5. DEFINTION
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
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7. STRUCTURE OF HEMOGLOBIN
• Hb is a spherical molecule consisting of 4 peptide
subunits (globins) = quartenary structure
(tetramer)
• Hb of adult (Hb A) is a tetramer consisting of 2
alfa- and 2 β-globins → each globin contains 1
heme group with a central Fe2+ ion (ferrous ion)
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8. Hemoglobin consists of two parts
1. Globin 96%
2. Heme 4%
Heme portion: Heme portion is
synthesized mainly from acetic acid and
glycine in the mitochondria of young RBC
Globin portion: Globin is composed of
four large polypeptide chains. Globin is
synthesized by ribosomes
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9. SYNTHESIS OF GLOBIN
Various types of globin combines with
haem to form different haemoglobin
Eight functional globin chains, arranged
in two clusters i.e,
- cluster (, , and globin “E” genes) on the
short arm of chromosome 11
- cluster ( and globin “Z” genes) on the short
arm of chromosome 16
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10. SYNTHESIS OF HAEM
Protoporphyrin ring with an iron
atom in centre
The main site is mitochondria
Mature red cell does not contain
mitochondria
10
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11. 3 major types of Hb
1. Adult Hb (Hb A) - 2 α and 2 β chains
forming a tetramer
• 97% adult Hb
• Postnatal life Hb A replaces Hb F by 6 months
2. Fetal Hb (HbF) – 2α and 2γ chains
• 1% of adult Hb
• 70-90% at term. Falls to 25% by 1st month and
progressively
3. Hb A2 – Consists of 2 α and 2 δ chains
• 1.5 – 3.0% of adult Hb
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12. INHERITANCE
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• Autosomal
recessive
• Beta thal - point
mutations on
chromosome 11
• Alpha thal -
gene deletions
on chromosome
16
13. Classification
• 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
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14. CLASSIFICATION OF
THALASSEMIA(type)
• α Thalassemia
• β Thalassemia
• γ Thalassemia
• δ Thalassemia
• δ β Thalassemia
• Hereditary
Persistence of Fetal
Hb (HPFH)
• Hemoglobin Lepore
syndrome
• Sickle cell
Thalassemia
• Hb C Thalassemia
• Hb D Thalassemia
(Punjab)
• Hb E Thalassemia
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15. CLASSIFICATION OF β
THALASSEMIA(genetic)
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CLASSIFICATI
ON
GENOTYPE CLINICAL
SEVERITY
β thal
minor/trait
β/β+, β/β0 Silent
β thal
intermedia
β+ /β+, β+/β0 Moderate
β thal major β0/ β0 Severe
19. PATHOPHYSIOLOGY
• Since Beta chain synthesis reduced -
1. gamma 2 and delta δ2 alpha2 chain
combines to produce Hb F (α2 2) , Hb A2 (α2
δ2) - Increased production of Hb F and Hb A2
2. 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
• Finally results in anenia
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20. PATHOPHYSIOLOGY
Anemia due to 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 MARROW EXPANSION
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21. 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
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22. 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 hepatitis28 April 2014 22
23. SPLENOMEGALY
• Extra medullary hematopoeisis
• Work hypertrophy due to constant
hemolysis
• Hypersplenism (progressive
splenomegaly)
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25. INFECTIONS -CAUSES
• Increased iron in body
• Blockage of monocyte-macrophage
system
• Hypersplenism- leukopenia
• Infections associated with
transfusions
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26. ACCUMULATION OF IRON
• Deposition in pituitary - endocrine
disturbance - short stature, delayed
puberty, poor sec. sexual
characteristics
• Hemochromatosis - cirrhosis of liver
• Cardiomyopathy (cardiac hemosiderosis)
-cardiac failure,, arrythmias, heart
block, sterile pericarditis
• Deposition in pancreas -diabetes
mellitus
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27. ACCUMULATION OF IRON
• Adrenal insufficiency
• Hypothyroidism,
hypoparathyroidism
• Lungs: restrictive lung defects
• Increased susceptibity to
infections (iron favours bacterial
growth) espc : Yersinia infections
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28. CLINICAL FEATURES (THAL
MAJOR)
INFANTS:
• Age of presentation: 6-9 mo (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
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29. CLINICAL FEATURES (THAL
MAJOR)
BY CHILDHOOD:
Growth retardation
Severe anemia-cardiac
dilatation
Transfusion dependant
Icterus
Changes in skeletal system
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30. SKELETAL CHANGES
CHIPMUNK FACIES (HEMOLYTIC FACIES):
• Frontal bossing, maxillary hypertrophy, depression of
nasal bridge , Malocclusion of teeth
PARAVERTEBRAL MASSES:
• Broad expansion of ribs at vertebral attachment
• Paraparesis
PATHOLOGICAL FRACTURES:
• Cortical thinning
• Increased porosity of long bones
DELAYED PNEUMATISATION OF SINUSES
PREMATURE FUSION OF EPIPHYSES - Short
stature28 April 2014 30
31. Others
• Delayed menarche
• Gall-stones, leg ulcers
• Pericarditis
• Diabetes/ cirrhosis of liver
• Evidence of hypersplenism
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32. CLINICAL FEATURES (THAL
INTERMEDIA)
• Moderate pallor, usually maintains Hb
>6gm%
• Anemia worsens with infections
(erythroid stress)
• Less transfusion dependant
• Skeletal changes present, progressive
splenomegaly
• Growth retardation
• Longer survival than Thal major
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33. CLINICAL FEATURES (THAL
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 Fe therapy
• Normal life expectancy
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37. DIAGNOSIS
• T. bilirubin, I. bilirubin – increased
• S. Fe, ferritin elevated,
Transferrin –saturated
• B.M. study: hyperplastic
erythropoesis
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38. DIAGNOSIS
• Red cell survival – decreased
• Folate levels- concurrently
decreased
• Free erythrocyte porphyrin -
normal
• Serum uric acid-raised
• Haemosiderinuria
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39. IRON OVERLOAD
ASSESSMENT
• S. Ferritin
• Urinary Fe excretion
• Liver biopsy
• Chemical analysis of tissue Fe
• Endomyocardial biopsies
• Myocardial MRI indexes
• Ventricular function – ECHO, ECG
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40. Radiological changes
• Small bones (hand ) – earliest bony change,
rectangular appearance,medullary portion
of bone is widened &bony cortex thinned
out with coarse trabecular pattern in
medulla
• Skull – widened diploid spaces –
interrupted porosity gives hair on end
appearance
• Delayed pneumatization of sinuses –
maxilla appears overgrown with prominent
malar eminences
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41. X ray skull
“ hair on end”
appearance
or
“crew-cut”
appearance
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42. DIAGNOSIS – Hb
ELECTROPHORESIS
Thal. Major - Hb F: 98 %
Hb A2: 2 %
Hb A: 0 %
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HEMOGLOB
IN
MAJOR
MINOR NORMAL
Hb F 10-98% variable <1%
Hb A Absent 80-90% 97%
Hb A2 variable 5-10%
(increased)
1-3%
43. Treatment:
• Blood Transfusion at 4-6 wks
interval (Hb~ 9.5 gm/dl)
Packed RBCs are transfused
• (if we desired to maintain–Hb at
Hypertransfusion>10gm/dl,
• Supertransfusion : >12 gm/dl)
• 10-15ml/kg PRBC raises Hb by 3-
5gm/dl
• Neocytes transfusion
• If regular transfusions- no
hepatomegaly, no abnormalfacies
(but results in Iron over load)
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44. CHELATION THERAPY -
DESFERRIOXAMINE
• ( 1 unit of blood contains 250 mg iron)
• Iron-chelating agents: desferrioxamine-
• Dose: 30-60mg/kg/day
• IV / s/c infusion pump over 12 hr period
5-6 days /wk
• Start when ferritin >1000ng/ml
• Best >5 yrs
• Vitamin C 200 mg on day of chelation -
enhances DFO induced urinary excretion
of Fe
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46. 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
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47. TREATMENT - 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 (>180-200
ml/kg/yr) packed RBC
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48. BONE MARROW
TRANSPLANTATION
• BEST METHOD FOR CURE
• Risk factors:
Hepatomegaly >2cm
Portal fibrosis
Iron overload
Older age
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49. Newer therapies:
• GENE MANIPULATION AND REPLACEMENT
• Remove defective β gene and stimulate γ gene
• 5-azacytidine increases γ gene synthesis
• Hb F AUGEMENTATION
• Hydroxyurea
• Myelaran
• Butyrate derivatives
• Erythropoetin in Thal intermedia
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50. 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
28 April 2014 50
56. α-thalassemia:
• Deletion on alpha globin locus on
Chr 16
• Defective synthesis of α-globin
chain
• Excess of - chains - in the fetus
(Hb Bart- 4)
Excess of β-chains in the adult (Hb
H- β4)
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58. ALPHA THALASSEMIA
• Highest prevalence in Thailand
• α chains shared by fetal as well as adult
life. Hence manifests both times
• These thalassemias don‟t have ineffective
erythropoesis because β and γ are soluble
chains and hence not destroyed always
• α Thalassemia trait mimics Fe deficiency
anemia
• Silent carrier – silent – not identified
hematologically, diagnosed when progeny
has Hb Barts/ Hb H
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60. Hb H DISEASE
• Seen middle east
• Moderate anemia (Hb 8-9 gm/dl), mild
jaundice
• Splenomegaly, gall stones
• PBS similar to thal major
• Hb electrophoresis: Hb H 2-40 %; rest are
Hb A, HbA2, HbF
• Not very transfusion dependant
• Bony deformities
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61. Hb BARTS
• Hb Barts has γ4, then later in
infancy β4
• Severe hypoxia as Hb Barts has
high affinity for oxygen
28 April 2014 61
62. Haemoglobin Bart‟s:
• 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
• Increased incidence of toxemia
of pregnancy
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63. • DIAGNOSIS
• Hb electrophoresis:
80-90 % Hb Bart‟s
Hb H
Hb Portland
No Hb A, Hb A2 or Hb F
• Treatment: immediate exchange
transfusion
28 April 2014 63
64. DIAGNOSIS OF α
THALASSEMIA
• CBC, PS, BM study
• Heinz bodies in HbH disease – brilliant
cresyl blue
• Hb electrophoresis – for HbH and Hb
Barts
• α/β chain ratio decreased
28 April 2014 64
65. Treatment:
• Generally not reqd
• Blood transfusion , iron chelation
therapy – For transfusion dependent
cases
• Avoidance of oxidant drugs
• Prompt treatment of infections
• Folic acid supplementation
• Splenectomy
• BM transplantation, gene therapy
28 April 2014 65
