Pathogenesis of Thalassemias
Alpha thalassemias – who do we see alpha thalassemias in? Asians (Far eastern) and blacks (all
genetic hematologic dz’s are seen in the black pop’n – alpha/beta thal, G6PD def, SCDz).
1. Hb electrophoresis – separates things based on size and charge, therefore you can clearly
separate HbA, HbF, and HbA2 clearly on cellulose acetate b/c they have different
migrations. So, they fluoresce it, and HbA, HbF and HbA2 all settle down. Then they stain
the cellulose acetate to see how much is there. Then, it produces density, and the density
correlates with the concentration of each of the Hb’s. How will they know the percent?
With a densitometer – it converts the density of the stain to the percentage. It turns out
that HbA (2 2 ) is the predominant Hb in an adult (95-95%). HbA2 is 1-2%; HbF = 1%. These
are the normal, which are expressed as a percentage.
2. Alpha thalassemias, auto rec, has a problem in making alpha globin chains. Do HbA2 and
HbF require HbA to be made? Yes. Therefore, all will be equally decreased. This will NOT
show up on an electrophoresis, b/c all are equally decreased, therefore, it shows to be
totally normal. There are four genes that control alpha globin synthesis. Deletion of one of
these four will not cause anemia. Deletion of 2 genes = problem b/c minimally decreased,
and therefore a mild anemia. It is microcytic b/c the globin part is decreased, meaning you
will get a microcytic anemia (decrease in Hb conc’n, which will be the stimulus). This called
alpha thalassemia minor, seen in the far eastern pop’n and black pop’n.
With a three gene deletion, that’s not good, and pt is really decreased (there is also a
hemolytic component to it). The beta chains get irritated that there is no alpha chains
around, so they from their own beta globin chains. So, four beta chains get together and
form HbH. If you do an electrophoresis, there will be a different result. HbH is a diff Hb, and
therefore will not migrate to the same place as other Hb’s. So, you can dx this alpha
thalassemia with Hb electrophoresis (why its called HbH dz). Four gene deletions –
spontaneous abortions (usually, therefore not usually born alive – aka hydrops fetalis).
Gamma chains form together (like the beta chains did earlier) and form a Hb with 4
gammas, which is called Hb Barts. This will show up on electrophoresis, but won’t matter
b/c baby is dead already. What is the spontaneous abortion rate in far east? High b/c this is
where alpha thalassemia is most commonly located. Therefore, if the incidence of
spontaneous abortions is increased, what cancer risk is increased? Choriocarcinoma
(increased hydatidiform moles, which leads to choriocarcinoma). So, there is a high
incidence of choriocarcinoma in the far east b/c of alpha thalassemia. Rx – DO NOT give Fe
(will Fe overload them). So, just leave them alone. (2 MCC jaundice = Gilbert’s dz – esp
with lack of food).
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.
Iron Deficiency Anemia (IDA):
1. Causes of Fe def anemia – look at age brackets:
a) Prematurity – everyday a baby is not in utero, it is losing Fe (all their Fe stores are
decreased, so baby must be given Fe supplements).
b) Newborn – check stool for their blood; need to know it’s not mom’s blood, which can be
swallowed. This is done with the apt test. Most of blood that comes out of baby’s
meconium is blood the baby swallowed from mom, and it has HbA in it. However, if it was
HbF blood that came out, the MCC is bleeding meckel’s diverticulum. Therefore, bleeding
meckel’s diverticulum = MCC Fe def in a newborn and child. Meckel’s diverticulum is NOT
the cause of Fe def in an adult, b/c most have bled by four years of age, and already would
have known pt has it.
c) Woman under 50 – MCC Fe def = menorrhagia, therefore need to get a good menstrual