1. The ThalassaemiasThe Thalassaemias
DR.RAFI AHMED GHORI
Professor
Medical Unit I1
LUMHS Jamshoro.

2. 

3. HaemoglobinHaemoglobin

4. Haemoglobin SynthesisHaemoglobin Synthesis

5. HISTORICAL INTRODUCTIONHISTORICAL INTRODUCTION
 FIRST RECOGNIZED in 1925 by
Thomas B. Cooley in
Series of infants profoundly anaemic with
splenomegaly during first year of life.
 VARIOUSLY CALLED
von Jaksch's anaemia, splenic anaemia,
erythroblastosis, Mediterranean anaemia,
or Cooley's anaemia.
 IN 1936 GEORGE WHIPPLE AND LESLEY
BRADFORD, invented the word THALASSAEMIA
from the Greek for Mediterranean Sea.

6. DEFINITIONDEFINITION
HETEROGENEOUS group of
GENETIC disorders of
HAEMOGLOBIN SYNTHESIS, all
of which result from
a REDUCED RATE of production
of one or more of the GLOBIN
CHAIN(S) OF HAEMOGLOBIN.

7. CLASSIFICATIONCLASSIFICATION
GENETICALLY
α-THALASSAEMIAS
 α+
β-THALASSAEMIAS
 βº
 β+
δβ-THALASSAEMIA
 (δβ) º
 Haemoglobin Lepore (δβ) +
(εγδβ) º-THALASSAEMIA
δ-THALASSAEMIA
CLINICALLY
Thalassaemia major
 Severe transfusion
dependent.
Thalassaemia
intermedia
 Anaemia and
Splenomegaly
 Does not require
regular transfusion.
Thalassaemia minor
 Symptomless carrier
state

8. β-THALASSAEMIASβ-THALASSAEMIAS
TYPE OF
THALASSAEMIA
FINDINGS IN
HOMOZYGOTE
FINDINGS IN
HETEROZYGOTE
βº Thalassaemia major
Hbs F & A2
Thalassaemia minor
Raised Hb A2
β+ Thalassaemia major
Hbs F, A &A2
Thalassaemia minor
Raised Hb A2
δβ Thalassaemia intermedia
Hb F only
Thalassaemia minor
Hb F5-15%; HbA2 normal
(δβ)+(Lepore) Thalassaemia major or
intermedia
Hbs F and Lepore
Thalassaemia minor
Hb F5-15%; HbA2 normal
εγδβ Not viable Neonatal haemolysis
Thalassaemia minor in adults,
Normal Hbs F & A2

9. β-THALASSAEMIASβ-THALASSAEMIAS
Most important types of thalassaemia
DISTRIBUTION
Mediterranean,parts of north and
west Africa,Middle East,Indian
subcontinent, South-East Asia.
HIGH-INCIDENCE ZONE:Yugoslavia and
Romania,southern parts of Russia,
southern regions of China.
Particularly common in South-East
Asia ,southern China,Thailand,Malay
peninsula,Indonesia ,Pacific island
populations.

10. MOLECULARMOLECULAR PATHOLOGYPATHOLOGY
 over 100 different
mutations.
 Complete
inactivation of
the β-globin genes
leading to the
phenotype of βº-
thalassaemia
 Reduced output
from the genes and
hence the picture
of β+-
thalassaemia.

11. PATHOPHYSIOLOGYPATHOPHYSIOLOGY

12. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
CLINICAL FEATURESCLINICAL FEATURES
MOST SEVERE FORMS
present within the first year of life with
 Failure to thrive
 Poor feeding
 Intermittent bouts of fever
 Failure to improve after an intercurrent
infection.
 Affected infant looks pale
Splenomegaly is already present

13. THALASSAEMICTHALASSAEMIC
CHILDCHILD

14. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
CLINICAL FEATURESCLINICAL FEATURES
IN THE WELL-TRANSFUSED CHILD
 Normal early growth and development.
 Minimal Splenomegaly.
 Failure of growth spurt.
 Tissue siderosis.
Diabetes
Hypoparathyroidism.
Adrenal insufficiency.
liver failure.
Delayed or absent 2˚ sexual characters.
Short stature.
Psychological problems.
Progressive cardiac damage.

15. ThalassaemicThalassaemic
adultadult


16. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
CLINICAL FEATURESCLINICAL FEATURES
INADEQUATELY TRANSFUSED CHILD
 Retarded growth and development.
 Progressive splenomegaly
 Hypersplenism
(anaemia, thrombocytopenia and a bleeding tendency).
 Bossing of the zygomata giving rise to the
classical mongoloid facies.
 Recurrent fractures.
 Increased proneness to infection.
 Hyperuricaemia and secondary gout.
 Poorly formed teeth and malocclusion.
 Chronic sinusitis and deafness.
 Features of Iron overload in adults.

17. BOSSING
OF THE
ZYGOMATA
giving rise
to the
classical
mongoloid
facies.

18. X-RAYX-RAY
SKULLSKULL
Hair onHair on
SkullSkull

19. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
HAEMATOLOGICAL CHANGESHAEMATOLOGICAL CHANGES
 Severe anaemia.
 Hb values range from 2 to 8g/dl.
 RBCs are hypochromic and microcytic.
 MCH, MCV are reduced.
 Peripheral blood film shows
Marked hypochromia, Poiklocytosis, Hypochromic,
macrocytes, Misshapen microcytes, Anisochromia
Basophilic, stippling.
 Elevation in the reticulocyte count.
 The bone marrow shows marked erythroid
hyperplasia with a myeloid/erythroid
(M/E) ratio of unity or less.

20. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
BIOCHEMICAL CHANGESBIOCHEMICAL CHANGES
 Elevated bilirubin.
 Absent haptoglobins.
 Shortened 51Cr red-cell survival.
 Elevated serum iron.
 Totally saturated iron-binding capacity.
 High plasma ferritin level.
 liver biopsies show a marked increase in
iron both in the reticuloendothelial and
parenchymal cells.
 vitamin E and ascorbate depletion.
 Hyperglycemia(Frank diabetes).


21. SEVERESEVERE HOMOZYGOUSHOMOZYGOUS β-THALASSAEMIASβ-THALASSAEMIAS
HAEMOGLOBIN CHANGESHAEMOGLOBIN CHANGES
(Hb Electrophoresis)(Hb Electrophoresis)
ELEVATED Hb F .
IN βº-THALASSAEMIA
NO Hb A.
Hb consists of F and A2.
IN Β+-THALASSAEMIA
Hb F 30 to 90 %.
Hb A2 level is usually normal.


22. HETEROZYGOUS β-THALASSAEMIAHETEROZYGOUS β-THALASSAEMIA
 Usually symptom free.
 During stress (pregnancy),they may become
anaemic.
 Splenomegaly is rarely present.
HAEMATOLOGICAL CHANGES
 Mild anaemia with Hb levels 9 to 11g/dl.
 Hypochromia and microcytosis.
 Low MCH and MCV.
 Moderate erythroid hyperplasia.
HAEMOGLOBIN CHANGES
 Elevated Hb A2.(4 to 6% range).
 Slight elevation of Hb F in the 1 to 3% range
in about 50 per cent of cases.

23. β-THALASSAEMIA IN ASSOCIATIONβ-THALASSAEMIA IN ASSOCIATION
WITH HAEMOGLOBIN VARIANTSWITH HAEMOGLOBIN VARIANTS
Individuals inherit a β-thalassaemia gene
from one parent and a gene for a
structural Hb variant from the other.
SICKLE-CELL Β-THALASSAEMIA
HAEMOGLOBIN C THALASSAEMIA
HAEMOGLOBIN E Β-THALASSAEMIA
This is the most common severe form of
thalassaemia in South-East Asia.
Clinical picture can closely resemble
homozygous βº-thalassaemia.

24. BOSSING OFBOSSING OF
HEADHEAD
ININ
HAEMOGLOBIN EHAEMOGLOBIN E
Β-THALASSAEMICΒ-THALASSAEMIC
CHILDCHILD

25. THE δβ-THALASSAEMIASTHE δβ-THALASSAEMIAS
 Deletions of the β&δ-globin genes.
 Mispaired synapsis and unequal crossing
over (β&δ-fusion genes).
 β&δ-fusion chains + α-chains =
 Lepore haemoglobins.
HOMOZYGOTES
 Mild anaemia Hb(8 to 10g/dl).
 Moderate splenomegaly.
 Symptomless except during stress.
 Hb electrophoresis 100% Hb F.
CARRIERS
 Thalassaemic blood pictures.
 Hb F (5 to 20 %)and normal Hb A2.

26. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
Severe homozygous forms cause death
in utero or in the neonatal period
Milder forms do not produce major
disability.
DISTRIBUTION
Mediterranean region, parts of West
Africa, Middle East, isolated parts
of the Indian subcontinent,
throughout South-East Asia,
southern China, Thailand, Malay
peninsula, Indonesia, Pacific
island populations.

27. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
DEFINITION AND INHERITANCEDEFINITION AND INHERITANCE
IN THE FETUS,
 Deficiency of α-chains leads to the
production of excess γ-chains, which
form γ4-tetramers, or Hb Bart's.
 Homozygous inheritance of αº-thalassaemia
IN ADULTS,
 Deficiency of α-chains leads to an
excess of β-chains which form β4-
tetramers, or Hb H.
 Coinheritance of both αº- and α+
-thalassaemia.

28. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
TYPE HOMOZYGOTES HETEROZYGOTES
αº Hb Bart’s hydrops Thalassaemia minor
α+(deletion) Thalassaemia minor Normal blood picture
α+(non-
deletion)
Hb H disease Normal blood picture

29. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
FETUS ADULT
Normalα2γ2
Hb F
α2β2
Hb A
α-Thalassaemiaα2 γ2 α2 β2
excess excess
γ4
β2
Hb Bart’s Hb H
HIGH O2 AFFINITY HIGH O2 AFFINITY
Unstable InclusionsHYPOCHROMIA
HEMOLYSIS
HYPOXIA

30. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
The Hb Bart's hydrops syndromeThe Hb Bart's hydrops syndrome
CLINICAL PICTURE
 Stillbirth b/w 28 and 40
wks.
 HYDROPS FETALIS
gross pallor,
generalized oedema,
massive hepatosplenomegaly.
 Very large, friable
placenta.
 Hb is 6 to 8g/dl.
 Nucleated RBCs on blood
COMPLICATIONS
Fetal death
Toxaemia of
pregnancy
Obstetric
difficulties
No α-chains at all.
Neither fetal nor adult haemoglobin.
Common cause of fetal loss.

31. HYDROPSHYDROPS
FETALISFETALIS

32. THE α-THALASSAEMIASTHE α-THALASSAEMIAS
Haemoglobin H diseaseHaemoglobin H disease
 αº-thalassaemia from one parent and
 α+ from the other.
CLINICAL FEATURES
•variable degree of
anaemia, splenomegaly
•Bone changes unusual.
•survive into adult life.
•Hypersplenism
Haemolysis,infection,
worsening of the anaemia.
•Sulphonamides may ppt
the anaemia
HAEMATOLOGICAL CHANGES
•Hb 7 to 10g/dl.
•Thalassaemic changes
on blood film.
•Reticulocytosis
•Inclusion bodies on
brilliant cresyl blue.
•5 to 40 per cent Hb
H,Hb A,normal or
reduced level of Hb
A2.

33. Haemoglobin H diseaseHaemoglobin H disease
(Poiklocytosis,Target cells,Anisocytosis,Pallor
red cells)

34. α-THALASSAEMIAS TRAIT withα-THALASSAEMIAS TRAIT with
GOLF BODIESGOLF BODIES

35. MarrowMarrow
ExpansionExpansion
inin
ThalassaemicThalassaemic


36. Fractures in aFractures in a
ThalassaemicThalassaemic

37. OTHER FORMS OFOTHER FORMS OF
α -THALASSAEMIAα -THALASSAEMIA
α-THALASSAEMIA/MENTAL RETARDATION
(ATR) SYNDROMES
ATR 16.
ATRX.
HAEMOGLOBIN H AND LEUKAEMIA

38. THALASSAEMIA INTERMEDIATHALASSAEMIA INTERMEDIA
DEFINITION AND PATHOGENESISDEFINITION AND PATHOGENESIS
NOT transfusion dependent.
Much more severe anaemia than carriers for α- or
β-thalassaemia.
Hb C or E thalassaemia, the various δβ-
thalassaemias and haemoglobin Lepore disorders
can result in Thalassaemia Intermedia.
α- thalassaemia determinant inheritance as well as
being homozygous for β- thalassaemia.
Reduced degree of globin-chain imbalance with
reduced severity of the dyserythropoiesis.

39. Thalassaemia intermediaThalassaemia intermedia
CLINICAL FEATURES
May be virtually symptom-free, with moderate
anaemia.
Other have Hb 5 to 7g/dl with
• Marked splenomegaly,
• Severe skeletal deformities
• Heavily iron-loaded
• Recurrent leg ulceration
• Folate deficiency
• Extramedullary haemopoietic tumour masses.
• Gallstones
• Infection

40. ExtramedullaryExtramedullary
haemopoietichaemopoietic
tumour masses.tumour masses.

41. BLOOD FEATURES inBLOOD FEATURES in
Thalassaemia intermediaThalassaemia intermedia

42. THE LABORATORY DIAGNOSISTHE LABORATORY DIAGNOSIS
OF THALASSAEMIAOF THALASSAEMIA
Blood Complete Picture
 Serum Fe , Ferritin, TIBC.
Hb ELECTROPHORESIS.
Bone Marrow Biopsy.
X-Rays Skull, Chest, Spine, Long Bones
etc….
U/S Abdomen.

43. PREVENTIONPREVENTION
 genetic counselling about the choice of
marriage partners at antenatal clinics.
 Prenatal diagnosis
PRENATAL DIAGNOSIS
 Globin-chain synthesis studies of fetal
blood samples obtained by fetoscopy at
18 to 20 weeks of gestation.
 Fetal DNA analysis on amniocentesis.
 Direct analysis of fetal DNA obtained by
chorion biopsy at about the tenth week
of gestation.

44. TREATMENTTREATMENT
REGULAR BLOOD TRANSFUSION
of either washed or frozen red cells,
every 6 to 8 weeks to maintain the Hb
b/w 9 and 14g/dl.
SPLENECTOMY
if hypersplenism develops.
 Chelating agents, DESFERRIOXAMINE
30 to 40mg/kg as an overnight infusion
lasting 8 to 12h. using a butterfly
needle placed subcutaneously in the
anterior abdominal wall.

45. TREATMENTTREATMENT
ORAL CHELATING AGENTS.
HYDROXYUREA for raising
fetal haemoglobin production
BMT 80 per cent chance of
curing the disease.

46.  Q NO-2 A 16 year old boy was admitted to hospital with 3 day
history of pain abdomen and jaundice. It was proceeded by sore throat,
fever and myalgia. He had experienced similar episodes at the age 6,
12 and 14 and on each occasion he had made uneventful recovery. His
temperature was 390 C. he had mild jaundice, pallor, congested throat
and spleen palpable 5 cm below the left costal margin. Rest of
examination was normal. Laboratory investigation: Blood – Hb 9.8
g/dl, WBC 6400/cmm. Platelet 10000/cmm, mono spot test – negative,
serum bilirubin 33 mmol/L, ALT 23 iu/L, urine urobilinogen +++.
 What type of jaundice is he suffering from?
 List four possible causes.
 List four tests which you would like to do?

47. THE ENDTHE END
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