THALASSEMIA

Dr. Anila Mani

DTM
Contents
• History
• Introduction
• Structure
• Synthesis
• Definition
• Inheritance
• Epidemiology
• Regional distribution
• Types and Classification
• Complications
• Clinical features
• Diagnosis
• Management
• Prevention
History
1925 Cooley and Lee described anemia with splenomegaly & bone
changes

 In 1932 Whipple and Bradford pathological description of the disease

True genetic character was decoded by 1940

Whipple coined the term thalassemic anemia

Greek word meaning from the sea

Patients were of Mediterranean origin

Thomas B. Cooley (1871-1945)
 Other names
• VON JAKSCH ANEMIA
• COOLEY’S ANEMIA
• “THALASSA” : GREEK WORD - GREAT SEA – first observed in
1930’s -
around MEDITTERANIAN SEA
Introduction
• The term “Thalassemia” refers to a genetic disorder of hemoglobin
synthesis characterized by a lack or decreased synthesis of one or
more of the four Globin chains causing excessive breakdown of RBC.

• "Thalassemia" is a Greek term derived from “Thalassa”, which means

"the sea" and “Emia” means "related to blood."
Structure of hemoglobin
Genetic Structure of hemoglobin
Site of Globin synthesis
Normal hemoglobin components
Hemoglobin distribution
Hb A - 2 α and 2 β chains forming a tetramer
• 97% adult Hb
• Postnatal life Hb A replaces Hb F by 6 months

Fetal Hb – 2α and 2γ chains

• 1% of adult Hb
• 70-90% at term. Falls to 25% by 1st month and progressively

Hb A2 – Consists of 2 α and 2 δ chains

• 1.5 – 3.0% of adult Hb
Definition
• Thalassemia sydromes are a heterogenous group of
inherited anemias characterised by reduced or absent
synthesis of either alpha or Beta globin chains of Hb A.

• Most common single gene disorder

Inheritance
• Autosomal recessive
• Beta thalassemia – point mutations on Chrom:11
• Alpha thalassemia – gene deletions on Chrom:16
Epidemiology
5 in every 100 people are thalassaemia carriers
Types of thalassemia
• If synthesis of α chain is suppressed – level of all 3 normal Hb A (2α ,
2β),A2 (2α ,2 δ),F(2α ,2γ) reduced – Alpha thalassemia

• If β chain is suppressed - adult Hb is suppressed - Beta thalassemia

Regional distribution
• β-thalassemias are distributed widely in Mediterranean
populations, the Middle East, parts of India and Pakistan,
and throughout Southeast Asia

• The α-thalassemias occur widely throughout Africa, the

Mediterranean countries, the Middle East, and Southeast
Asia
Classification of Thalassemia
Alpha Thalassemia
Alpha Thalassemia
• Deficient/absent alpha subunits
▫ Excess beta subunits
▫ Excess gamma subunits newborns
• Encoding genes on chromosome 16
• Each cell has 4 copies of the alpha globin gene
• Each gene responsible for ¼ production of alpha globin
Chromosome No:16 defects
Molecular genetics
• Promoter region mutations - Transcription defects
• Chain terminator mutations - Translation defects
• Splicing mutations - RNA splicing defects (processing
defects)
• Possible mutation states:
Loss of ONE gene - silent carrier
Loss of TWO genes - thalassemia minor (trait)
Loss of THREE genes - Hemoglobin H disease

• Accumulation of beta chains

• Association of beta chains in groups of 4 - Hemoglobin H
• Hb constant spring similar to HbH but no microcytosis

Loss of FOUR genes - Hemoglobin Barts

 NO alpha chains produced ∴ only gamma chains present
 Association of 4 gamma chains - Hemoglobin Barts
Clinical Presentation
Pathophysiology of α thalassemia
• Chains are shared by both fetal and adult hemoglobin
manifest in both fetal and adult life.
• β4(Hb H) and Υ4(Hb Barts) tetramers are soluble, they do not
precipitate in the marrow, ineffective erythropoesis less
severe
• Damage mature red cells leading to hemolysis but red cell
membranes are hyperhydrated & hyperstable.
Clinical outcomes
Silent carriers
• Asymptomatic

Alpha Thalassemia minor (trait)

• No anemia
• Microcytosis
Alpha Thalassemia intermedia (Hemoglobin H)
• Anemia and microcytosis
• Bone deformities
• Splenomegaly
Hb H & Hb Barts

Red cell hemolysis,

apoptotic cell death due
to inclusion bodies, High oxygen affinity, no
unstable red cells heme-heme
interactions,poor oxygen
carrying capacity
Hemoglobin Bart's - Hydrops Fetalis Syndrome
• Most severe manifestation of alpha thalassemia
• Hydrops fetalis – Fatal unless intrauterine transfusions
• Stillborn or die within a few hours
• Severe anemia , edematous, mildly jaundiced, ascites,
hepatosplenomegaly, cardiac failure
• Looks like Rh incompatilibity
Diagnosis
• Hb electrophoresis: 80-90 % Hb Bart’s
• Hb H
• Hb Portland
• No Hb A, Hb A2 or Hb F
• • Treatment: immediate exchange transfusion
Hemoglobin H
• Seen in South East Asia, middle east
• Moderate anemia (Hb 8-9 gm/dl), mild jaundice
• Splenomegaly, gall stones
• PBS similar to thalassemia major
• Hb electrophoresis: Hb H 2-40 %; rest are Hb A, HbA2, HbF
• Bony deformities
• Not usually transfusion dependant
Hemoglobin Constant Spring
• Similar to HbH but no microcytosis
• Relatively asymptomatic
• Moderate hemolytic anemia with splenomegaly and characteristic
hematologic findings
• Hb 9-12 g/dl , MCV normal
• Anemia
• Growth delay
DIAGNOSIS OF α THALASSEMIA
CBC:
• Silent Carrier: no microcytosis , no anaemia.
• α-Thalassemia trait: microcytosis, hypochromia,mild anaemia.
• Hb H disease: variable severity of anemia & hemolysis.
• PBF: Hb H inclusion body – Heinz bodies (brilliant cresyl blue) in
Hb H disease – Golf ball appearance
• α/β chain ratio decreased
Hemoglobin Electrophoresis
Hb H:
• (2-40%) Hb H
• others Hb A
• Hb F & Hb A2

Hb Bart's:
• (80-90%) Bart's,
• no Hb A, Hb F, Hb A2
Treatment
• Generally not required
• Blood transfusion, iron chelation therapy – For transfusion dependent
cases
• Avoidance of oxidant drugs
• Prompt treatment of infections
• Folic acid supplementation
• Silent carrier & trait: do not require treatment.
• Hb H disease: usually does not require regular transfusions. But,
with intercurrent illnesses, patient may require transfusion .
Beta Thalassemia
• β-thalassaemia includes three main forms:

Thalassemia Major referred to as :

• “Cooley’s Anaemia”
• “Mediterranean Anaemia”

Thalassemia Intermedia

• Thalassemia Minor also called “β-thalassaemia carrier”, “β-

thalassaemia trait” or “heterozygous β-thalassaemia”.
Pathophysiology of β thalassemia
• In homozygous β-thalassemia , β-globin synthesis is either absent or
markedly reduced.

• Excess α globin chains precipitate in red cell precursors.

• These large inclusions are responsible for intramedullary destruction

of red cell precursors

• Ineffective erythropoesis
• Since ẞ chain synthesis reduced - gamma γ2 and delta δ2 chain
combines with normally produced α chains ( Hb F (α2 2) , Hb A2 (α2 δ2) -
Increased production of Hb F and Hb A2

• Relative excess of α chains → α tetramers forms aggregates →precipitate in

red cells → inclusion bodies → premature destruction of maturing
erythroblasts within the marrow (Ineffective erythropoiesis) or in the
periphery (Hemolysis)→ destroyed in spleen
Beta- thalassemia variants
• Anemia result from lack of adequate Hb A
→ tissue hypoxia→↑EPO production →
↑ erythropoiesis in the marrow and sometimes extramedullary
→ expansion of medullary cavity of various bones

• Liver & spleen enlarge → extramedullay hematopoiesis

General features
• Gradual Pallor
• Fatigue
• Dyspnoea on exertion
• Poor appetite
• Palpitation
• Poor growth
Effects of marrow expansion
• Pathological fractures due to cortical thinning
• Deformities of skull and face
• Sinus and middle ear infection due to ineffective drainage
• Folate deficiency
• Hypermetabolic state - fever, wasting
• Increased absorption of iron from intestine
COMPLICATIONS
Features of extramedullary hematopoiesis
• Hepatosplenomegaly
• Scoliosis, Kyphosis, vertebral collapse with cord compression
Hepatomegaly
• Extra medullary erythropoeisis
• Iron released from breakdown of endogenous or transfused RBCs
cannot be utilized for Hb synthesis – hemosiderosis
• Hemochromatosis
• Infections – transfusion related - Hep B,C,HIV
• Chronic active hepatitis
Splenomegaly
• Extra medullary hematopoeisis
• Hypertrophy due to constant hemolysis
• Hypersplenism (progressive splenomegaly)
Jaundice
• Unconjugated hyperbilirubinemia - hemolysis
• Hepatitis - transfusion, hemochromatosis
• GB stones - obstructive jaundice
• Cholangitis
Infections – Causes:
• Anemia
• Poor nutrition
• Blockage of monocyte-macrophage system
• Hypersplenism - leukopenia
• Iron overload – Yersinia, Klebsiella
• Splenectomy – Pneumococci, Meningococci, Hemophilus Influenzae
• Transfusion related – HBV, HCV, HIV etc.
Iron overload
• Deposition in pituitary – endocrine disturbance - short stature,
delayed puberty, poor sec. sexual characteristics

• Hemochromatosis - cirrhosis of liver

• Cardiomyopathy (cardiac hemosiderosis) –

cardiac failure, sterile pericarditis, arrythmias,
heart block

• Deposition in pancreas - Diabetes mellitus

• Lungs: restrictive lung defects
• Adrenal insufficiency
• Hypothyroidism & Hypoparathyroidism
• Increased susceptibity to infections (iron favours
bacterial growth) especially : Yersinia infections
Features of Iron overload
Hypercoagulable state
Complications due to blood transfusion
• Acute hemolytic reactions
• Delayed transfusion reaction
• Autoimmune hemolytic anemia
• Febrile transfusion reaction
• Allergic reaction
• Transfusion related acute lung injury (TRALI)
• Transfusion associated Graft versus host disease (TA-GVHD)
• TACO
• TTI’s – HCV, HBV, HIV
Complications of thalassemia
• Excessive erythropoiesis
• Iron overload
• Chronic hemolysis
• Hypercoagulable disease
• Infection
• Transfusion related complications
• Treatment of related complications
Causes of death in thalassemia

• Cardiac hemochromatosis - Congestive heart failure

• Arrhythmia
• Sepsis due to increase susceptibility to infection
• Multiple organ failure due to hemochromatosis
Clinical features (Thalassemia major)
INFANTS:
• Age of presentation: 6-9 months (Hb F replaced by Hb A)
• Progressive pallor and jaundice
• Cardiac failure
• Failure to thrive, gross motor delay
• Feeding problems
• Bouts of fever and diarrhea
• Hepatosplenomegaly
CHILDHOOD:
• Growth retardation
• Severe anemia-cardiac dilatation
• Icterus
• Changes in skeletal system
• Transfusion dependant
Bone changes
• Medullary expansion & Cortical thinning
• Increased porosity of long bones
• Delayed pneumatisation of sinuses
• Premature fusion of epiphyses - short stature
• risk of fracture, osteopenia, osteoporosis, backache.
• Vertebral expansion lead to spinal cord compression – neurological
manifestations
• Pathological fractures

Paravertebral masses:
• Broad expansion of ribs at vertebral attachment
• Paraparesis
Skeletal changes
CHIPMUNK FACIES (Hemolytic facies):
• Frontal bossing, maxillary hypertrophy, depression of
nasal bridge , Malocclusion of teeth, Chronic sinusitis,
impaired hearing
Other features
Chronic hemolysis
Jaundice, Gall-stones - Gallstone 50-70% by around 15 years of age,
Hyperuricemia-Gout
• Leg ulcers
• Delayed menarche
• Pericarditis
• Diabetes/ cirrhosis of liver
• Evidence of hypersplenism
Clinical features (Thalassemia intermedia)
• Moderate pallor, usually maintains Hb >6gm%
• Anemia worsens with pregnancy and Infections (erythroid stress)
• Less transfusion dependant
• Skeletal changes present, progressive Splenomegaly
• Growth retardation
• Longer survival than Thalassemia major
Clinical features (Thalassemia minor)
• Usually ASYMPTOMATIC
• Mild pallor, no jaundice
• No growth retardation, no skeletal Abnormalities, no
splenomegaly
MAY PRESENT AS IRON DEFICIENCY ANEMIA
• Hypochromic microcytic anemia
• Unresponsive/ refractory to Iron therapy
• Normal life expectancy
Hb E β-Thalassemia
• Haemoglobin E disorder is the most common structural variant with
thalassaemic properties.

• It is also prevalent in parts of the Indian subcontinent, including India, Pakistan,

Bangladesh and Sri Lanka.

• Double heterozygous state.

• Lysine substitutes glutamic acid in 26th position.

• Divided into mild, moderate & severe form with clinical features varying from
thalassemia intermedia to thalassemia major
Variants of Hb E β-thalassemia
Investigations and Diagnosis
CBC:
• Hb level - Depends on severity
– β-thalassemia minor: 10-13 gm/dl
– β-thalassemia intermedia: 7-10 gm/dl
– β-thalassemia major: 3-6 gm/dl

• TC/DC – normal / increased / decreased

• Platelet - normal / decreased
• RBC Indices - MCV, MCH, MCHC are low
• RDW - Normal or raised
• Reticulocyte count - Increased (5-10%) Normal <1%

Peripheral smear : Microcytic hypochromic cells with marked anisocytosis, poikilocytosis

and other abnormal cells.
Blood picture
• PS: Microcytic hypochromic anemia,
anisopoikilocytosis, target cells,nucleated RBC, basophilic
stippling, tear drop cells

• Cytoplasmic inclusion bodies in α Thalassemia

• Post splenectomy : Howell-Jolly and Heinz bodies
• Reticulocyte count increased (upto 10%)
Hypochromic , Microcyte ,Target cell, Tear drop cell, Elliptocyte,
Target cells
• Codocytes  (also known as) - (Codo- bell shaped)
• dark center (a central, hemoglobinized area) surrounded by a white ring (an
area of relative pallor), followed by dark outer (peripheral) second ring
containing a band of hemoglobin.

• Electron microscopy they appear very thin and bell shaped .

• Because of their thinness they are referred to as leptocytes and because of
the wavy bowl shape they are referred to as Mexican hat cells or sombrero
cells.

• Leptocytes the central spot is not completely detached from the peripheral
ring, i.e. the pallor is in a C shape rather than a full ring.
Principle of Menzter Index
• In iron deficiency, the marrow cannot produce as many RBCs and
they are small (microcytic), so the RBC count and the MCV will both
be low, and as a result, the index will be greater than 13.

• In thalassemia, which is a disorder of globin synthesis, the number of

RBCs produced is normal, but the cells are smaller and more fragile.
Therefore, the RBC count is normal, but the MCV is low, so the index
will be less than 13.
Mentzer index
• The Mentzer index, described in 1973 by William C.
Mentzer - differentiate iron deficiency anemia from beta
thalassemia
• Osmotic fragility test : increased- resistance to hemolysis
• T. bilirubin, I. bilirubin – increased
• Haptoglobulin and Hemopexin – depleted
• S. Iron & Ferritin : elevated, Transferrin – Highly saturated
• Folate levels - concurrently decreased
• Free erythrocyte porphyrin - normal
• Serum uric acid -raised
• Haemosiderinuria
• B.M. study: Hyperplastic erythropoesis
• B.M Iron staining – Increased hemosiderin deposition
Diagnosis – Hemoglobin Electrophoresis – Diagnostic test
Hemoglobin Electrophoresis
Radiological changes
• Skull – widened diploid spaces – interrupted porosity gives hair on
end appearance, Thinning of cortex

• Delayed pneumatization of sinuses – maxilla appears overgrown

with prominent malar eminences
X ray skull:
“ hair on end”
appearance
or
“crew-cut”
appearance
Small bones (hand ) –
• earliest bony change
• Rectangular appearance
• medullary portion of bone is widened
• bony cortex thinned out
• Mosaic pattern - coarse trabecular pattern in medulla
X-Ray of forearm and ribs
Iron overload assessment
• S. Ferritin
• Urinary Iron excretion
• Liver biopsy
• Chemical analysis of tissue Iron
• Endomyocardial biopsies
• Myocardial MRI indexes
• Ventricular function – ECHO, ECG
• DNA analysis: Determine specific defect at molecular
DNA level.

• HPLC (High Performance Liquid Chromatography):

Identify & quantify large number of abnormal Hb
To assess complications
• Liver function test
• Thyroid function test
• Pituitary - FSH, LH, Testosterone, Estradiol
• Blood Sugar
• Bone profile
• Parathyroid - Ca, Phosphate, PTH
• Liver Iron Concentration (LIC): T2 MRI, Liver Biopsy, SQUID
• Cardiac Iron Measurement by: T2 MRI
Liver - MRI to assess Iron overload
SQUID
• Stands for Superconducting Quantum Interference Device
• Very sensitive magnetic detector.

• Using a small magnetic field, the device is able to directly measure

iron concentration in the liver, the primary location of iron in the
body, by detecting its response to a changing magnetic field or
magnetic susceptibility.
Diagnosis of thalassemia
Management
• Supportive

• Curative

• Preventive
Objectives of supportive management
• Maintenance of growth and development
• Correction of anemia
• Prevention of iron overload
• Treatment of complications
• Counselling and Prevention
Supportive management
• Multi-disciplinary approach
• Focus on each patient’s clinical course
Blood Transfusion
Primary Goals
• To prevent anemia
• To suppress endogenous erythropoeisis
• To prevent abnormal fragile red cells being produced
Whom to transfuse ??

Confirmed diagnosis of thalassemia major

Laboratory criteria:
• Hb < 7gm/dl on 2 occasions > 2 weeks apart
OR
• Hb > 7gm/dl with:
Facial changes
Poor growth
Fractures
Extramedullary hematopoiesis
Pre-requisites before starting transfusion
• Use careful donor selection and screening, favoring voluntary, regular, non-
remunerated blood donors
• ABO and Rh(D) compatibile
• Before first transfusion, perform extended red cell antigen typing of patients at least for
C, E, and Kell
• At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell
antigen is highly recommended
• If the patient is already transfused, antigen typing can be performed using molecular
rather than serologic testing.
• Preferably genotype matched red cells either at the first transfusion or in case of
severe allo-immunisation
• Before each transfusion, perform a full cross-match and screen for new antibodies
• Use leucoreduced packed red cells

• Pre-storage filtration is strongly recommended, but blood bank pre-transfusion filtration is

acceptable.

• Bedside filtration is only acceptable if there is no capacity for pre-storage filtration or blood bank
pretransfusion filtration

• Use washed red cells for patients who have severe allergic reactions

• Transfuse red cells stored in CPD-A within one week of collection and red cells stored in additive
solutions within two weeks of collection.

• It is recommended to provide fresh units (less than 7-14 days old) if possible for SCD and
thalassemia patients, as fresher units may reduce frequency of transfusion – (ISBT)
• Screening of donor blood for HBV, HCV, HIV, Syphilis, Malaria.

• Serologic testing for hepatitis A, B, C and HIV should be performed as baseline

measures, and all patients who do not have serologic immunity to hepatitis B virus
should start a vaccination program and show evidence of immunity before the
start of the transfusion. 

• Before first transfusion, a course of hepatitis B vaccination should be started and

completed if possible.

• Avoidance of transfusion first-degree relative donors.

• Cytomegalovirus-negative blood products are recommended for potential candidates

for curative stem cell transplantation (SCT).
• Leucodepletion packed red blood cells with a minimum hemoglobin content
of 40g.

• Transfuse every 2-5 weeks, maintaining pre-transfusion haemoglobin above

9-10.5 g/ dl or higher levels (11-12 g/dl) for patients with cardiac
complications .

• Keep a record of red cell antibodies, transfusion reactions, volume and

hematocrit of transfused unit and annual transfusion requirements for each
patient
Age and alloimmunisation risk - The risk of alloimmunisation appears to be
greater in patients who begin transfusion therapy after the first few years of life
Transfusion protocol
• To maintain pre transfusion Hb >9–10.5 gm/dl.

Typical programs:
• Transfusion of 10–15 cc/kg of packed Leuko-depleted red
cells
• Lifelong regular blood transfusions, every 2–5 weeks
Two regimens
• Hypertransfusion Regimen : 10 – 12 gm/dl
• Supertransfusion Regimen : 12 - 14 gm/dl – Iron
overload
Hypertransfusion protocol
• Most popular
• Hemoglobin to be aimed at 12.5 g/dl
• Pre-transfusion hemoglobin not less than 10 g/dl

Advantages :
• Permits normal growth & physical activities
• Suppress erythropoiesis
• Prevents gastrointestinal iron absorption
• Prevents extramedullary erythropoiesis – thus prevents splenomegaly and
hypersplenism
• Requirement of blood is high only at start of therapy
A higher pre-transfusion hemoglobin level of 11-12 gm/dl for
patients with:
• Heart disease or other medical conditions
• Patients who do not achieve adequate suppression of bone marrow
activity at lower Hb level.
Blood products for transfusion
• Packed red cell

• Leukocyte reduced red cell – to reduced FNHTR, HLA alloimmunisation, CMV

transmission

• Frozen and thawed red cells – Rare blood group and alloimmunisation with
multiple allo-antibodies

• Washed red cell – H/o severe allergic reactions, IgA deficient patients, No
facility for leucoreduction

• Neocyte
Neocyte transfusions

• Propper et al in 1980 introduced the concept of neocyte transfusion in thalassemic

children
• Neocytes are young RBC’s
• Mean life span of normally transfused RBC’s will be 60 days
• Neocytes can survive upto 90 days
• Reduces number and frequency of transfusions
• Limits donor exposure

Drawbacks:
• Very expensive
• Highly skilled personnel & costly equipments required
• Processing is time-consuming
How much volume to transfuse ?
Relationship between annual blood requirements and rate of
daily iron loading
Regular transfusion allows
• Normal growth
• Normal physical activities
• Adequately suppresses bone marrow activity
• Minimizes iron accumulation
Diet and supplementation
• High iron contained food should be avoided.
• Diet which decreases iron absorption such as milk & milk
products should be taken adequately
• Folic acid
• Zinc
• Vit. D, Vit. E
Chelation Therapy
Primary goals of chelation therapy
Goals of chelation Therapy is achieved by:
• Keeping serum ferritin <1000-2,000 ng/mL or
• Liver Iron Concentration (LIC) <15 mg/g dry weight
Guidelines for starting treatment of iron overload in patients with β-
thalassemia major
• Thalassemia International Federation guidelines for the clinical
management of thalassemia (2008) recommend that chelation therapy is
considered when patients:

Have received 10–20 transfusion episodes

OR
Have a serum ferritin level of >1000 ng/mL
Iron Chelating Agents
• Desferrioxamine (DFO)
• Deferiprone
• Deferasirox
Desferrioxamine
(1 unit of blood contains 250 mg iron)
Dose: 30-60mg/kg/day
• IV / s/c infusion pump over 12 hr period x 5-6 days /wk
• Start when ferritin >1000ng/ml
• Vitamin C 200 mg on day of chelation - enhances DFO
induced urinary excretion of Fe
• Regular rotation of the site of infusion allows proper absorption of the
medication and decreases the risk of skin breakdown and scar tissue
formation.
• The most common sites are abdomen, thighs and upper arms.
• Intensive chelation with Desferrioxamine – continuous 24-hourly infusions
IV or SC.

Indications:
a) Persistently high serum ferritin
b) LIC > 15 mg/g dry weight
c) Significant heart disease
d) Prior to pregnancy or bone marrow transplantation

Dose: 50 mg/kg/day (up to 60 mg/kg/day)

• In-dwelling catheters: danger of infection and thrombosis
Adverse effects: Desferrioxamine
• Cardiotoxicity – arrythmias
• Eyes - cataract
• Ears - sensorimotor hearing loss
• Bone dysplasia-growth retardation
• Rapid infusion- histamine related
• Reactions - hypotension, erythema, pruritis
• Infection, sepsis
Chelation therapy- Deferiprone
Oral chelator - > 2yrs old Dose: 50-100mg/kg/day
Adverse effects:
• Reversible arthropathy
• Drug induced lupus
• Agranulocytosis

• Other oral chelators

• Deferrothiocine
• Pyridoxine hydrazine
• ICL-670 – removes Fe from myocardial cells
Fetal hemoglobin induction (HbF)
• Increasing the synthesis of fetal hemoglobin can help to alleviate anaemia and thereby
improve the clinical status of patients with thalassemia intermedia.
• Agents including cytosine arabinoside and hydroxyurea may alter the pattern of
erythropoiesis and increase the expression of alpha-chain genes.

Induction agents :
• Hydroxyurea
• Myelaran
• Butyrate derivatives
• Erythropoietin
• 5-Azacytadine
• Erythropoietin has been shown to be effective, with a possible additive effect in combination with
hydroxyurea.
Splenectomy
• Deferred as long as possible. At least till 5-6 yrs age

Splenectomy (indications):
• Massive splenomegaly causing mechanical discomfort
• Progressively increasing blood transfusion requirements - packed RBC 200 to
220 mL RBCs/kg per year with a hematocrit of 70% (equal to 250-275 mL/kg
per year of packed RBCs with a hematocrit of 60%

• Hypersplenism
Risk of Splenectomy
Preventative measures
Immunoprophylaxis –
• At least 2 weeks before splenectomy
• Pneumococcus/meningococcus/Hemophilus
Chemoprophylaxis-
• Chemoprophylaxis with life-long oral penicillin.
• Educate the parents
Curative therapies
• Bone marrow transplantation
• Stem cell transplantation
• Gene therapy
Bone marrow/Stem cell transplantation

Only curative option available.

Overall outcome depends on -
• Inadequate chelation therapy,
• hepatomegaly
• presence of portal fibrosis
• Treatment-related mortality is approximately 10%.
Risk stratification for BMT
• Hepatomegaly >3cms
• Liver fibrosis
• Inadequate chelation

 Class I – no risk factors

 Class II- one to two risk factors
 Class III- all three risk factors
Outcome of BMT in thalassemia
Allogenic stem cell transplantation
• The first curative allogeneic SCT to a thalassemia patient from an
human leukocyte antigen (HLA) identical sibling donor was reported
in 1982.

• Since then, >3000 successful transplantations have been reported.

• The probability of overall event-free survival has been recently

reported as high as 89%-97% for patients with no advanced disease
and of 80%-87% for patients with advanced disease.
• Donor selection is of great importance because transplantations may fail or be lethal
resulting from immunologic complications.

• The best results have been obtained with HLA-matched siblings.

• Approximately 10% of SCT patients are transfusion-free for years, although they experience
persistent mixed hematopoietic chimerism.

• This suggests that only a few engrafted donor cells are sufficient for correction of donor
phenotype.

• Despite a successful engraftment, previously iron-overloaded patients may require

phlebotomy after transplantation to prevent the risks of residual iron excess causing hepatic
fibrosis or other endocrine complications
Umbilical Cord blood transplantation
• The potential benefits of umbilical cord blood (UCB) treatment are the low risk
of viral contamination from a graft, the decreased incidence of acute and
chronic GVHD, and easier accessibility.

• The small size or small number of stem cells in the UBC collection relative to
the number required for engraftment are probably the main causes of failure
of UCB transplantation; therefore, this procedure is being used mainly in
pediatric patients.
Gene Therapy
• Insertion of normal globin genes into marrow stem cell
may ultimately cure Thalassemia .
• Globin gene transfer in autologous CD34+cells is
beginning to be evaluated
• • As per FDA recommendation, the current study is
restricted to adults.
• Paediatric patients will be included at a later date after
reviewing safety and efficacy data obtained in adults.
Gene manipulation and replacement
• Remove defective β gene and stimulate γ gene
• 5-azacytidine increases γ gene synthesis
Role of surgery in thalassemia
• Cholelithiasis – Cholecystectomy
• Choledocholithiasis – Choledocholithotomy
• Cirrhosis (due to iron overload) – Liver biopsy and liver
transplantation
• Leg ulcer – Surgical dressing
• Pathological fracture – Surgical correction
• Spinal cord compression - Laminectomy
Other supportive measures
• Tea – thebaine and tannins– chelate iron
• Vitamin C – increases iron excretion
• Restrict Fe intake – decrease meat, liver, spinach
• Folate – 1 mg/day
• Genetic counselling
• Psychological support
• Hormonal therapy – GH, estrogen, testosterone,L-thyroxine
• Treatment of CCF
Follow up
Monthly:
• Complete blood count
• Complete blood chemistry (including liver function tests, BUN,
creatinine) if taking deferasirox
• Record transfusion volume.

Every 6 months:
• Complete physical examination including Tanner staging - Monitor
growth and development
• Dental examination
Every year:
• Cardiac function – echocardiograph, ECG, Holter monitor (as indicated)
• Endocrine function (TFTs, PTH, FSH/LH, fasting glucose,
testosterone/estradiol, FSH, LH, IGF-1, Vitamin D levels)
• Ophthalmological examination and auditory acuity
• Viral serologies
• Bone densitometry
• Ongoing psychosocial support.
Every 2 years:
• Evaluation of tissue iron burden
• Liver iron measurement – R2 MRI, SQUID, or biopsy
• T2* MRI measurement of cardiac iron (age .10 years).
Prevention and control
Prevention and control
• Career detection/Screening
• Genetic counseling
• Prenatal diagnosis
• Health education
Screening
• RBC indices (MCV, MCH, MCHC)
• HbA2
Automated CBC:
• Thalassemic red cells are microcytic and hypochromic
• WHO recommends MCV <77fl and MCH <27 pg as screening tools to
pick up cases for confirmation by electrophoresis
• DCIP (Di Chloro phenol indol phenol): Screening for HbE
• NESTROFT
NESTROFT

• Mass screening: NESTROFT (Naked Eye Single Tube Red Cell

Osmotic Fragility Test)
• Very cheap and easy to perform
• requires small amount of blood
• Based on principle that Thalassemic red cell resists hypotonic
solution more than that of normal person
• Give positive result on NESTROFT
• Sensitivity 90-98% and specificity 85-90%
Genetic counselling
• Index case parents and relatives.
• Antenatal visits of pregnant mothers.
Prenatal diagnosis
Chorionic Villus Biopsy
Prevention
• Antenatal diagnosis and Early intervention
• Preventing marriage b/w traits
Health education/awareness
• Knowledge of genetic nature of thalassemia
• Transmission of the disease
• Ways to avoid to have further child with the disease
• Awareness about economic burden to the family and govt.
Prognosis
Thalassemia major-life expectancy:
• Without regular transfusion - Less than 10 years
• With regular transfusion and no or poor iron chelation - Less than 25
years
• With regular transfusion and good iron chelation – 40 years, or
longer?
• The commonest cause of death is iron overload
Thalassemia minor/ trait:
• Hb : Normal or mildly reduced - MCV/ MCH reduced
• PBS- anisopoikilocytosis, microcytosis,hypochromia,target cells
• Serum bilirubin- Normal or mildly raised
Hb electrophoresis
• HbA2: 3.5- 7 %
• Hb A: 90-95 %
• Hb F: 1-5 %
• Moderate reduction of β-chain synthesis
• Treatment : Counselling- treatment usually not required
Thalassemia and blood donation
• Thalassemia minor (trait) can donate blood, if the
hemoglobin is normal.

• Hemoglobinopathies with established hemolysis, should

be permanently defered.
Thalassemia day
• 8th May is the international Thalassemia Day.
• This day is dedicated to Thalassemia, to raise public awareness for
prevention of Thalassemia and to highlight the importance of clinical
care for Thalassemia patients in all countries.
Thank You