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Perth Haematology :: Dr Steven Ward

Thalassaemia / Haemoglobinopathy

 

Thalassaemia = reduced rate of globin synthesis due to genetic defect of globin genes (α or β)

 

Haemoglobinopathy = production of abnormal Hb due to genetic change in amino acid sequence

 

Genetic Classification

Type
Heterozygous (trait)
Homozygous
a-thalassaemia (--/)
MCV, MCH low
Hydrops Fetalis
a+-thalassaemia -a/
MCV, MCH N
MCV, MCH low
߰-thalassaemia
HbA2 >3.5%
Thal major
HbF 98% HbA2 2%
+-thalassaemia
HbA2 >3.5%
Thal Major or Intermedia (HbF 70-80% HbA 10-20%)
d-thalassaemia
HPFH
HbF 5-20%   HbA2 N
Thal intermedia
HbF 100%
Hb Lepore
HbA 80-90%   Hb Lepore 10%    A2 ↓
Thal Major or intermedia
HbF 80%  L 10-20%  HbA A2 0

 

α Thalassaemia

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Text Box: 1 gene deletion: Silent
 
2 gene deletion: α -thal trait
   MCV, MCH low
   RCC high; Hb normal
   Hb electro=N;
   occ HbH bodies
 
3 gene deletion: Hb H disease
   Hb 70-100; MCV, MCH low
   splenomegaly, Hb H (4)
   fetal: Hb Barts (g 4)

4 gene deletion: Hydrops
Due to gene deletions

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4 alpha globin genes in humans (duplicated)

bullet a -chain is essential in fetal and adult Hb

 

 

 

 

 

 

         

       = normal gene         = abnormal gene

      

 

β Thalassaemia

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Due to point mutations of -globin gene (>200)

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2 Beta globin genes in human

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Very common genetic defect 4.8% of world population carry globin variants 1.7% thal trait

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Ineffective erythropoiesis and haemolysis

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Diagnosis:

        Elevated HbA2

        DNA: tests available for the common defects (IVS1, codon 39)

 

 

 
DISEASE (2 genes)
TRAIT (1 gene)
MCV
MCV 50 (but pt Transfused)
MCV 70
Hb
Hb low (Dimorphic Tx) nRBC
Hb 90-110
Blood film
Retics, Targets, Basophilic stippling
Some targets
Hb electrophoresis
No HbA
99% HbF  some A2
Hb A2 >3.5%
HbF normal/slightly hi

 

 

Other Hb defects

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Hereditary Persistence of Fetal haemoglobin (HPFH)
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Group of conditions due to deletions or cross-overs affecting or g chain production

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d-thalassaemia
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Failure of both and d chains. HbF 5-20% in heterozygous, so like thal-minor. Homozygous only HbF ; thal-intermedia

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Hb Lepore
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Abnormal Hb due to unequal cross-over of and  d chains producing a chain consisting d-chain at amino end and -chain at carboxyl end. This chain is produced inefficiently and normal - and d-chain synthesis is abolished.

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Heterozygous: Thal-trait;   Homozygous: thal-intermedia

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-thalassaemia with other defects
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HbE--thalassaemia: Tx dependant thal major

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HbS--thalassaemia: Like Sickle cell anaemia

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Hb Constant Spring (HbCS)
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Hb formed from combination of two structurally abnormal a-chains (each elongated by 31 amino acids at the carboxy-terminus) with two normal -chains

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Thailand. Overall deficiency in a-chain synthesis - a-thal.-like phenotype

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Heterozygotes show no clinical abnormalities

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A mild anaemia with mild jaundice and splenomegaly is normal

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Hb Electrophoresis (Homozygous): Hb Bart (g4) HbCS  5-7%  HbA2 - Reduced     

  n

Hb Structure defects

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Globin chain has amino acid substitution

nn nn nn
n
n
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nHbS: -chain AA#6: Glu Val
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Sickle Cells

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nHbC: -chain AA#6: Glu Lys
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Target cells++ Mild. Hb 90-100

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nHbE: -chain AA#26: Glu Lys
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Target cells++ Very mild anaemia; MCV low

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nHbD: -chain AA#121: Glu Gln
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Slight targets in homozygous; asymptomatic

 

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nDiagnosis:
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Blood film and red cell indices

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Hb electrophoresis / HPLC

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Sickle Test

 

 

Hb electrophoresis

 

 

Text Box: +

Text Box: A D E G
Lepore 
H I J