%

Fetal Hb-F 2 2 0.5-1%

Embryonic Hb-Gower 1 2 2

Hb-Gower 2 2 2

Hb-Portland 2 2

GENETIC TYPES OF THALASSEMIA :

There are two basic groups of thalassemia.

Alpha ( )Thalassemia

In alpha-thalassemia, the alpha genes are deleted;

loss of one gene (α-/α) or both genes (α-/α-) from each

chromosome 16 may occur, in association with the

production of some or no alpha globin chains

Beta ( )Thalassemia

In beta-thalassemia defective production usually

results from disabling point mutations causing no (β0) or

reduced (β-) beta chain production.

CHROMOSOMES

Thalassemia is inherited as an autosmal recessive

disease.

EPIDEMIOLOGY

Recent data indicate that about 7% of the world

population is carrier of hemoglobin disorder.

About 100,000 children are born every year world

over with the homozygous state for thalassemia.

There are around 65,000 - 67,000 thalassemia

patients in our country.

In India prevalence of this gene varies, 1-17 %

(3.3%).

Common in certain Communities like sindhis,

punjabis, khatris, khukrajas, bhanushalies, baniyas,

lohanas, kuchies, mahars, kolies, agries, goudas,

lingayats .

ALPHA THALASSEMIA

Alpha Thalassemia: deficient/absent alpha subunits

Excess beta subunits

Excess gamma subunits newborns

Tetramers formed:

Hemoglobin H adults

Hemoglobin Bart’s newborns

types:

Silent Carrier

Trait (Minor)

Hemoglobin H Disease

Hydrops fetalis(Hb Bart’s)

GENETIC BASIS OF ALPHA THALASSEMIA

Encoding genes on chromosome 16 (short arm)

Each cell has 4 copies of the alpha globin gene

Each gene responsible for ¼ production of alpha globin

4 possible mutation states:

Loss of ONE gene silent carrier

Loss of TWO genes thalassemia minor (trait)

Loss of THREE genes Hemoglobin H Accumulation of beta chains

Association of beta chains in groups of 4 Hemoglobin H

Loss of FOUR genes Hemoglobin Barts NO alpha chains produced ∴ only gamma chains present

Association of 4 gamma chains Hemoglobin Barts

CLASSIFICATION & TERMINOLOGY

ALPHA THALASSEMIA

• Normal /

• Silent carrier - /

• Minor -/-

--/

• Hb H disease --/-

• Barts hydrops fetalis --/--

CLINICAL OUTCOMES OF ALPHA THALASSEMIA

Silent carriers

• asymptomatic

• “normal”

Alpha Thalassemia trait

• no anemia /mild anemia

• microcytosis

-unusually small red blood cells due to fewer Hb in RBC

Hb H disease

• microcytosis & hemolysis (breakdown of RBC)

- results in severe anemia

• bone deformities

• splenomegaly (enlargement of spleen)

• “severe and life threatening”

• Golf ball inclusions on micrscopy

CLINICAL OUTCOMES OF ALPHA THALASSEMIA

Bart’s Hydrops fetalis

• Hb Bart’s

• fatal hydrops fetalis

- fluid build-up in fetal compartments, leads to

death occurs in utero

BETA THALASSEMIA

Beta Thalassemia: deficient/absent beta subunits

Commonly found in Mediterranean, Middle East, Asia,

and Africa

Three types:

Minor

Intermedia

Major (Cooley anemia)

asymptomatic at birth as HbF functions

GENETIC BASIS OF BETA THALASSEMIA

Encoding genes on chromosome 11 (short arm)

Each cell contains 2 copies of beta globin gene

beta globin protein level = alpha globin protein level

Suppression of gene more likely than deletion

2 mutations: beta-+-thal / beta-0-thal

“Loss” of ONE gene thalassemia minor (trait)

“Loss” of BOTH gene complex picture

2 beta-+-thal thalassemia intermedia / thalassemia

major

2 beta-0-thal thalassemia major

Excess of alpha globin chains

CLASSIFICATION & TERMINOLOGY

BETA THALASSEMIA

• Normal /

• Minor /0

/+

• Intermedia 0/+

+/+

• Major 0/0

+/

CLINICAL OUTCOMES OF BETA THALASSEMIA

Beta Thalassemia minor (trait)

• asymptomatic

• microcytosis

• minor anemia

• Elevated HbA2 >3.4%

Beta Thalassemia intermedia .

• symptoms similar to Cooley Anemia but less severe

Beta Thalassemia major (Cooley Anemia)

• most severe form

• moderate to severe anemia

• intramedullary hemolysis (RBC die before full development)

• peripheral hemolysis & splenomegaly

• skeletal abnormalities (overcompensation by bone marrow)

• congestive heart failure,pulmonary hypertension

PATHOPHYSIOLOGY

Disturbance of ratio between Alpha & non

alpha globin chain synthesis then absent or

decrease production of one or more globin

chains

Formation of abnormal Hb structures

Ineffective erythropoiesis

Excessive RBCs Destruction

Iron Overload

Extra-medullary hematopoiesis

PATHOPHYSIOLOGY..CONT..

SIGNS & SYMPTOMS

Beta Thalassaemia Minor :Usually no signs or symptoms except for a mild persistent anemia not responding to hematinics.

BetaThalassaemia Major : manifests after 6 months1. Pallor- fatigue, irritability2. Growth retardation.3. Recurrent infections4. Bony abnormalities specially of the facial

bones,hemolytic facies, caput quadtratum5. Enlarged spleen and liver.6. Delayed sexual development7. Features of complications .

THALASSEMIA COMPLICATIONS

Complications can be grouped as

(1) transfusion-transmitted infections,

(2) transfusional iron overload,

(3) toxicities of iron chelation therapy, and

(4) bacterial infections

COMPLICTIONS ..CONT..

Cardiac complications

Liver complications

Endocrine complications

Bone complications

Other complications

Infections: yersinia,parvovirus B19

Dental Complications

Growth retardation

Leg ulcers

CARDIAC COMPLICATIONS

Cardiac dysfunction(both systolic and diastolic dysfuction)

Arrhythmias

Ferritin greater than 2500 mg/L or a liver iron concentration > 15 mg Fe/g dry weightis associated with high risk of cardiac death in thalassemia

ferritin and liver iron may not correlate with cardiac iron load, cardiac iron can be specifically and reproducibly measured using cardiac MRI T2*. Cardiac MRI T2* less than 20 ms correlates with a progressive and significant decline in LVEF

CARDIAC COMPLICATIONS CONT..

Monitoring: 6 monthly cardiac physical examination,

cardiac function yearly starting at age of 10 years, if

history suggestive of arrhythmias ECG, 24-hour

Holter monitoring should be done.

Chelation therapy to reduce high iron load lowers

the likelihood of developing cardiac dysfunction

CARDIAC COMPLICATIONS..CONT

Cardiac MRI T2 Cardiac iron load Cardiac function intervention

values greater

than 20 ms

not usually

associated with

significant iron load

not usually

associated with

cardiac dysfunction

compliance and

importance of

chelation stressed

values between 10

and 20 ms

significant cardiac

iron deposition

a risk of eventual

cardiac

decompensation

more aggressive

chelation program

should be

implemented

values < 10 ms Very high cardiac

iron load

significant risk of

more immediate

cardiac

decompensation

without aggressive

intervention

Aggressive

chelation therapy

should be started

immediately and

cardiac function

monitored

CARDIAC COMPLICATIONS..CONT

Where cardiac MRI T2* is not available, • chelationdecisions should be based on ferritin, LIC and cardiac function assessment

Patients with ferritin > 2500 mg/ml and LIC >15g Fe/g dry weight should be chelated more aggressively.

those with ferritin < 2500 mg/ml and LIC 7 – 15 g Fe/g dry weight should have chelation adjusted accordingly and compliance encouraged.

Cardiologic intervention and management for heart failure and arrhythmia should follow cardiology standards apart from aggressive chelation

LIVER COMPLICATIONS

includes- transfusion-related viral hepatitis

(Hepatitis B, C), iron overload, drug toxicity, and

biliary disease due to gallstones.

Liver enzymes should be monitored routinely.

Liver iron concentration should be monitored

routinely and chelation therapy initiated and

adjusted to reduce complications of iron overload.

In the presence of elevated liver iron, liver fibrosis,

and cirrhosis may be accelerated by alcohol, liver-

toxic drugs, and untreated viral hepatitis, Limit such

exposure.

ENDOCRINE COMPLICATIONS

Iron overload is responsible for dysfunction of many

of endocrine glands like thyroid, parathyroid

pituitary gland, gonads and pancreas.

These include-

short stature (34%),

delayed puberty, hypogonadotropic hypogonadism (35

– 55%),

hypothyroidism (10%),

hypoparathyroidism (4%), and

diabetes mellitus (5.6 – 20%)

ENDOCRINE COMPLICATIONS -

INTERVENTIONS

Short stature-

The diagnosis of growth hormone deficiency, other

hormonal or nutritional deficiencies or deferoxamine

toxicity should be considered

Growth hormone stimulation testing should be done

and, if indicated, growth hormone therapy started

Hypothyroidism

TSH levels should be measured annually beginning at

12 years of age since hypothyroidism often develops

after adolescence.

Hypothyroidism should be treated with thyroid hormone

replacement.

ENDOCRINE COMPLICATIONS -

INTERVENTIONS

Impaired Glucose Tolerance and Diabetes

Improvement of iron load with adequate combination

chelation therapy may decrease insulin resistance and

decrease glucose intolerance

Impaired glucose tolerance and diabetes should be

managed as per diabetes protocols with emphasis on

glycemic control, diet, exercise, and management of

complications.

ENDOCRINE COMPLICATIONS -

INTERVENTIONS

Delayed Puberty and Hypogonadism

most common endocrine complication

all children should be assessed yearly from the age of 10

years

All patients with delayed puberty or hypogonadism should

receive appropriate investigations including bone age and

hormonal assessments, hormonal replacement therapy, and

subsequent follow-up by an endocrinologist

Hypoparathyroidism

All patients over the age of 12 years should have calcium and

phosphate levels checked at least every 6 months.

If these are abnormal, parathyroid hormone level should be

measured. Hypoparathyroidism should be managed as per

endocrine standards

BONE COMPLICATIONS

Bone disorders are common and multifactorial in patients with thalassemia .

Related to inadequate transfusion, iron-overload, over-chelation, and other endocrine factors contribute to the development of osteopenia and osteoporosis

Interventions:

Adequate blood transfusions

Adequate chelation therapy should be maintained

No Over-chelation

Hormone replacement therapy

Calcitonin,bisphosphonates

Diet rich in calcium and vitamin D

HYPERSPLENISM- SPLENECTOMY

Indictions of splenectomy

An increase in the yearly requirement of packed cells

more than 1.5 times the basal requirement, i.e. packed

cell 200 to 220 cc per kg/ year.

Massive splenic enlargement posing risk of splenic

rupture, or when it is associated with left upper

quadrant pain or erly satiety

Presence of leukopenia or thrombocytopenia due to

hyperspleenism

Splenectomy should be delayed till the patientis 5

years of age as there is risk of overwhleming sepsis

below this age

Risk of post-splenectomy serious infections can be

reduced by:

Immunization against pneumococcal, meningococcal,

and Hib and salmonella typhi infection atleast 3 weeks

before splenectomy

Chemoprophylaxis with oral penicillin,

125 mg twice daily for children upto 2 years

250 mg twice daily for children 2 years and above

Post splenectomy there may be transient or

persistent thrombocytosis. Aspirin 50-100 mg/day

for patients if platelet count >8,00,000/mm3

IMMUNIZATION PRIOR TO SPLENECTOMY

Pneumcoccal vaccine. 0.5 ml SC

If child has received a complete primary course PLUS

a single booster dose

Age<2 years: ( give one dose PCV13 Prevenar13 )

Age > 2years: ( give one dose PPV 23 Pneumovax 23

revaccinate after 3 years )

If child has not recieved primary course

Age 16 months – 5years : give two doses PCV13 Prevenar13

8 weeks apart

If aged 5-18 years - one dose

give one dose PPV 23 Pneumovax 23 at least 8 weeks after

the last PCV13 dose , revaccinate after 3 years.

Meningococcal vaccine:

Quadravalent meningococcal (Menactra) 0.5

mL IM upper deltoid.

o Children aged 2 through 6 years :Two doses of

Menactra® at least 8 weeks apart, followed by a single

booster dose 3 years later and then a single booster

dose every 5 years

Children aged 7 years and over and adults through

55 years :Two doses of Menactra® at least 8 weeks

apart, followed by a single booster dose every 5 years

Haemophilus b conjugate : One dose

regardless of previous vaccination history

RECOMMENDED MONITORING FOR COMPLICATIONS

OF B-THALASSEMIA

RECOMMENDED MONITORING FOR

COMPLICATIONS OF B-THALASSEMIA

CAUSES OF DEATH

Congestive heart failure

Arrhythmia

Sepsis secondary to increased susceptability to

infection post spleenectomy

Multiorgan failure due to hemochromatosis

LABORATORY

DIAGNOSIS OF

THALASSEMIA44

Complete Blood Count (CBC) with red cell indices and Peripheral Blood Film (PBF) Examination and reticulocyte count.

Hb low, total RBC count and Hct decreased

Thalassemics have uniform microcytosis with out increase in RDW

PS of Thalassemia Child

Characteristic bizarre picture of red cells, which are microcytic, hypochromic, with poikilocytosis, polychromasia, moderate basophilic stippling, and fragmented erythrocytes, target cells, and large number of normoblasts

Thalassemia trait Iron deficiency

anemia

RDW Normal(11.5-14.5) high

RBC count High relative to

hematocrit,Hb

levels

low

Thalassemia major Iron deficiency

anemia

serum Iron

levels

Serum iron high

Sr.ferritin high

TIBC decreased

Transferrin

saturation:

increased

Low

Low

Increased

decreased

The baseline serum ferritin and liver enzymes

including ALT, AST, bilirubin, lactate dehydrogenase

(LDH) should be measured.

Full red cell phenoptype [C, c, D, E, e, K, k, Jka,

Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis]

Serologic testing for hepatitis A, B, and C, and HIV

should be performed as baseline measures.

All first-degree family members should undergo

HLA-typing, if potential future allogeneic

hematopoietic stem cell transplant is considered an

option.

HB ELECTROPHORESIS

LAB DIAGNOSIS ..CONT. Osmotic fragility test : decreased

Urinary urobilinogen: increased (Ehrlich test)

Stool examination: dark stools, increased

stercobilinogen.

Radiological changes: seen after 1 year

X-ray of metacarpals,ribs, vertebra show thinning of cortex

X-ray of skull shows “hair on end appearance”

Generalised skeletal osteoporosis

MANAGEMENT OF THALASSEMIA MAJOR

Comprehensive management includes the following:

• Confirmation of the diagnosis

• Correction of anemia– Packed red cell transfusions

• Removal of excess iron– Chelation Therapy

• Management of complications – Endocrine and

Cardiac complications

• Pharmacological methods to increase gamma chain synthesis

• Supportive care

• Curative Treatment– Stem Cell Transplantation

• Future treatment– Gene replacement therapy.

A team approach includes:

• Pediatric hematologist,

• Pediatrician,

• Blood transfusion specialist

• Endocrinologist,

• Psychologist and

• Social worker, etc

TRANSFUSION THERAPY IN

THALASSEMIA

Transfusion therapy in thalassemia has

two goals:

• To prevent anemia

• To suppress endogenous erythropoiesis

Regular Blood Transfusions are Presently the

Mainstay of Treatment of Thalassemia Major.

Concept of Neocyte transfusion

TRANSFUSION PROTOCOLS

Palliative– Pretransfusion - Hb level is around < 7 gm% and mean Hb maintained is < 8.5 gm/dl.

Hyper Transfusion– Pretransfusion Hb level is

around > 10gm% and mean Hb. Maintained is

> 12 gm%.

Super Transfusion– Pretransfusion Hb level is

around > 12gm% and mean Hb. Maintained is

>14gm%.

Moderate– Transfusion- Pretransfusion- Hb level is around 9-10.5 gm% and mean Hb. Maintained is >12gm %.

Current recommendation?

TYPE OF TRANSFUSION

Leukoreduced packed red cell transfusion is

desired type of blood for thalassemic children

Reduction of leukocytes to 5000000 is considered

adequate.(reduced by 70%)

It helps in prevention of transfusion reactions and is

achieved by centrifugation;/saline washing/filtration.

METHODS FOR LEUKODEPLETION

Centrifugation– Packed red cell transfusions

Saline-cell washing (Triple Saline Washed)

Deglycerolized–red cells.

Third generation leucocyte filters

Irradiated blood cells

BENEFITS OF BLOOD TRANFUSION-

THALASSEMIA

Improves tissue oxygenation, and prevents chronic

hypoxia

Improves normal growth and development

Prevents erythropoiesis thus avoiding expansion of

the bone marrow and extra medullary

erythropoiesis

Reduces hemolytic facies

Reduces hepatosplenomegaly and cardiomyopathy

Reduces gastro-intestinal absorption of iron.

WHEN TO START THE TRANSFUSION

Blood transfusion is started as soon as diagnosis

firmly established (Except in children > 18 months of

age).

If age is > 18 months, these children are observed to r/o

Thalassemia Intermedia and if Hb drops < 7 gms%,

regular transfusion started.

The most ideal way to transfuse thalassemics is using

group and type specific saline washed packed red

cells (HCT - 65 to 75%) that are compatible by direct

antiglobulin test (Coomb’s crossmatched)

RATE AND FREQUENCY OF

TRANSFUSIONS

10-15 ml/kg of saline washed packed red cells every 3 to 4 weeks.

Rate not more than 5 ml/kg/hr, however, in patients with cardiac dysfunction not more than 2-3 ml/kg/hr should be given.

Shorter intervals of 2 to 3 weeks are more physiological.

Average time taken is 3-4 hours

Approximately 180 ml/kg of red cells are required to be transfused per year in non-splenectomized, nonsensitized patients to maintain the hemoglobinabove 10 gms%, whereas splenectomized patients require 133 ml/kg per year.

Even without hypersplenism, the requirement is 30%

higher in non-splenectomized patients

COMPLICATIONS OF TRANSFUSION

NHFTR (Non hemolytic febrile transfusion reaction)

Allergic reactions

Acute hemolytic reactions

Delayed hemolytic reactions

TRALI-transfusion related acute lung injury

TACO- transfusion associated circulatory overload

Alloimmunizaton.

Transfusion transmitted infections

Iron overload

Steps to Prevent These Infections Include

Screening of blood products.

All thalassemic children should recieve hepatitis vaccination if not previously immunised

Leukodepletion can minimize CMV infection

IRON OVERLOAD AND CHELATION THERAPY

Iron Overload Occurs in Thalassemic Patients

due to

Treatment with multiple transfusions

Ineffective erythropoiesis

Excessive dietary absorption of iron from gut, to

compensate the large turnover of red cell mass

Lack of physiologic excretory mechanism for the

excess iron

The goal of iron chelation is to reduce the iron

store and subsequently maintain at low level

(sr.ferritin less than 1000ng/ml).

INITIATION OF CHELATION THERAPY

Serum ferritin >1000ng/dl

Patient has received 15-20 transfusions

Hepatic iron concentration exceeds 3.2mg/ g dry

weight

CHELATING AGENTS

Deferoxamine(DFO)

Route:SC/IV

Dose: 25-50 mg/kg/day

Schedule: over 8 to 10 hrs for 5-6 nights a week with the

help of subcutaneous desferal infusion pump

MOA:chelates loosely bound iron, iron from

ferritin,hemosiderin ,not from transferrin

Excretion :Urine(80%,urine red)/Feces

Plasma clearance t1/2: 20 minutes

Adverse effects Local skin reaction, ototoxicity, infections

,ophthalmic toxicity, skeletal impairment

Monitoring Long bone films in growing children, annual

eye and ear check-up

CONSIDERATION OF AGGRESSIVE CHELATION

THERAPY

Severe iron over load

Persistently very high ferritin value

Liver iron >15mg/ g dry weight

Significant cardiac disease

Cardiac arrhythmias

Evidence of falling left ventricular function

Evidence of very severe heart iron loading(MRI T2* <6

ms)

Prior to bone marrow transplantation when rapid

reversal of iron loading may be desirable

tab Vitamin C 1hr prior to infusion .

Deferipone(Kelfer)

It mobilizes iron from transferrin, ferritin, and

hemosiderin.

Dose: 75 to 100 mg/kg body weight/day in

three to four divided doses

Excretion:Urine

Plasma clearance t1/2:53-166 minutes

Adverse effects: Agranulocytosis, GIT

disturbances,transaminase elevation,

arthralgias

Monitoring:Weekly CBC

DEFERIPONE ..CONT

Drug should be discontinued whenever

Total count drops to < 3000/mm 3

Absolute neutophil count drops to < 1000/mm 3

Zinc deficiency may develop, zinc supplementation

may be necessary

It should be first line drug for patients not receiving

DFO because of high cost, toxicity or poor

compliance of the later.

Deferasirox (exjade)

A novel chelating agent belongs to tridentate tiazole,with

high affinity to iron as Fe+++ and chelates at a ratio of

2:1 (Deferasirox: Iron).

Dose :20-30 mg/kg/day

Schedule: daily ,OD

Excretion:Feces

Plasma clearance t1/2:1-16 hours

It should be given approximately same time each day on

an empty stomach 30 minutes prior to food. Tablet

should be dispersed in water/orange /apple juice.

It is available as 250/500 mg tablet for oral suspension

dispersible tablets

Monitoring:Monthly RFT, LFT and urine analysis

Side effects: GI disturbances , rash, renal dysfunction

SHUTTLE HYPOTHESIS

Co-administration of ICL 670 (Deferasirox) with Inj

DFO has synergic effect and helps in reducing dose

of both the drugs thus improving the compliance

and cost of the treatment as is done with oral

chelation therapy with deriprone and inj. desferal.

Shuttle effect

also seen with this combination, as ICL 670-

Deferasirox acts as intracellular chelator and DFO as

extracellular.

MANIPULATION OF HBF SWITCHING

Hydroxyurea

Histone Deacetylase Inhibitors

Butyric Acid Analogs

5-azacytidine,( risk of cancer –not used now)

Erythropoietin has been tried to induce HbF

production with varying success

STEM CELL TRANSPLANTATION

This is only the curative therapy available today.

Sources of stem cells:Bone Marrow, Peripheral

Blood, Cord Blood,Fetal Liver.

Though expensive, it is cost effective as compared

to yearly cost of regular blood transfusion and

chelation therapy.

cost 8-10 lakhs.

Umblical cord stem cells have good results(lower

GVHD, longer engraftment)

GENE THERAPY

Lenti Viral vector derived from Human

Immunodeficiency Virus, where a large fragment of

human beta gene and its locus control region, have

been introduced, though experimental, more

effectiv therapies will become available near future

to cure the disease.

PREVENTION OF THALASSEMIA-CARRIER

SCREENING

Thalassemia minor or carrier state can be easily detected in a person by doing simple blood test HbA2 by hemoglobin electrophoresis or variant machine or column chromatography

Prevention includes population education, mass screening, genetic counseling and antenatal diagnosis and therapeutic abortion of affected pregnancy

Carrier detection:The only confirmatory test is HbA2 estimation.

To conduct an effective mass screening program, the targeted population should belong to the premarital and newly married groups, i.e. before they have begun their families.

ANTENATAL DIAGNOSIS

When both partners, who are thalassemia minors, plan to have their baby, they are told to report to their hematologist as soon as possible after pregnancy is confirmed.

Chorionic villous sampling (CVS) done between 9th and 11th week of pregnancy.

amniocentesis or cordocentesis-16 to 18 weeks of pregnancy.

Test result:

‘Affected’ which means the fetus has thalassemia

major, or

‘Unaffected’ meaning that the fetus is either

thalassemia minor or normal.

Affected fetuses are advised to be terminated and

unaffected fetuses to be continued

REFERENCES

IAP TEXT BOOK OF PEDIATRICS 5th Ed

Advances in pediatrics pedicon 2012

IAP Pediatric Hematology

Nelson Text Book Pediatrics

Standards for the Clinical Care of Children and

Adults with Thalassaemia in the UK

Guidelines for the Clinical Care of Patients with

Thalassemia in Canada

Thank you