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Alpha Thalassemia

Introduction:

  • It is a group of hereditary anemiascharacterized by reduced or absent production of alpha chains of hemoglobin.

 

Epidemiology:

  • Common in Africa, Mediterranean countries, middle east and south east Asia.

 

Etiology:

  • Autosomal co-dominant inheritance.
  • Deletion of genes coding for α chain of hemoglobin.
  • This gene is located on short arm of chromosome 16.
  • Unlike β & δ which are single for haploid genotype, α is duplicated on chromosome 16.
  • As both HbA and HbF contain α chains, in α thalassemia both fetus and adults are affected.

 

Pathogenesis:

  • In newborn, excess of γ chains aggregate to form γ4 tetramers, which are known as Hb Barts. Hb Barts has very high oxygen affinity, which results in severe tissue anoxia and intrauterine death.
  • In adults, excess of β chains also aggregate to form β 4 tetramer, which is known as HbH. Oxygen affinity of HbH is 10 times that of HbA due to lack of heme-heme interaction and absence of Bohr effect. Oxygen dissociation curve is a rectangular parabola shifted to extreme left.
  • HbH is unstable and precipitates causing hemolytic anemia.

 

Types α thalassemia

Genotype

Phenotype

Hematological

findings

Severity           

Hemoglobin patterns

-α/ αα

Silent carrier

Normal or slight reticulocytosis

Normal

Normal

-α/ -α

α thalassemia trait

Mild anemia, microcytic hypochromic RBCs, target cells, basophilic stippling, poikilocytosis

Mild to moderate

Newborns- HbBarts

Adults- Normal or some HbH

--/ αα

--/ -α

Hemoglobin H disease

Moderate to marked anemia, microcytic hypochromic RBCs, target cells, basophilic stippling, poikilocytosis

Chronic, moderately severe hemolytic anemia, Splenomegaly

Newborns- HbBarts

Adults- HbH

--/ --

Hydropsfetalis with Hemoglobin Barts

Marked anemia, macrocytic hypochromic RBCs, marked Anisopoikilocytosis,

numerous NRBC

Fatal

HbBarts

Hb Portland

 

Investigations:

  • Hemogram:
    • Hemoglobin- Reduced.
    • Blood indices-MCV and MCH are disproportionately low when compared with severity of anemia.
    • Microcytic hypochromic RBCs
    • Many targets cells are seen.
    • Acanthocytosis.
    • Basophilic stippling present.
    • RBCs are pitted several times and they look like surface of golf ball.
  • Reticulocyte count- Increased.
  • Hemoglobin electrophoresis on cellulose acetate at pH 8.6- Both HbH and HbBarts are fast moving hemoglobins.
  • Demonstration of HbH inclusions: Done by incubating blood with solution of redox dye-Ex –Brilliant cresyl blue.
  • Globin chain synthesis rate studies- Done by using radioactive amino acids.
  • Gene analysis study
  • Antenatal diagnosis can be done by analyzing the cells obtained through amniocentesis and chorionic villi biopsy

 

Treatment: Only HbH disease must be treated. Treatment is similar to beta thalassemia major/ intermedia

  • Chronic hypertransfusion.
  • Splenectomy.
  • Folic acid supplements.
  • Treatment of endocrine deficiencies occurring due to hemochromatosis.
  • Avoid oxidant injury.

 

Related Disorders:

  • Hemoglobin constant spring (HbCS)
    • Elongated α chain variant of HbH
    • Combination of two structurally abnormal α chains, each elongated by 31 amino acids at the carboxy terminal end, and two normal β chains.
    • It occurs due to mutation of chain termination codon. (UAA changes to CAA which codes for glutamine, transcription of mRNA continues till next stop codon is reached)
    • Abnormal α chains are ineffectively synthesized due to reduced stability of mRNA translocation apparatus. This leads to overall deficiency of α chains.
    • These patients present with mild anemia.

 

  • α Thalassemia –mental retardation syndrome.
    • 2 forms
      • Mutation of ATR-16- Gene on chromosome 16
      • Mutation of ART-16-Gene in X chromosome.
    • Associated with widespread dysmorphic features

 

  • α -Thalassemia with myelodysplasia (Acquired alpha thalassemia).
    • Seen in patients with MDS or AML.
    • Associated mutation of ATR-X gene which leads to inactivation of alpha genes in neoplastic hematopoietic cells.
    • Have dimorphic anemia with RBCs containing HbH.

 

Figures:

 

Figure 8.13.1.jpg

Figure 8.13.1- Alpha thalassemia trait- Peripheral smear

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