Thalassemia syndromes are quantitative defects in globin chain synthesis where heme synthesis is normal. The main types are alpha and beta thalassemia. Alpha thalassemia involves reduced alpha globin chain synthesis leading to excess non-alpha chains forming abnormal hemoglobins like HbH and Hb Barts. Beta thalassemia involves reduced beta chain synthesis. This causes imbalanced globin chain production and hemolysis. The severity depends on the number of affected globin genes and can range from thalassemia minor to major. Thalassemia major requires lifelong blood transfusions.

1. Thalassemia Syndromes
Dr.CSBR.Prasad, M.D.,

2. Thalassemias
• They are QUANTITATIVE defects in globin
chain synthesis
• Heme synthesis is normal

3. Name some diseases involving heme synthesis?
Porphyrias

4. Cooley’s anemia

6. Usual types of HGBs in adults
• Different types of HGBs seen in adults
– Hb A (α2 β2) (97%)
– Hb A2 (α2 δ2) (1.5-3.5%)
– Hb F (α2 γ2) (<1%)

7. Fetal hemoglobin - HbF
• The main oxygen transport protein in
the fetus during the last seven months of
development in the uterus and
• After birth HBF levels gradually fall reaching
adult levels by the age of 6-9 months

8. Oxygen dissociation curve

9. Facial abnormalities

10. Organomegaly

11. Hemoglobin
• HbA (α2β2)
• FOUR α-globin genes on chr 16
• TWO β-globin gene on chr 11

12. Globin genes

14. Thalassemia
• Inherited genetic disorder of globin chain
synthesis of HbA (α2β2)
• AR
• Decreased synthesis may involve α or β globin
chain
 α-Thalassemias [↓ α-chain]
 β-Thalassemias [↓ β-chain]

15. Normal HGB
• Hb A - α2β2
• α : β = 1:1 (+/- 0.05)
• Disproportionate synthesis is associated with
relative excesses of the other

16. Figure 1. The two
chromosomes #11 have one
beta globin gene each (for a
total of two genes). The two
chromsomes #16 have two
alpha globin genes each (for a
total of four genes).
Hemoglobin protein has two
alpha subunits and two beta
subunits. Each alpha globin
gene produces only about half
the quantity of protein of a
single beta globin gene. This
keeps the production of
protein subunits equal.
Thalassemia occurs when a
globin gene fails, and the
production of globin protein
subunits is thrown out of
balance.

17. Thalassemia
• Low HGB levels
• Relative excess of unimpaired chains form
insoluble inclusions  Hemolysis

19. β-Thalassemia

20. β-Thalassemia
• ↓ Synthesis of structurally normal β globin
chain with unimpaired synthesis of α globin
chain
• β globin chain is coded by two globin genes
located on Ch 11
• α globin chain is coded by two pairs of globin
genes located on Ch 16

21. β-Thalassemia
• β0 Thalassemia – Total absence of β globin
chain in homozygous state
• β+ Thalassemia – reduced β globin chain
synthesis in homozygous state

22. β-Thalassemia
• More than 100 different causative MUTATIONS
• Point mutations – most common
• Promoter region mutations
– Reduces transcription rate by 75-80% - Β+ Thalassemia
• Chain terminator mutation
– Premature chain termination - Β0Thalassemia
• Splicing mutation
– More common cause of Β+ Thalassemia

24. β-Thalassemia
• Thalassemia major
– Homozygous for β-Thalassemia genes
– Genotype β0 / β0 or β+ / β+
– Severe tranfusion dependent anemia
• Thalassemia minor
– Heterozygous with one thalassemia gene and one normal
gene β0 / β or β+ / β
• Thalassemia intermedia
– Genetically heterogenous group with milder variant of β0 /
β0 or β+ / β+ and severe form of heterozygous thalassemia
β0 / β or β+ / β

25. Thalassemia major
• Mediterranean, Africa and south east Asia
• Manifest 6-9 months after birth
• Hb – 3-6 gm/dl
• PBS
– Anisocytosis - microcytes,
– poikilocytosis, target cells, basophilic stippling, fragmented
RBC, NRBCs
– Reticulocytosis
– ↑ ↑ Hb F
– Hb A2 - N, ↑, ↓

26. Transfusion dependent anemia

27. Hereditary - AR

28. Microcytic hypochromic RBCs

29. Target cells

30. NRBs and Punctate
basophilia

31. Thalassemia major
• Morphology
• Bone marrow hyperplasia – “CREW CUT” appearance
on skull X ray
• Splenomegaly – upto 1500 gms
• Hemosiderosis and secondary hemochromatosis –
due to repeated blood transfusion and ↑ absorption
of dietary iron – affects heart, liver and pancreas
• Early death in untreated cases

33. “CREW CUT” appearance
on skull X ray

34. Thalassemia minor
• More common
• Heterogenous carrier of β0 or β+ gene
• Asymptomatic / mild anemia
• PBS – Microcytic hypochromic RBCs,
basophilic stippling
• ↑ Hb A2 ; 4-8% (N 2.5%)
• DD – Iron deficiency anemia

35. α Thalassemia

36. Demographics: Thalassemia
• Found most
frequently in the
Mediterranean, Africa,
Western and
Southeast Asia, India
and Burma
• Distribution parallels
that of Plasmodium
falciparum

37. Classification & Terminology
Alpha Thalassemia
• Terminology
• Silent carrier
• Minima
• Minor
• Intermedia
• Major

38. Symbolism
Alpha Thalassemia
• Greek letter used to designate globin
chain:


39. Symbolism
Alpha Thalassemia
/ : Indicates division between genes
inherited from both parents:
/
• Each chromosome 16 carries 2 genes. Therefore the
total complement of  genes in an individual is 4

40. Symbolism
Alpha Thalassemia
- : Indicates a gene deletion:
-/

41. Classification & Terminology
Alpha Thalassemia
• Normal /
• Silent carrier - /
• Minor -/-
--/
• Hb H disease --/-
• Barts hydrops fetalis --/--

42. Symbolism
Other Thalassemia
• Greek letter used to designate globin
chain:


43. Symbolism
Other Thalassemia
+:Indicates diminished, but some
production of globin chain by gene:
+

44. Symbolism
Other Thalassemia
0 :Indicates no production of globin chain by
gene:
0

45. Symbolism
Other Thalassemia
Superscript T denotes nonfunctioning gene:
T

46. Classification & Terminology
Beta Thalassemia
• Normal /
• Minor /0
/+
• Intermedia 0/+
• Major 0/0
+/+

47. Special Cases
Thalassemia
• Hb Lepore:  fusion seen in some types
of  thalassemia
• Hb Constant Spring
•  chain with 31 additional amino acids
• --/cs
• Hereditary persistence of fetal hemoglobin
(HPFH)

48. Special Cases: Thalassemia
• Hb H
• 4 tetramer
• Associated with --/- thalassemia

49. Special Cases: Thalassemia
• Hb Barts & hydrops fetalis
• Barts is a 4 tetramer
• Associated with --/--
• Lethal
• High concentrations are capable of sickling

50. Different types of HGBs seen in adults
• Hb A (α2 β2) 97%
• Hb A2 (α2 δ2) (1.5-3.5%)
• Hb F (α2 γ2) <1%
• Adult HbH (β4)
• Neonate Barts (γ4)

51. α Thalassemia
• Reduced or absent synthesis of α globin chains
• Excess of non α chain –ß, γ, δ
– Hb A (α2 β2)
– Hb A2 (α2 δ2)
– Hb F (α2 γ2)

52. α Thalassemia
• New born – formation of γ4 tetramer – Hb
Barts
• Adults – ß4 tetramer – HbH
• Free ß, & γ chains are more soluble than α
chains – hemolysis is less severe

53. α Thalassemia
• Sevearity varies depending on number of α globin
genes affected
• DELETION of α- globin genes are more common
• Hydrops fetalis -/- -/-
• HbH disease -/- -/ α
• α Thalassemia trait -/- α/ α (asian)
-/ α -/ α ( black african)
• Silent carrier -/ α α/ α

54. Figure 3. People of Asian ancestry often
have two alpha globin genes deleted on the
same chromosome #16. The parents each
have the mild thalassemia that results with
two functioning alpha globin genes. The
offspring that inherits the double deletion
from one parent and the single from the
other will have Hemoglobin H disease
(Scenario 1). The offspring who inherits no
alpha genes from the parents dies in utero
(Scenario 2; hydrops fetalis).

55. Figure 4. People of
African ancestry usually
have only one alpha
globin gene deleted per
chromosome. The
parents each have the
mild thalassemia that
results with two
functioning alpha
globin genes. The
offspring can, at most,
inherit the relatively
mild condition of the
parents.

56. Hb H disease
• Tetramer of β globin chain
• High affinity for oxygen
• Unstable HbH form precipitates
• Resemble β-Thalassemia intermedia

57. HBH inclusions

58. HPLC pattern of a patient with HbH disease. The peaks
of the different hemoglobins are indicated

59. Hydrops fetalis
• Hb barts – tetramer of γ globin chains
• ζ2 γ2 -Severe tissue anoxia
• Pallor, generalised edema, massive
hepatosplenomegaly
• High mortality

60. Hydrops fetalis

61. Other causes for Hydrops fetalis
• Rh incompatibility
• Hypoplastic left heart syndrome

62. Common mechanism
• Alfa thal- Deletion
• Beta thal – Mutation

63. Gamma gene can be induced to
function by some drugs
• What is the clinical implication of this finding?

64. END

65. Dr.CSBR.Prasad, M.D.,
Associate Professor of Pathology,
Sri Devaraj Urs Medical College,
Kolar-563101,
Karnataka,
INDIA.
csbrprasad@reiffmail.com