THALASSEMIA-TYPES & PATHOPHYSIOLOGY

1.      What are the types of mutations of beta Thalassemia?

 
        Beta thalassemia is a spectrum of disrorder characterised by variable clinical and                        laboratory features that occur due to varying degree of beta gene defect resulting into                defect in eta globin synthesis.
 
        The beta globin synthesis may be completely absent or it may be reduced or it may be                present with other disorders of Hb synthesis.
 
        Depending upon the abnormality of globin synthesis beta mutation can be
        ·  β⁺= reduced beta globin synthesis
        · β⁰=complete absence of beta globin synthesis


        Since 2 beta genes are present one in each chromosome the mutation in two genes will             determine the clinical presentation.

        Both these conditions cause TRANSFUSION DEPENDENT BETA THALASSEMIA                MAJOR.

        Severe anemia, dependent on regular blood transfusion for survival

        HbF elevated.

 

PATHOPHYSIOLOGY

 2   What are the determinants of severity of β-thalassemia?

       The major determinant of severity is the ratio of alpha and non-alpha globin chains.
 
       The degree of non-alpha (i.e. beta in this case) production depends upon the type of                   mutation(β⁺ or β⁰ ) and zygosity (β⁺/ β⁰ or β⁰/β⁰ or β⁺/β⁺ ).
 
 3  What are the other modifiers of disease severity?
      i)     Concomitant alpha thalassemia-

        Reduces disease severity
        Because the ratio of alpha and beta is partially normalized
            

           ii) Increased HbF

        Reduces severity as gamma chains will be available to form tetramer with alpha chains.

       iii) Sickle-beta thalassemia –

         Co-inheritance of the sickle hemoglobin   mutation on one beta globin allele and a                     thalassemic mutation at the other beta globin allele leads to a form of sickle cell disease,             the severity of which depends on the nature of the beta thalassemic mutation (ie,                         whether it results in reduced versus absent beta globin production).

 iv) Co-inheritance of hemoglobin E –

    Hemoglobin E results from a beta globin mutation that reduces beta globin production.     The clinical phenotype is similar to beta thalassemia but less severe. Hemoglobin E is         commonly seen in India and Southeast Asia.

  Co-inheritance of heterozygosity for a beta thalassemia mutation and a hemoglobin E       mutation is responsible for a large proportion of severe beta thalassemia throughout the   world.

 

  The phenotype appears to be especially severe in Sri Lanka . The pathophysiology of          this  heterogeneity and its severity remain a puzzle. Co-inheritance of alpha thalassemia    appears to have a significant impact.

 

 

4.     What is HPFH?

   Hereditary persistemce of fetal hemoglobin.

   It is due to absence of one or both delta or beta chains with resulting increase gamma           chains leading to increased HbF.

 

   Most of the cases have no anemia with increased HbF levels in electrophoresis.

 

   They can get co-inherited with other defects like sickle cell where they can reduce the            severity of sickle cell disease.

 

 5.  What leads to the ineffective erythropoiesis /intramedullary             hemolysis?

          In thalassemia the RBCs formed containing abnormal HB gets destroyed within the BM           thus k/a intramedullary hemolysis. 

          Thus the premature RBC death caused by maturation arrest followed by apoptosis due               to the toxic  alpha globin chain causes ineffective erythropiesis.

 

  6.       Why is there accelerated hemolysis in Thalassemia?

           Hemolysis is Thalassemia is primarily intracorpuscular.

 

    The causes of accelerated RBCs derstruction in THALASSEMIA are:

·         The unstable alpha globin peptides which appear as inclusions in the RBC membrane which makes RBC memebrane unstable.

·         The RBC membrane composed of Band 3, Band 4.1 rotein,ankyrin and spectrin are destabilized.

·         The oxidative stress is high. 

·         Also the thalassemic RBCs have low Hb and are dehydrated.

 7. Why is there high oxidative stress in RBCs of thalassemic patients?

 Oxidation of Hb occurs in all the RBCs in normal individual forming small fraction of methemoglobin which gets reduced back to Hb by cytochrome b5 reductase.

 

       In thalassemia oxidation of alpha and beta chain produce HEMICHROMES which cannot        get reduced back to normal Hb.

 

       These iron conatining hemichromes can produce reactive oxygen species thus damaging           the proteins and lipids of RBC membrane.

8. Why are the RBCs of thalassemia patient dehydrated?

      Due to excessive activation of k and Cl channel which draws water along with it                         extracellularly.

     Thus MCHC is high in Thalassemia.

9. There is found to increased risk of thrombosis in Thalassemia patients may be due to increased expression of phosphotidylserine C in the RBC membrane.

 

10.Increased risk of infection with Yersinia enterocolitica.

 

11. What are the types of alpha thalassemia?

12. Why is alpha thalassemia less severe than beta thalassemia?

        In the alpha thalassemias, the excess beta or gamma globin chains can form partially                 soluble but ineffective hemoglobin homotetramers.

 

        These homotetramers do not precipitate extensively until they are exposed to damaging            effects in the circulation, mostly oxidant in nature.

 

        However the HB barts i.e. Hydrops fetalis is imcompatible with life.

 

13. What is hemoglobin constant spring?

        It is a non deletional type of alpha thalassemia where the genes are not deleted but                     mutated.

        It is commonly associated with HBH disease.

        In contrast to beta thalassemia alpha thalassemia are hyperhydrated.

        The Hb constant spring produce more severe anemia and more severe disease.

 14. What is hemoglobin Lepore?

        A fusion globin due to unequal crossover of the β- and δ-globin genes (the globin is                    produced at a low level because it is under δ-globin regulation).

        These patients are asymptomatic.

 15.   Anti –Lepore also results from opposite crossover between the β- and δ-globin genes.

 16.      Hb Kenya — Hb Kenya is an interesting, clinically innocent hemoglobinopathy that results from an unequal crossover and recombination event between the beta and A(gamma) globin genes

 

17. Why is there iron overload in the patients of thalassemia even before the transfusion?

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