Pathogenesis of Thalassemias

ALPHA THALASSEMIAS
Mainly seen in Asian and Black population. Its mainly genetic. It is diagnosed with Hb electrophoresis by which it separates things based on size and charge so youcan clearly differentiate HbF, HbA, HbA2 clearly on cellulose acetate because they have different migrations. With the density we can know which one is which.
       Ok so alpha thalassemias are autosomal recessive have a problem in making alpha globin chains. There are four genes that control alpha globin synthesis.  Deletion of one of these four will not cause anemia. You dont have to worry abt that, nothing wrong. Deletion of 2 genes = problem because minimally decresed and therefore a mild anemia. Its microcytic because the globin chain is decreased,  so microcytic anemia [decrease in Hb concentration which will be the stimulus]. This is called alpha thalassemia minor which is seen in the far eastern culture. With 3  gene deletion, which is not good and decreased. which is also called HbH disease.  so this is formed by four beta chains get together and form HbH. Four gene deletions, so gamma chains form together which is Hb with 4 gammas, which is called Hb Barts. This will show up on the electrophoresis, but this really doesnot matter because the baby will be born dead. So this is real bad and result in spontaneous abortion. Which is see in far eastern culture more prominently. A correlation which can be given in this is, like if the incidence of spontaneous abortions is increased what cancer risk is increased? CHORIOCARCINOMA - which is increased hydatifidorm moles. so high incidence of choriocarcinoma in the far east b/c of alpha thalassemia.

BETA THALASSEMIA

blacks, Greeks, Italians.  B (by itself) = making normal beta chains; B (with a “+”) = making beta chains, but not enough; B (with a “0”) = not making beta chains at all.   Beta thal is auto rec, and has to do with splicing defects, stop codons.  The most severe form is due to stop codon (therefore terminate synthesis of beta chains, and don’t even make them).  Mild thalassemia: slightly decreased beta chains, prob due to a splicing defect; beta chains are slightly decreased, alpha chains are okay, delta chains are okay, gamma chains fine (confined to fetus).  So, HbA will decrease, and delta will get together (hence increase in HbA2) and gamma chains get together (hence increase in HbF). Therefore, see a decrease in HbA and an increase in HbA2 and HbF; this WILL show up on electrophoresis.  This happened b/c beta chain is decreased, and it showed a decreased HbA.  It is just a mild thalassemia and is very common.  So, only way to dx Beta thal is with Hb electrophoresis.  Cannot do anything about it.  Hopefully it is not the severe type, where not making any beta chains – aka Cooley’s anemia and will not live past 30 y/o.  Will have a constant transfusion requirement; many of these pts die from Fe overload, or Hep C or multiple transfusions or HIV.

MC in black pop’n – beta-delta thalassemia (decreased beta chains and decreased delta chains, so what’s left are alpha and gamma chains).  What will the electrophoresis show? HbF.  This called hereditary persistence of HbF.  No anemia, just dominant HbF.

For thalassemias, know they are genetic, what groups of people they are in, and that you DON’T do anything to them, esp giving Fe b/c all their Fe studies are normal.