5th-year medical student seminar presentation under the supervision of Dr. Nuraini, a specialist.

1. T H A L A S S E M I A
P R E S E N T E D B Y
A U D I A D I B A H R A H M A N
N I K N O R L I Y A N A

2. INTRODUCTION
THALASSEMIA
1930: from Greek thalassa ‘great sea’ (because the disease was first
known around the Mediterranean Sea)

3. INTRODUCTION
WHAT IS THALASSEMIA?
Thalassemia is a group of hemoglobin disorders in which the production of
normal hemoglobin is partially or completely suppressed as a result of a
defective synthesis of one or more globin chains.
Thalassemia is inherited by autosomal recessive
Hemoglobin
Heme
Globin (thalassemia)
Fe (iron deficiency anemia)
Protophorphyrin (sideroblastic anemia)

4. INTRODUCTION

5. EPIDEMIOLOGY

6. HEMOGLOBIN
H E M O G L O B I N A
H E M O G L O B I N A 2
H E M O G L O B I N F
 2α and 2β chains forming a tetramer
 97% of adult hemoglobin
 Post-natal life, HbA replaces HbF by 6 months
 2α and 2δ chains
 1.5 to 3% of adult hemoglobin
 2α and 2γ chains
 1% of adult hemoglobin
 70 – 90% at term and falls to 25% by first month and progressively
The oxygen carrying capability of the red blood cells (RBCs) relies on hemoglobin, a tetramer protein
that comprises 4 globin chains bound to the heme molecule.
There are 4 major types of globins: alpha (α), beta (β), gamma (γ), and delta (δ).
α
α
α
α
α
α
β
β
δ
δ
γ
γ

7. THALASSEMIA
α
β
T H A L A S S E M I A
1. Silent carrier
2. Trait (minor)
3. HbH Disease (Intermediate)
4. Hb Bart’s (Major)
1. Trait (minor)
2. Intermedia
3. Cooley’s anemia (Major)

8. a-THALASSEMIA
a - t h a l a s s e m i a
 Gene deletion
 Deficient / absent of alpha subunits
o Excess beta subunits
o Excess gamma subunits in newborns
 Encoding genes on chromosomes 16
 Has 4 copies of the alpha globin gene where each gene is responsible for ¼
production of alpha globin

9. a-THALASSEMIA
C L A S S I F I C AT I O N
C L A S S I F I C A T I O N G E N O T Y P E N O . O F G E N E S P R E S E N T
Silent carrier a a / - a 3
α-thalassemia trait - a / - a or a a / - - 2
Hemoglobin H - a / - - 1
Hb Bart’s / Hydrops fetalis - - / - - 0
n o r m a l s i l e n t c a r r i e r
α - t h a l a s s e m i a t r a i t
H e m o g l o b i n H
H b B a r t ’ s / H y d r o p s f e t a l i s

10. β -THALASSEMIA
 Gene mutation
 β0 refers to the complete absence of production of β-globin
on the affected allele
 β+ refers allele with some residual production of β-globin
(around 10%)
 Encoding genes on chromosomes 11
 Synthesis of β-globin is controlled by 2 genes
β- t h a l a s s e m i a

11. β -THALASSEMIA

12. β -THALASSEMIA
C L A S S I F I C AT I O N
A n a b s e n c e o r d e f i c i e n c y o f β c h a i n s y n t h e s i s o f a d u l t H b A
β- t h a l a s s e m i a m i n o r
Loss of ONE gene – thalassemia minor trait
N o r m a l M i n o r t r a i t I n t e r m e d i a
β- t h a l a s s e m i a m i n o r
Loss of BOTHS genes – thalassemia intermedia and major
 β+β+ or β0β+ (thalassemia intermedia)
 β0β0 (thalassemia major)
M a j o r
β0 β0β+ β+β β+
β β β0 β+

13. APPROACH
History taking
Physical findings
Lab investigations
 Symptoms of anemia
 Positive family history
 History of blood transfusion
 Failure to thrive
Features of
1. Severe anemia
2. Ineffective erythropoiesis
3. Extra medullary
hematopoiesis
4. Iron overload resulting
from transfusion and
increased iron absorption.
5. Complications

14. CLINICAL PRESENTATION
T H A L A S S E M I A M I N O R
 Usually asymptomatic / mild pallor
 May present as iron deficiency anaemia (hypochromic
microcytic anaemia)
 Mild persistent anemia not responding to hematinic
 Normal life expectancy

15. CLINICAL PRESENTATION
G E N E R A L F E AT U R E S
 Pallor
 Fatigue
 Dyspnea on exertion
 Poor apetite
 Palpitations
 Poor growth
E X C E S S I V E E R Y T H R O P O E I S I S
 Maxillary overgrowth (chipmunk)
 Increased spaces, overbite and
malocclusion of teeth
 Frontal bossing
 Chronic sinusitis
 Impaired hearing
F E AT U R E S O F H E M O LY S I S
 Jaundice
 Hyperuricaemia (Gout)
 Gallstones
T H A L A S S E M I A M A J O R

16. CLINICAL PRESENTATION
B O N E C H A N G E S
 Medullary expansion – cortical
thinning, risk of pathological
fracture
 Bone pain, backache
 Vertebral expansion lead to spinal
cord compression – neurological
manifestations
E X T R A M E D U L L A R Y
 Hepatomegaly
 Spleenomegaly
E X C E S S I V E E R Y T H R O P O E I S I S

17. CLINICAL PRESENTATION
E N D O C R I N E F A I L U R E
 Short stature
 Delayed puberty
 Estrogen / testosterone deficiency
 Diabetes mellitus
 Hypoparathyroidism
C A R D I A C I N V O LV E M E N T
 Arrhythmia
 Cardiomyopathy
 Pericarditis
 CCF
I R O N O V E R L O A D
H E PAT I C I N V O LV E M E N T
 Cirrhosis
 Hepatic fibrosis
H Y P E R C O A G U L A B L E D I S E A S E
 Deep vein thrombosis
 Pulmonary embolism

18. CLINICAL PRESENTATION

19. DIFFERENTIAL DIAGNOSIS
A NE MIA O F CHRO NIC DIS EA S E A ND R E NA L FA ILUR E
IRON DE FICIENCY ANE MIA
LEA D NE PHRO PATHY
S IDE RO BLA STIC A NE MIA S

20. DIAGNOSIS
i. Clinical features
ii. Lab investigations
iii. Screening family members
i. Confirm the diagnosis
ii. Exclusion of other differential diagnosis
iii. To find the cause of anemia
iv. To assess the complications
v. For further management
DIAGNOSIS IS BASED ON:
AIMS OF INVESTIGATIONS

21. CLINICAL OUTCOMES OF
a-THALASSEMIA
S I L E N T C A R R I E R S
a - T H A L A S S E M I A M I N O R ( T R A I T )
a - T H A L A S S E M I A I N T E R M E D I A ( H E M O G LO B I N H )
 Asymptomatic
 No anemia
 Microcytosis
 Anemia and microcytosis
 Bone deformities
 Splenomegaly

22. H E M O G LO B I N C O N S TA N T S P R I N G
a - T H A L A S S E M I A M A J O R
 Similar to HbH but no microcytosis
 Anemia
 Growth delay
 Hemoglobin Bart’s
 Fatal hydrops fetalis
CLINICAL OUTCOMES OF
a-THALASSEMIA

23. CLINICAL FEATURES LABORATORY FEATURES
THALASSEMIA
MAJOR
 Anemia
 Hepatosplenomegaly
 Growth failure
 Hb : < 7 g/dL
 HbF : > 90%
 HbA2: normal or high
 HbA : usually absent
THALASSEMIA
INTERMEDIA
 Milder anemia
 Thalassemia facies
 Hepatosplenomegaly
 Hb : < 8-10 g/dL
 HbF : > 10%
 HbA2: 4-9%, if > 10% suggests HbE
 HbA : 5-90%
b THALASSEMIA
TRAIT
 Normal to mild anemia
 No organomegaly
 Hb : < 10 g/dL
 MCH : < 27 pg
 HbF : > 2.5-5%
 HbA2: 4-9%, if >20% suggests HbE
trait
 HbA : > 90%
DIAGNOSTIC CRITERIA

24. ALGORITHM FOR SCREENING OF
THALASSEMIA IN MALAYSIA
Screening blood test (FBC/ RBC
indices)
Normal
Suspected thalassemia
carrier
Confirmatory blood test
Normal THALASSEMIA CARRIER
For family screening

25. LABORATORY FINDINGS
 Normal red blood cells
 They have a zone of central pallor about 1/3 the size of RBC
 RBC’s demonstrate minimal variation in size (anisocytosis) and shape (poikilocytosis)
 A few small fuzzy blue platelets are seen
 In the center of the field are a band neutrophil on the left & a segmented neutrophil
on the right

26. LABORATORY FINDINGS
 Smaller size of RBC
 Increase zone of center pallor
 Indicative of hypochromic and microcytic anemia
 Increase anisocytosis and poikilocytosis
LABORATORY FINDINGS

27. LABORATORY FINDINGSLABORATORY FINDINGS

28. LABORATORY FINDINGSLABORATORY FINDINGS

29. BASELINE INVESTIGATIONS
F U L L B L O U D C O U N T/ P E R I P H E R A L B L O O D F I L M
H B A N A LY S I S / H I G H P E R F O R M A N C E L I Q U I D C H R O M AT O G R A P H Y
( H P L C )
S E R U M F E R R I T I N
R E D C E L L P H E N O T Y P I N G
D N A A N A LY S I S
L I V E R F U N C T I O N T E S T
I N F E C T I O N S C R E E N
H L A T Y P I N G
BASELINE INVESTIGATIONS

30. INVESTIGATIONS
E XCLUS IO N O F OTHE R DIF F E R E NTIA L DIAGNO S IS
I R O N S T U D I E S
 To distinguish mild microcytic anemia due to b-thalassemia carrier state from any
other causes
 Iron studies are useful in excluding iron deficiency and the anemia of chronic
disorders as the cause of patient’s anemia
M E N T Z E R I N D E X
 Calculation of Mentzer index (mean corpuscular volume per red cell count) may be
helpful
 <13 suggests patient has thalassemia trait
 >13 suggests patient has iron deficiency

31. TRANSFUSION REQUIREMENT

32. TRANSFUSION-DEPENDENT
THALASSEMIA
Regular maintenance blood transfusion and iron chelation
therapy is the mainstay of treatment in this patient
b THALASSEMIA MAJOR
When to start blood transfusion ?
 After completing blood investigations for confirmation of diagnosis
 Hb < 7 g/dL on 2 occasions > 2 week apart (in absence other factors e.g.
infection)
 Hb > 7 g/dL in b+ thalassemia major/severe forms of HbE-b-thalassemia
if impaired growth, severe bone changes, enlarging liver and spleen

33. TRANSFUSION DEPENDENT
THALASSEMIA
Transfusion target
 Maintain pre-transfusion Hb level at 9-10 g/dL
 Keep mean post-transfusion Hb at 13.5-15.5 g/dL
 Keep mean Hb 12-12.5 g/dL
The above targets allow for normal physical activity and
growth, abolishes chronic hypoxemia, reduce
compensatory marrow hyperplasia which causes
irreversible facial bone changes and para-spinal masses
TRANSFUSION-DEPENDENT
THALASSEMIA

34. TRANSFUSION DEPENDENT
THALASSEMIA
Transfusion interval
 Usually 4 weekly interval (usual rate of Hb decline is at 1 g/dL/week)
 Interval varies from individual patients (range from 2 to 6 weekly)
Transfusion volume
 Volume: 15-20 mls/kg (maximum) packed red cells (PRBC)
 In the presence of heart failure or Hb < 5 g/dL, use lower volume PRBC (
< 5 ml/kg) at slow infusion rate over > 4 hours with IV Frusemide 1 mg/kg
(20 mg maximum dose)
 It is recommended for patients to use leucodepleted (pre-storage, post
storage or bedside leucocyte filters) PRBC < 2 weeks old
 It will minimize non-hemolytic febrile reactions and alloimmunization by
removing white cells contaminating PRBC
TRANSFUSION-DEPENDENT
THALASSEMIA

35. Regular maintenance blood transfusion and iron chelation
therapy is the mainstay of treatment in this patient
a THALASSEMIA (HbH DISEASE)
 Transfuse only if Hb persistently < 7 g/dL and/or symptomatic
TRANSFUSION-DEPENDENT
THALASSEMIA

36. IRON CHELATION THERAPY
DFO: DESFERRI OXAMI NE (DESFERAL®)
DF P: DEF ERI PRONE (F ERRI PROX® /KEL F ER®)
DFX: DEF ERASI ROX (EXJADE® )

37. IRON CHELATION THERAPY
DFO: DESF ERRI OXAMI NE (DESF ERAL ® )
WHEN TO START ?
 Usually when the child is > 2-3 years old
 When serum ferritin reaches 1000 mg/L
 Usually after 10-20 blood transfusions
DOSAGE & ROUT E
 Average daily dose is 20-40 mg/kg/day
 By S/C continuous infusion using a portable pump over 8-10 hours daily, 5-7
nights a week
COMPLI CATI ONS
 Local skin reaction
 Yersinia infection
 Ocular/auditory toxicity
 Skeletal lesion

38. DFP DFX
 An alternative if iron chelation is
ineffective on inadequate despite
optimal Desferal® use, or if Desferal®
use is contraindicated
 Deferiprone is given 75-100 mg/kg/day
in 3 divided doses
 Can also be used in combination with
Desferal®, using a lower dose of 50
mg/kg/day
 Risks of GI disturbance, arthritis and
rare occurance of idiopathic
agranulocytosis
 Stop if neutropenic ( < 1500/mm3)
 Can also be used for transfusion iron
overload in patients 2 years or older
 Expensive
 The dose is 20-30 mg/kg/day in liquid
dispersible tablet, taken once daily
 There are risks of transient skin rash,
GI disturbance and a reversible rise in
serum creatinine

39. ORGANS THAT MAY BE
AFFECTED BY IRON OVERLOAD
IRON OVERLOAD
Capacity of serum transferrin to
bind iron is exceeded
Non-transferrin-bound iron
circulates in the plasma
Excess iron promotes the generation of
free hydroxyl radicals, propagators of
oxygen-related tissue damage
Insoluble iron complexes are
deposited in body tissues and
end organ toxicity occurs
Cardiac
failure
Liver cirrhosis/
fibrosis/ cancer
Diabetes
mellitus
Infertility Growth failure

40. DEGREE OF IRON OVERLOAD
M I L D M O D E R AT E S E V E R E
Serum ferritin (mg/L) < 2500 2500 – 5000 > 5000
LIC (mg Fe/g DW) < 7 7 – 15 > 15
Cardiac T2* MRI (ms)  20 10 – 20 < 10

41. SPLENECTOMY
I NDI CAT I ONS
 Blood consumption volume of pure RBC > 1.5X normal or > 200-220
mls/kg/year in those > 5 years of age to maintain average hemoglobin
levels
 Evidence of hypersplenism

42. PATIENT MONITORING
ASSESSMENT AND INVESTIGATIONS
BLOOD INVESTIGATION
 HbsAg
 Anti HCV
 Anti HIV 6 monthly
GROWTH
 Weight
 Height
 3 to 6 monthly
IRON OVERLOAD
 Serum ferritin 3 monthly
 Patient > 10 years old:
i. ECG, ECHO annually
ii. LIC MRI 1-2 yearly
iii. Cardiac MRI T2 1-2 yearly
DRUG TOXICITY
 DFO: auditory/ophthalmology annually
 DFP: FBC weekly, ALT 3 monthly
 DFX: RFT, LFT, urine protein monthly,
auditory/ophthalmology annually

43. PATIENT MONITORING
ASSESSMENT AND INVESTIGATIONS
COMPLICATIONS
(especially in > 10
years old)
I. Growth failure
DM, hypothyroidism, delayed puberty, bone
disorder
II. Delayed puberty, hypogonadism
Tanner staging 6 monthly
LH, FSH, estradiol/testosterone
III. Hypothyroidism: TFT
IV. Diabetes mellitus: FBS, OGTT
V. Osteoporosis/osteopenia
Serum Ca, PO4, ALP, X-ray, DEXA scan
VI. Hypoparathyroidism: PTH
VII. Hypoadrenalism
Baseline morning cortisol
ACTH stimulation test

44. MANAGEMENT OF
COMPLICATIONS
TREATMENT CRITERIA TREATMENT
HEPATITIS B
I. HBsAg positivity > 6 months AND
II. Serum HBV DNA > 20 000 IU/ml (105
copies/ml) in HBeAg positive cases,
serum HBV DNA > 2000 IU/ml (104
copies/ml) in HBeAg negative cases
AND
III. Persistent or intermittent elevation in
ALT/AST levels, > 2x upper limit of
normal or significant liver disease on
liver biopsy
 Interon a (IFN a) for 4-6 months for
HBeAg positive patients and at least a
year for HBeAg negative patients OR
 Peg-IFN for at least 6 months for HBeAg
positive patients and 12 months for
HBeAg negative patients OR
 Lamivudine

45. MANAGEMENT OF
COMPLICATIONS
TREATMENT CRITERIA TREATMENT
HEPATITIS C
I. Persistent antiHCT positivity > 6
months AND
II. Serum HCV RNA positivity (regardless
of viral titre) AND
III. Significant liver disease on liver
biopsy
 Combination therapy (either
conventional or PEG-IFN) with ribavirin
 Treatment duration depends on HCV
genotype
BACTERIAL INFECTIONS
I. Significant fever especially post-
splenectomy
 Stop iron chelation therapy
 Broad spectrum anti-Klebsiella and anti-
Pseudomonal agents

46. MANAGEMENT OF
COMPLICATIONS
TREATMENT CRITERIA TREATMENT
CARDIAC SIDEROSIS
Asymptomatic, mild to moderate cardiac
siderosis and normal cardiac function
Intensity iron chelation monotherapy or
switch to combination therapy
Symptomatic or severe cardiac iron
overload
Appropriate cardiac therapy, continuous IV
DFO or combination therapy
DELAYED PUBERTY
Absence of pubertal changes at 13 years
old (girls) and 14 years old (boys)
 Girls: Oral ethinyl oestradiol or
conjugated estrogen preparation
 Boys: Depot testosterone

47. MANAGEMENT OF
COMPLICATIONS
TREATMENT CRITERIA TREATMENT
SHORT STATURE
 Treat other causes of short stature
 Growth hormone injection may be
considered if confirmed growth hormone
deficiency
DIABETES MELLITUS Subcutaneous insulin injection
HYPOTHYROIDISM (primary or central) Oral L-thyroxine
OSTEOPOROSIS/OSTEOPAENIA
 Oral calcium and Vitamin D supplements
 Biphophonates may be considered in
osteoporosis
HYPOPARATHYROIDISM Oral calcitriol and calcium
HYPOADRENALISM Oral hydrocortisone

48. DIET AND SUPPLEMENTS
 Oral folate at minimum 1 mg daily
 Low dose Vitamin C at 3 mg/kg augments iron excretion for
those on Desferral only. Dose:
i. < 10 years: 50 mg daily
ii. > 10 years: 100 mg daily given only on desferral days
 Avoid iron rich food such as red meat and iron fortified cereals
or milk
 Tea may help decrease intestinal iron absorption
 Dairy products are recommended as they are rich in calcium
 Vitamin E as antioxidant
 Calcium and zinc

49. BONE MARROW
TRANSPLANTATION
 Potential curative option when there is an HLA-compatible
sibling donor
 Results from matched unrelated donor or unrelated cord blood
transplant are still inferior with higher morbidity, mortality and
rejection rates
 Classification of patients into PESARO risk groups based on the
presence of 3 risk factors:
i. Hepatomegaly > 2cm
ii. Irregular iron chelation
iii. Presence of liver fibrosis
 Best results if performed at the earliest age possible in Class
1 patients

50. BONE MARROW
TRANSPLANTATION
PESARO RISK GROUPS AND OUTCOME FOLLOWING BMT
CLASS
NO. OF RISK
FACTORS
EVENT FREE
SURVIVAL %
MORTALITY
%
REJECTION %
1 0 91 7 2
2 1-2 83 13 3
3 3 58 21 28
Adults - 62 34 -

51. INDEX CASE:
DIAGNOSIS
CONFIRMED
Consider stem
cell
transplantation
Genetic counselling
Family cascade
screening
Dietary advice
REGULAR TRANSFUSION THERAPY:
 Use leucodepleted PRBC < 14 days old
 Pre transfusion Hb: 9-10 g/dL
 Post transfusion Hb: 13.5-15.5 g/dL
Monitor for transfusion
related complications:
 Hepatitis B
 Hepatitis C
 HIV
Monitor for iron
overload:
 Serum ferritin
 Liver iron
concentration
 Cardiac T2*
Iron chelation therapy:
 Desferrioxamine
 Deferiprone
 Deferasirox
 Combination therapy
Monitor for side effects
of chelators
Monitor for
complications:
 Cardiac
 Infections
 Endocrine
 Hypersplenism
Has
unaffected
siblings

52. TAKE HOME MESSAGES
WHAT I S T HAL ASSEMI A?
GENET I C T RANSMI SSI ON AND VARI AT I ONS
FAMI LY SCREENI NG
PAT I ENT EDUCAT I ON AND COMPL I ANCES
COMPLI CATI ONS

53. REFERENCES