5.2c Microcytic Anemias

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S… Speaker 1 (5.2c Microcytic Anemias)

The last of the microcytic anemias would be due to thalassemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

Thalassemia is due to a decreased synthesis of globin chains.

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S… Speaker 1 (5.2c Microcytic Anemias)

That's what we find in a thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

that there's gonna be decreased production of globin chains.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so if there's decreased production of globin chains,

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S… Speaker 1 (5.2c Microcytic Anemias)

there's going to be decreased hemoglobin,

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S… Speaker 1 (5.2c Microcytic Anemias)

because globin would be down,

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S… Speaker 1 (5.2c Microcytic Anemias)

so hemoglobin would be down,

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S… Speaker 1 (5.2c Microcytic Anemias)

and decreased hemoglobin would then result in a microcytic anemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

as per the paradigm that we've established.

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S… Speaker 1 (5.2c Microcytic Anemias)

So that's the general idea behind thalassemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

I'd like to just stop here for a second and remind you of a

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S… Speaker 1 (5.2c Microcytic Anemias)

little bit of a technicality.

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S… Speaker 1 (5.2c Microcytic Anemias)

Notice that I'm saying that we're talking about a decrease in synthesis

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S… Speaker 1 (5.2c Microcytic Anemias)

of the globin chain.

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S… Speaker 1 (5.2c Microcytic Anemias)

So a decrease in synthesis or production of the amount of globin

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S… Speaker 1 (5.2c Microcytic Anemias)

chain is called thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

whereas you could have some diseases in which there is an abnormality.

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S… Speaker 1 (5.2c Microcytic Anemias)

of the globin chain after it's produced,

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S… Speaker 1 (5.2c Microcytic Anemias)

for example,

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S… Speaker 1 (5.2c Microcytic Anemias)

like in sickle cell anemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

So in sickle cell anemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

you're producing globin chain,

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S… Speaker 1 (5.2c Microcytic Anemias)

however the globin chain is defective.

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S… Speaker 1 (5.2c Microcytic Anemias)

So in thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

the key is a decrease in synthesis of the globin chain.

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S… Speaker 1 (5.2c Microcytic Anemias)

Thalassemia is usually due to an inherited mutation.

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S… Speaker 1 (5.2c Microcytic Anemias)

Prevalence of thalassemia is explained by the fact

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S… Speaker 1 (5.2c Microcytic Anemias)

that carriers are protected against plasmodium falciparum malaria.

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S… Speaker 1 (5.2c Microcytic Anemias)

It's not enough to know that they're protected against malaria.

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S… Speaker 1 (5.2c Microcytic Anemias)

You need to know that they're protected against plasmodium falciparum malaria.

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S… Speaker 1 (5.2c Microcytic Anemias)

Thalassemia is divided into alpha and beta thalassemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so if there's a decrease in production of alpha chains,

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S… Speaker 1 (5.2c Microcytic Anemias)

we call that alpha thalassemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

And if there's a decrease in production of beta chains,

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S… Speaker 1 (5.2c Microcytic Anemias)

then we call that beta thalassemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

It's worth taking a moment here to remind ourselves of the normal types

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S… Speaker 1 (5.2c Microcytic Anemias)

of hemoglobin.

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S… Speaker 1 (5.2c Microcytic Anemias)

So the three normal types of hemoglobin usually seen in

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S… Speaker 1 (5.2c Microcytic Anemias)

a human being are fetal hemoglobin,

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S… Speaker 1 (5.2c Microcytic Anemias)

which is alpha two,

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S… Speaker 1 (5.2c Microcytic Anemias)

gamma two.

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S… Speaker 1 (5.2c Microcytic Anemias)

hemoglobin A,

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which is alpha 2,

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beta 2,

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S… Speaker 1 (5.2c Microcytic Anemias)

and then hemoglobin A2,

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which is alpha 2,

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delta 2.

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S… Speaker 1 (5.2c Microcytic Anemias)

Of all of these hemoglobins,

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S… Speaker 1 (5.2c Microcytic Anemias)

you can see that there's a consistent use of alpha.

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S… Speaker 1 (5.2c Microcytic Anemias)

In one way,

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S… Speaker 1 (5.2c Microcytic Anemias)

you can think of it as sort of the most important of all of the globin

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S… Speaker 1 (5.2c Microcytic Anemias)

chains,

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S… Speaker 1 (5.2c Microcytic Anemias)

and alpha is used by everybody.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now I use that to remind me that there are actually four copies

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S… Speaker 1 (5.2c Microcytic Anemias)

of the alpha gene,

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S… Speaker 1 (5.2c Microcytic Anemias)

i .e.

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S… Speaker 1 (5.2c Microcytic Anemias)

alpha is particularly important,

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S… Speaker 1 (5.2c Microcytic Anemias)

and so therefore there's a couple extra copies of the alpha gene.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so when you think about the genetics of the alpha chain,

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S… Speaker 1 (5.2c Microcytic Anemias)

it's important to know that the alpha chain,

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S… Speaker 1 (5.2c Microcytic Anemias)

that there are normally four alpha alleles,

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S… Speaker 1 (5.2c Microcytic Anemias)

and that they're present on chromosome 16.

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S… Speaker 1 (5.2c Microcytic Anemias)

So basically, this is what it looks like.

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S… Speaker 1 (5.2c Microcytic Anemias)

This is one copy of chromosome 16,

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S… Speaker 1 (5.2c Microcytic Anemias)

and there'd be two genes here,

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S… Speaker 1 (5.2c Microcytic Anemias)

and then one copy of chromosome 16,

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S… Speaker 1 (5.2c Microcytic Anemias)

and there'd be two genes here.

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S… Speaker 1 (5.2c Microcytic Anemias)

So it's important to know that there are four normal

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S… Speaker 1 (5.2c Microcytic Anemias)

alpha alleles.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now, in alpha thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

the problem is going to be gene deletion.

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S… Speaker 1 (5.2c Microcytic Anemias)

This is also important to know.

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S… Speaker 1 (5.2c Microcytic Anemias)

You need to know that in alpha thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

the problem is gene deletion.

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S… Speaker 1 (5.2c Microcytic Anemias)

So what's going to happen is we're going to knock out genes,

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S… Speaker 1 (5.2c Microcytic Anemias)

and the knockout of the gene

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S… Speaker 1 (5.2c Microcytic Anemias)

is then going to result in clinical findings.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now the first possibility would be that one gene is deleted.

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S… Speaker 1 (5.2c Microcytic Anemias)

So imagine again that we've got two copies of alpha on this one chromosome

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S… Speaker 1 (5.2c Microcytic Anemias)

and two alleles here on the other chromosome.

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S… Speaker 1 (5.2c Microcytic Anemias)

If we knock out one alpha,

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S… Speaker 1 (5.2c Microcytic Anemias)

the patients are asymptomatic.

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S… Speaker 1 (5.2c Microcytic Anemias)

So that makes it easy because we don't have to worry about

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S… Speaker 1 (5.2c Microcytic Anemias)

one gene deleted.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now what about if we knock out two genes?

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S… Speaker 1 (5.2c Microcytic Anemias)

Well, if we knock out two genes,

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S… Speaker 1 (5.2c Microcytic Anemias)

for example,

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here and here,

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and then here and here,

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S… Speaker 1 (5.2c Microcytic Anemias)

if we knock out two genes,

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S… Speaker 1 (5.2c Microcytic Anemias)

then the patients develop a mild anemia with a slightly

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S… Speaker 1 (5.2c Microcytic Anemias)

increased red blood cell count.

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S… Speaker 1 (5.2c Microcytic Anemias)

So there'll be a mild anemia with a slightly increased red blood cell count.

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S… Speaker 1 (5.2c Microcytic Anemias)

Not something that you have to worry about too much clinically.

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S… Speaker 1 (5.2c Microcytic Anemias)

Sometimes these patients don't even know that they have

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S… Speaker 1 (5.2c Microcytic Anemias)

alpha thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

and not something that you have to worry too much about on exams either.

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S… Speaker 1 (5.2c Microcytic Anemias)

But what is important for examination purposes,

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S… Speaker 1 (5.2c Microcytic Anemias)

and somewhat clinically,

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S… Speaker 1 (5.2c Microcytic Anemias)

is that really there's two possibilities when you knock out two genes.

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S… Speaker 1 (5.2c Microcytic Anemias)

So it's possible that you could knock out both genes on the same chromosome.

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S… Speaker 1 (5.2c Microcytic Anemias)

For example,

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S… Speaker 1 (5.2c Microcytic Anemias)

both of them are here on this same chromosome.

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S… Speaker 1 (5.2c Microcytic Anemias)

We name that a cis.

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S… Speaker 1 (5.2c Microcytic Anemias)

deletion,

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S… Speaker 1 (5.2c Microcytic Anemias)

cis means with,

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S… Speaker 1 (5.2c Microcytic Anemias)

or it's possible that you could knock out these on opposite chromosomes,

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S… Speaker 1 (5.2c Microcytic Anemias)

and that's called trans.

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S… Speaker 1 (5.2c Microcytic Anemias)

One possibility is cis and the other possibility is trans.

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S… Speaker 1 (5.2c Microcytic Anemias)

And the cis deletion is important because the cis deletion

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S… Speaker 1 (5.2c Microcytic Anemias)

is worse than the trans deletion.

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S… Speaker 1 (5.2c Microcytic Anemias)

So that's a question that could be asked.

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S… Speaker 1 (5.2c Microcytic Anemias)

Which is worse,

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the cis or the trans?

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S… Speaker 1 (5.2c Microcytic Anemias)

And the reason that the cis is worse is because it's associated

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S… Speaker 1 (5.2c Microcytic Anemias)

with an increased risk of severe thalassemia in the offspring.

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I .e.,

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if a person has two genes deleted,

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S… Speaker 1 (5.2c Microcytic Anemias)

like this,

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S… Speaker 1 (5.2c Microcytic Anemias)

then it's possible that when they pass this chromosome,

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S… Speaker 1 (5.2c Microcytic Anemias)

they could pass both deleted copies.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so if that person happens to receive another bad copy

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S… Speaker 1 (5.2c Microcytic Anemias)

from, let's say,

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S… Speaker 1 (5.2c Microcytic Anemias)

a parent,

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S… Speaker 1 (5.2c Microcytic Anemias)

that would then result in the risk for severe anemia in offspring.

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S… Speaker 1 (5.2c Microcytic Anemias)

So that's one important feature of the cyst deletion.

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S… Speaker 1 (5.2c Microcytic Anemias)

The second important feature of the cyst deletion is that it's more commonly seen in Asians.

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S… Speaker 1 (5.2c Microcytic Anemias)

And some people say that

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S… Speaker 1 (5.2c Microcytic Anemias)

the higher rate of spontaneous abortion seen in Asia.

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S… Speaker 1 (5.2c Microcytic Anemias)

I guess one point to be aware of is that in Asia there's a higher rate

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S… Speaker 1 (5.2c Microcytic Anemias)

of spontaneous abortion,

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S… Speaker 1 (5.2c Microcytic Anemias)

and some believe that it's actually due to the fact

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S… Speaker 1 (5.2c Microcytic Anemias)

that cis deletions are more common in Asia.

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S… Speaker 1 (5.2c Microcytic Anemias)

And by the way,

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S… Speaker 1 (5.2c Microcytic Anemias)

the trans deletions are more common in Africa.

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S… Speaker 1 (5.2c Microcytic Anemias)

Cis deletions more common in Asia,

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S… Speaker 1 (5.2c Microcytic Anemias)

trans deletions more common in Africa.

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S… Speaker 1 (5.2c Microcytic Anemias)

Patients who have three genes deleted,

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S… Speaker 1 (5.2c Microcytic Anemias)

they get a severe anemia.

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S… Speaker 1 (5.2c Microcytic Anemias)

Again,

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if you're going to knock out three genes,

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S… Speaker 1 (5.2c Microcytic Anemias)

you really don't have much choice.

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S… Speaker 1 (5.2c Microcytic Anemias)

You've got to knock out two on one chromosome,

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S… Speaker 1 (5.2c Microcytic Anemias)

and then the other one would be knocked out here.

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S… Speaker 1 (5.2c Microcytic Anemias)

What's then going to happen is that as the patient develops

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S… Speaker 1 (5.2c Microcytic Anemias)

in utero,

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S… Speaker 1 (5.2c Microcytic Anemias)

there really is no clinically detected problem.

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S… Speaker 1 (5.2c Microcytic Anemias)

Remember that the hemoglobin F,

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S… Speaker 1 (5.2c Microcytic Anemias)

which was the fetal hemoglobin,

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S… Speaker 1 (5.2c Microcytic Anemias)

is basically composed of alpha 2 and then gamma 2.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so even though only one alpha gene is being expressed,

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S… Speaker 1 (5.2c Microcytic Anemias)

the presence of that one alpha gene is sufficient enough

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S… Speaker 1 (5.2c Microcytic Anemias)

for the fetus to really avoid any problems.

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S… Speaker 1 (5.2c Microcytic Anemias)

When the fetus is born and the patient begins to produce hemoglobin

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S… Speaker 1 (5.2c Microcytic Anemias)

A and hemoglobin A2,

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S… Speaker 1 (5.2c Microcytic Anemias)

that's going to increase the risk of forming tetramers

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S… Speaker 1 (5.2c Microcytic Anemias)

of beta chains.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now, I guess to understand that,

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S… Speaker 1 (5.2c Microcytic Anemias)

you have to know that normally what happens is sort of the alpha becomes a...

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S… Speaker 1 (5.2c Microcytic Anemias)

dimer, and then the beta becomes a dimer,

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and so alpha 2 and beta 2 sort of join together,

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and then that forms hemoglobin.

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S… Speaker 1 (5.2c Microcytic Anemias)

However,

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S… Speaker 1 (5.2c Microcytic Anemias)

if the patient doesn't have alpha,

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S… Speaker 1 (5.2c Microcytic Anemias)

then what'll happen is the betas will sort of join with another beta 2,

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S… Speaker 1 (5.2c Microcytic Anemias)

so the beta 2 will join with beta 2,

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S… Speaker 1 (5.2c Microcytic Anemias)

and that would result in a tetramer of beta,

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S… Speaker 1 (5.2c Microcytic Anemias)

and the problem with that tetramer of beta is that it damages the red blood cells.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now a tetramer of beta is called hemoglobin H.

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S… Speaker 1 (5.2c Microcytic Anemias)

That's important to know.

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S… Speaker 1 (5.2c Microcytic Anemias)

And hemoglobin H would be seen on electrophoresis in alpha

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thalassemia,

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S… Speaker 1 (5.2c Microcytic Anemias)

in which three genes are deleted.

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S… Speaker 2 (5.2c Microcytic Anemias)

Now,

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S… Speaker 1 (5.2c Microcytic Anemias)

if four genes are deleted,

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S… Speaker 1 (5.2c Microcytic Anemias)

then you've got a major problem,

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S… Speaker 1 (5.2c Microcytic Anemias)

and it's going to express itself in the fetus,

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S… Speaker 1 (5.2c Microcytic Anemias)

because remember that hemoglobin F,

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S… Speaker 1 (5.2c Microcytic Anemias)

which was the hemoglobin in the fetus,

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contains alpha 2 and gamma 2.

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S… Speaker 1 (5.2c Microcytic Anemias)

And so if there's no alpha,

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then gamma 2 is going to join with another gamma 2,

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and that's going to result in a tetramer of gamma.

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And the tetramer of gamma would then damage the red blood cells.

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And these patients,

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they die in utero.

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And so this disease is lethal in utero.

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It's also called hydrops fetalis.

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S… Speaker 1 (5.2c Microcytic Anemias)

Now what would we see on hemoglobin electrophoresis?

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We'd see hemoglobin BARTs.

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S… Speaker 1 (5.2c Microcytic Anemias)

And what is hemoglobin BARTs?

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It is a tetramer of gamma chains.

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S… Speaker 1 (5.2c Microcytic Anemias)

So it represents...

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tetramer of gamma chains.

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S… Speaker 1 (5.2c Microcytic Anemias)

Alright,

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so that's alpha thalassemia,

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and now we go to beta thalassemia.

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And what's important to know about beta thalassemia,

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first of all, there are two beta genes.

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One is on chromosome,

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and the other is on the second copy of the chromosome.

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So there are two beta genes,

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and they're present on chromosome 11.

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S… Speaker 1 (5.2c Microcytic Anemias)

And perhaps particularly important,

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for this discussion and high yield is that beta thalassemia is due to

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gene mutations,

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not deletions.

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Remember, alpha thalassemia,

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gene deletions.

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Beta thalassemia,

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gene mutations.

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Now,

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these mutations can create a variable production of beta chain.

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If the mutation results in complete knockout of the ability to produce beta

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chain, then we call that beta null.

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And if the mutation results in decreased production of beta chain,

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then we call that beta plus.

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So these are the two possibilities.

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Now this creates a wide spectrum of disease.

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So for example,

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a patient could have beta,

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a normal beta,

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and then beta plus,

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or a patient could have beta plus,

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beta plus,

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or a patient could have beta plus,

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beta null,

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or a patient could have beta null,

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beta null.

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So there's a lot of permutations of beta plus and beta

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null that could exist.

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what we're going to do is we're just going to focus on the extremes.

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So one extreme,

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sort of the most,

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the least severe extreme,

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the mildest form of disease would be to have one normal beta and to

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have one beta plus where there was a slight decrease in the production of beta.

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This is called beta thalassemia minor.

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It's usually asymptomatic,

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and the patients may have an increased red blood cell count.

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They usually have a microcytic hypochromic anemia with some target

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S… Speaker 1 (5.2c Microcytic Anemias)

cells, but again,

9:45

S… Speaker 1 (5.2c Microcytic Anemias)

they are asymptomatic.

9:47

S… Speaker 1 (5.2c Microcytic Anemias)

Now,

9:47

S… Speaker 1 (5.2c Microcytic Anemias)

it's worth discussing for a moment here what target cells are,

9:51

S… Speaker 1 (5.2c Microcytic Anemias)

because this is the first time that we're encountering a target cell.

9:55

S… Speaker 1 (5.2c Microcytic Anemias)

So let's go back and remind ourselves that the normal red blood cell has

9:59

S… Speaker 1 (5.2c Microcytic Anemias)

a bi -

10:00

S… Speaker 1 (5.2c Microcytic Anemias)

biconcave shape to it.

10:01

S… Speaker 1 (5.2c Microcytic Anemias)

And the biconcave shape is such that the

10:06

S… Speaker 1 (5.2c Microcytic Anemias)

edges here are thicker and they contain hemoglobin.

10:11

S… Speaker 1 (5.2c Microcytic Anemias)

And the center is thinner,

10:13

S… Speaker 1 (5.2c Microcytic Anemias)

and it contains less hemoglobin.

10:14

S… Speaker 1 (5.2c Microcytic Anemias)

Now, when you look down at the red blood cell on the microscope,

10:18

S… Speaker 1 (5.2c Microcytic Anemias)

what you're actually seeing is the red blood cell with an area of central pallor.

10:22

S… Speaker 1 (5.2c Microcytic Anemias)

This represents the central pallor.

10:24

S… Speaker 1 (5.2c Microcytic Anemias)

And you see the edges,

10:25

S… Speaker 1 (5.2c Microcytic Anemias)

which are full of hemoglobin.

10:27

S… Speaker 1 (5.2c Microcytic Anemias)

So this is the normal image that you see when you look down on the microscope.

10:31

S… Speaker 1 (5.2c Microcytic Anemias)

Now,

10:32

S… Speaker 1 (5.2c Microcytic Anemias)

a target cell,

10:32

S… Speaker 1 (5.2c Microcytic Anemias)

basically, is when there is a bleb of membrane

10:36

S… Speaker 1 (5.2c Microcytic Anemias)

That results.

10:37

S… Speaker 1 (5.2c Microcytic Anemias)

And the bleb of membrane allows for hemoglobin to build

10:42

S… Speaker 1 (5.2c Microcytic Anemias)

up in that bleb,

10:43

S… Speaker 1 (5.2c Microcytic Anemias)

which then creates a little bit of redness within the center of the cell.

10:47

S… Speaker 1 (5.2c Microcytic Anemias)

And so this is the target cell will then give you this little dot of red in the center

10:51

S… Speaker 1 (5.2c Microcytic Anemias)

of the area where there should be central pallor.

10:54

S… Speaker 1 (5.2c Microcytic Anemias)

So that's a target cell.

10:55

S… Speaker 2 (5.2c Microcytic Anemias)

Now,

10:56

S… Speaker 1 (5.2c Microcytic Anemias)

when would we see a target cell?

10:57

S… Speaker 1 (5.2c Microcytic Anemias)

Well, a target cell,

11:00

S… Speaker 1 (5.2c Microcytic Anemias)

in order to see a target cell,

11:01

S… Speaker 1 (5.2c Microcytic Anemias)

we need to have either

11:04

S… Speaker 1 (5.2c Microcytic Anemias)

decrease in the cytoplasm or increase in the amount of membrane.

11:08

S… Speaker 1 (5.2c Microcytic Anemias)

Maybe the better way to understand this would be to think about a basketball.

11:11

S… Speaker 1 (5.2c Microcytic Anemias)

If you have a basketball and you press on the surface of the basketball,

11:15

S… Speaker 1 (5.2c Microcytic Anemias)

you're not going to be able to indent the surface at all.

11:18

S… Speaker 1 (5.2c Microcytic Anemias)

However,

11:18

S… Speaker 1 (5.2c Microcytic Anemias)

if you remove some air,

11:20

S… Speaker 1 (5.2c Microcytic Anemias)

then you can potentially indent the surface or you could create a

11:24

S… Speaker 1 (5.2c Microcytic Anemias)

bleb of the surface of the basketball.

11:26

S… Speaker 1 (5.2c Microcytic Anemias)

So in the same way,

11:28

S… Speaker 1 (5.2c Microcytic Anemias)

what's happening in thalassemia

11:30

S… Speaker 1 (5.2c Microcytic Anemias)

is that we're sort of reducing the hemoglobin that's in the cytoplasm,

11:33

S… Speaker 1 (5.2c Microcytic Anemias)

and by reducing the hemoglobin that's in the cytoplasm,

11:36

S… Speaker 1 (5.2c Microcytic Anemias)

it's like taking the air out of this ball,

11:38

S… Speaker 1 (5.2c Microcytic Anemias)

which then creates the opportunity to have a little excess membrane

11:43

S… Speaker 1 (5.2c Microcytic Anemias)

to be able to produce this bleb and form a target.

11:47

S… Speaker 1 (5.2c Microcytic Anemias)

And here's an image of a target cell,

11:49

S… Speaker 1 (5.2c Microcytic Anemias)

and it's exactly the way I drew it.

11:51

S… Speaker 1 (5.2c Microcytic Anemias)

Here I'm highlighting the target cell for you.

11:53

S… Speaker 1 (5.2c Microcytic Anemias)

Normally,

11:53

S… Speaker 1 (5.2c Microcytic Anemias)

this area in the center should actually be an area of central pallor.

11:57

S… Speaker 1 (5.2c Microcytic Anemias)

However, in this particular case,

11:58

S… Speaker 1 (5.2c Microcytic Anemias)

you can clearly see that there is a target sort of in the center there.

12:02

S… Speaker 1 (5.2c Microcytic Anemias)

All right,

12:03

S… Speaker 1 (5.2c Microcytic Anemias)

now in this particular disease,

12:06

S… Speaker 1 (5.2c Microcytic Anemias)

which again is beta thalassemia minor,

12:08

S… Speaker 1 (5.2c Microcytic Anemias)

the key hemoglobin electrophoresis finding is that there's going

12:12

S… Speaker 1 (5.2c Microcytic Anemias)

to be usually an isolated increase in hemoglobin A2.

12:17

S… Speaker 1 (5.2c Microcytic Anemias)

That's really the key finding.

12:18

S… Speaker 1 (5.2c Microcytic Anemias)

So I would say when you think about beta thalassemia major,

12:22

S… Speaker 1 (5.2c Microcytic Anemias)

it's usually asymptomatic.

12:24

S… Speaker 1 (5.2c Microcytic Anemias)

The patients have a microcytic hypochromic anemia with target cells.

12:28

S… Speaker 1 (5.2c Microcytic Anemias)

And then a key finding is an isolated or an independent increase

12:32

S… Speaker 1 (5.2c Microcytic Anemias)

in hemoglobin A2.

12:33

S… Speaker 1 (5.2c Microcytic Anemias)

And that's the key take -home message here.

12:37

S… Speaker 1 (5.2c Microcytic Anemias)

The other extreme of disease would be to knock out both beta chains completely,

12:41

S… Speaker 1 (5.2c Microcytic Anemias)

so that it would be beta null,

12:42

S… Speaker 1 (5.2c Microcytic Anemias)

beta null, and that's the most severe form of disease,

12:46

S… Speaker 1 (5.2c Microcytic Anemias)

so it is the opposite extreme of beta thalassemia minor.

12:50

S… Speaker 1 (5.2c Microcytic Anemias)

So in beta thalassemia major,

12:52

S… Speaker 1 (5.2c Microcytic Anemias)

both beta chains are knocked out,

12:54

S… Speaker 1 (5.2c Microcytic Anemias)

and so will there be a problem in the fetus?

12:57

S… Speaker 1 (5.2c Microcytic Anemias)

The answer is no,

12:58

S… Speaker 1 (5.2c Microcytic Anemias)

because fetal hemoglobin is actually alpha 2.

13:02

S… Speaker 1 (5.2c Microcytic Anemias)

and so we don't need beta in the fetus,

13:04

S… Speaker 1 (5.2c Microcytic Anemias)

and so there's no problem in the fetus.

13:05

S… Speaker 1 (5.2c Microcytic Anemias)

However,

13:06

S… Speaker 1 (5.2c Microcytic Anemias)

as soon as the baby's born,

13:08

S… Speaker 1 (5.2c Microcytic Anemias)

there'll be a demand to produce hemoglobin A,

13:10

S… Speaker 1 (5.2c Microcytic Anemias)

and so these patients will present with severe anemia.

13:13

S… Speaker 1 (5.2c Microcytic Anemias)

Now, it takes a few months for the disease to develop,

13:16

S… Speaker 1 (5.2c Microcytic Anemias)

and that's because the baby has fetal hemoglobin floating around

13:20

S… Speaker 1 (5.2c Microcytic Anemias)

in the blood,

13:21

S… Speaker 1 (5.2c Microcytic Anemias)

and so that fetal hemoglobin is temporarily

13:25

S… Speaker 1 (5.2c Microcytic Anemias)

protected,

13:26

S… Speaker 1 (5.2c Microcytic Anemias)

so it's gonna take a few months to develop.

13:28

S… Speaker 1 (5.2c Microcytic Anemias)

Now,

13:29

S… Speaker 1 (5.2c Microcytic Anemias)

what's going to...

13:30

S… Speaker 1 (5.2c Microcytic Anemias)

happen because there are no beta chains,

13:32

S… Speaker 1 (5.2c Microcytic Anemias)

correct?

13:33

S… Speaker 1 (5.2c Microcytic Anemias)

The beta chains are knocked out.

13:34

S… Speaker 1 (5.2c Microcytic Anemias)

So now as alpha chains are produced,

13:36

S… Speaker 1 (5.2c Microcytic Anemias)

the alpha chains will dimerize,

13:38

S… Speaker 1 (5.2c Microcytic Anemias)

and then eventually you'll have alpha 2 looking to join beta 2,

13:41

S… Speaker 1 (5.2c Microcytic Anemias)

but because there's no beta 2,

13:43

S… Speaker 1 (5.2c Microcytic Anemias)

eventually alpha 2 will join alpha 2,

13:45

S… Speaker 1 (5.2c Microcytic Anemias)

which will then produce tetramers of alpha.

13:47

S… Speaker 1 (5.2c Microcytic Anemias)

And these alpha tetramers will precipitate,

13:50

S… Speaker 1 (5.2c Microcytic Anemias)

and they'll damage the red blood cell.

13:52

S… Speaker 1 (5.2c Microcytic Anemias)

When they damage the red blood cell,

13:54

S… Speaker 1 (5.2c Microcytic Anemias)

that'll result in something called ineffective erythropoiesis.

13:57

S… Speaker 1 (5.2c Microcytic Anemias)

What that means is that as the red blood cells are being made and alpha is

14:01

S… Speaker 1 (5.2c Microcytic Anemias)

being produced,

14:02

S… Speaker 1 (5.2c Microcytic Anemias)

the alpha will actually precipitate and damage the red blood cell as

14:06

S… Speaker 1 (5.2c Microcytic Anemias)

they're being generated.

14:07

S… Speaker 1 (5.2c Microcytic Anemias)

Another problem is that even if the red blood cell does manage to get out of the

14:11

S… Speaker 1 (5.2c Microcytic Anemias)

bone marrow, the spleen will recognize the abnormality of

14:15

S… Speaker 1 (5.2c Microcytic Anemias)

this precipitated hemoglobin present within the red

14:19

S… Speaker 1 (5.2c Microcytic Anemias)

blood cell and will actually destroy the red blood cell.

14:23

S… Speaker 1 (5.2c Microcytic Anemias)

within the splenic macrophages.

14:25

S… Speaker 1 (5.2c Microcytic Anemias)

And so this is the reason why these patients have severe anemia.

14:29

S… Speaker 1 (5.2c Microcytic Anemias)

Now, because they have such severe anemia,

14:32

S… Speaker 1 (5.2c Microcytic Anemias)

they get a massive erythroid hyperplasia.

14:35

S… Speaker 2 (5.2c Microcytic Anemias)

What do I mean by that?

14:36

S… Speaker 1 (5.2c Microcytic Anemias)

Well, before you can understand massive erythroid hyperplasia,

14:39

S… Speaker 1 (5.2c Microcytic Anemias)

you need to recognize and remind yourself that usually erythropoiesis

14:44

S… Speaker 1 (5.2c Microcytic Anemias)

and hematopoiesis

14:46

S… Speaker 1 (5.2c Microcytic Anemias)

in particular erythropoiesis,

14:48

S… Speaker 1 (5.2c Microcytic Anemias)

occurs usually in the central axial skeleton.

14:51

S… Speaker 1 (5.2c Microcytic Anemias)

Now when a baby's born,

14:52

S… Speaker 1 (5.2c Microcytic Anemias)

erythropoiesis and hematopoiesis will be present throughout most

14:56

S… Speaker 1 (5.2c Microcytic Anemias)

of the skeleton.

14:57

S… Speaker 1 (5.2c Microcytic Anemias)

But as the patient grows,

14:59

S… Speaker 1 (5.2c Microcytic Anemias)

usually the erythropoiesis is limited to

15:04

S… Speaker 1 (5.2c Microcytic Anemias)

the central axial skeleton.

15:06

S… Speaker 1 (5.2c Microcytic Anemias)

In this particular case,

15:07

S… Speaker 1 (5.2c Microcytic Anemias)

because there's massive erythroid hyperplasia,

15:10

S… Speaker 1 (5.2c Microcytic Anemias)

there's such severe anemia that there's gonna be massive amounts of erythropoietin

15:14

S… Speaker 1 (5.2c Microcytic Anemias)

being released by the kidney in response to that anemia,

15:17

S… Speaker 1 (5.2c Microcytic Anemias)

and that massive amounts of erythropoietin will actually go to the bone marrow and drive

15:21

S… Speaker 1 (5.2c Microcytic Anemias)

the bone marrow to undergo hyperplasia.

15:23

S… Speaker 1 (5.2c Microcytic Anemias)

There'll actually be expansion of the hematopoiesis into unique

15:28

S… Speaker 1 (5.2c Microcytic Anemias)

areas such as the skull and the facial bones.

15:30

S… Speaker 1 (5.2c Microcytic Anemias)

Now when there's expansion of hematopoiesis into the skull,

15:33

S… Speaker 1 (5.2c Microcytic Anemias)

that's gonna produce a classic

15:35

S… Speaker 1 (5.2c Microcytic Anemias)

crew cut appearance on x -ray,

15:37

S… Speaker 1 (5.2c Microcytic Anemias)

and so that's high yield to be familiar with.

15:39

S… Speaker 1 (5.2c Microcytic Anemias)

And at the same time,

15:40

S… Speaker 1 (5.2c Microcytic Anemias)

when there's expansion of hematopoiesis into the facial bones,

15:44

S… Speaker 1 (5.2c Microcytic Anemias)

that's gonna thicken the facial bones and give the patient a chipmunk

15:48

S… Speaker 1 (5.2c Microcytic Anemias)

-like face.

15:49

S… Speaker 1 (5.2c Microcytic Anemias)

What will also occur is that these patients will get extramedullary

15:53

S… Speaker 1 (5.2c Microcytic Anemias)

hematopoiesis so that the liver and spleen will also begin to

15:57

S… Speaker 1 (5.2c Microcytic Anemias)

produce red blood cells,

15:59

S… Speaker 1 (5.2c Microcytic Anemias)

obviously that would be extramedullary,

16:01

S… Speaker 1 (5.2c Microcytic Anemias)

and that's gonna result in hepatosplenomegaly.

16:05

S… Speaker 1 (5.2c Microcytic Anemias)

Another complication that can be seen in these patients is a risk of aplastic

16:09

S… Speaker 1 (5.2c Microcytic Anemias)

crisis with parvovirus B19 infection.

16:11

S… Speaker 1 (5.2c Microcytic Anemias)

To understand this,

16:13

S… Speaker 1 (5.2c Microcytic Anemias)

we have to remind ourselves that these patients are dependent on every

16:17

S… Speaker 1 (5.2c Microcytic Anemias)

single red blood cell that's produced by the bone marrow along with extramedullary

16:22

S… Speaker 1 (5.2c Microcytic Anemias)

hematopoiesis.

16:23

S… Speaker 1 (5.2c Microcytic Anemias)

Now parvovirus B19 is a virus that infects erythroid

16:27

S… Speaker 1 (5.2c Microcytic Anemias)

precursors,

16:28

S… Speaker 1 (5.2c Microcytic Anemias)

and when it infects erythroid precursors,

16:30

S… Speaker 1 (5.2c Microcytic Anemias)

it shuts them down.

16:32

S… Speaker 1 (5.2c Microcytic Anemias)

Normally, it's a self -limited infection,

16:35

S… Speaker 1 (5.2c Microcytic Anemias)

and it'll last for a week or two weeks,

16:38

S… Speaker 1 (5.2c Microcytic Anemias)

and in most patients,

16:40

S… Speaker 1 (5.2c Microcytic Anemias)

in the normal patient,

16:41

S… Speaker 1 (5.2c Microcytic Anemias)

it wouldn't really have any effect because,

16:43

S… Speaker 1 (5.2c Microcytic Anemias)

for example,

16:43

S… Speaker 1 (5.2c Microcytic Anemias)

you and I have a tremendous reserve in our bone marrow,

16:47

S… Speaker 1 (5.2c Microcytic Anemias)

and we can afford to shut down production of red blood

16:51

S… Speaker 1 (5.2c Microcytic Anemias)

cells for a week or two.

16:52

S… Speaker 1 (5.2c Microcytic Anemias)

However,

16:52

S… Speaker 1 (5.2c Microcytic Anemias)

these patients,

16:53

S… Speaker 1 (5.2c Microcytic Anemias)

the beta thalassemia major patients,

16:55

S… Speaker 1 (5.2c Microcytic Anemias)

are so dependent on every single red blood cell that they produce that

16:59

S… Speaker 1 (5.2c Microcytic Anemias)

they can't

17:00

S… Speaker 1 (5.2c Microcytic Anemias)

risk shutdown even for a day.

17:02

S… Speaker 1 (5.2c Microcytic Anemias)

And so parvovirus B19 in these patients would create an

17:06

S… Speaker 1 (5.2c Microcytic Anemias)

aplastic crisis.

17:07

S… Speaker 1 (5.2c Microcytic Anemias)

And so that's an important thing to be familiar with.

17:10

S… Speaker 1 (5.2c Microcytic Anemias)

Here's a classic image that shows up on examinations.

17:13

S… Speaker 1 (5.2c Microcytic Anemias)

This is the crew cut appearance of the skull.

17:16

S… Speaker 1 (5.2c Microcytic Anemias)

And again,

17:17

S… Speaker 1 (5.2c Microcytic Anemias)

it's indicative of massive expansion of hematopoiesis

17:21

S… Speaker 1 (5.2c Microcytic Anemias)

into regions where hematopoiesis would not normally occur

17:25

S… Speaker 1 (5.2c Microcytic Anemias)

within the bone.

17:28

S… Speaker 1 (5.2c Microcytic Anemias)

It's not uncommon for these patients to be dependent on transfusions,

17:32

S… Speaker 1 (5.2c Microcytic Anemias)

and so chronic transfusions are often necessary.

17:34

S… Speaker 1 (5.2c Microcytic Anemias)

Now,

17:35

S… Speaker 1 (5.2c Microcytic Anemias)

this will lead to a risk for secondary hemochromatosis,

17:38

S… Speaker 2 (5.2c Microcytic Anemias)

and what do we mean by that?

17:39

S… Speaker 1 (5.2c Microcytic Anemias)

Well,

17:40

S… Speaker 1 (5.2c Microcytic Anemias)

basically, remember that every time you're giving a bag of blood,

17:43

S… Speaker 1 (5.2c Microcytic Anemias)

you're actually giving a bag of iron because those red blood cells are gonna be broken down,

17:47

S… Speaker 1 (5.2c Microcytic Anemias)

and that iron is now gonna be present within the body.

17:50

S… Speaker 1 (5.2c Microcytic Anemias)

Remember that the body really has no way of getting rid of iron.

17:53

S… Speaker 1 (5.2c Microcytic Anemias)

So every bag of blood is basically a bag of iron.

17:56

S… Speaker 1 (5.2c Microcytic Anemias)

And as iron begins to build up within the tissues,

17:59

S… Speaker 1 (5.2c Microcytic Anemias)

eventually the complication of having excess iron in tissues

18:03

S… Speaker 1 (5.2c Microcytic Anemias)

is called hemochromatosis.

18:05

S… Speaker 1 (5.2c Microcytic Anemias)

And that's a disease we'll talk about later in the liver lectures.

18:09

S… Speaker 1 (5.2c Microcytic Anemias)

However,

18:10

S… Speaker 1 (5.2c Microcytic Anemias)

at this point,

18:11

S… Speaker 1 (5.2c Microcytic Anemias)

you should recognize that it's secondary because it's secondary due to chronic

18:15

S… Speaker 1 (5.2c Microcytic Anemias)

transfusions.

18:17

S… Speaker 1 (5.2c Microcytic Anemias)

On blood smear,

18:18

S… Speaker 1 (5.2c Microcytic Anemias)

these patients will have a microcytic hypochromic anemia with

18:22

S… Speaker 1 (5.2c Microcytic Anemias)

target cells,

18:23

S… Speaker 1 (5.2c Microcytic Anemias)

and I've already explained that.

18:24

S… Speaker 1 (5.2c Microcytic Anemias)

At the same time,

18:25

S… Speaker 1 (5.2c Microcytic Anemias)

there will be some nucleated red blood cells.

18:27

S… Speaker 1 (5.2c Microcytic Anemias)

Now normally,

18:28

S… Speaker 1 (5.2c Microcytic Anemias)

our red blood cells do not have nuclei,

18:30

S… Speaker 1 (5.2c Microcytic Anemias)

and we remove those nuclei before the red blood cells can go out

18:34

S… Speaker 1 (5.2c Microcytic Anemias)

into the blood.

18:35

S… Speaker 1 (5.2c Microcytic Anemias)

However,

18:36

S… Speaker 1 (5.2c Microcytic Anemias)

if red blood cells are made in an abnormal location,

18:39

S… Speaker 1 (5.2c Microcytic Anemias)

for example,

18:40

S… Speaker 1 (5.2c Microcytic Anemias)

the spleen or the liver,

18:41

S… Speaker 1 (5.2c Microcytic Anemias)

as would occur in this disease,

18:42

S… Speaker 1 (5.2c Microcytic Anemias)

some of the nucleated red blood cells

18:45

S… Speaker 1 (5.2c Microcytic Anemias)

can actually escape out into the blood,

18:46

S… Speaker 1 (5.2c Microcytic Anemias)

and so we might see circulating nucleated red blood cells in this

18:51

S… Speaker 1 (5.2c Microcytic Anemias)

particular disease.

18:51

S… Speaker 1 (5.2c Microcytic Anemias)

On electrophoresis,

18:53

S… Speaker 1 (5.2c Microcytic Anemias)

the key finding,

18:54

S… Speaker 1 (5.2c Microcytic Anemias)

no hemoglobin A.

18:56

S… Speaker 1 (5.2c Microcytic Anemias)

The only hemoglobins that the patient will have are hemoglobin A2.

18:59

S… Speaker 1 (5.2c Microcytic Anemias)

And again,

19:00

S… Speaker 1 (5.2c Microcytic Anemias)

A2 is made up of alpha 2 and delta 2.

19:04

S… Speaker 1 (5.2c Microcytic Anemias)

And so there's no beta needed to make A2.

19:06

S… Speaker 1 (5.2c Microcytic Anemias)

And they'll have hemoglobin F.

19:08

S… Speaker 1 (5.2c Microcytic Anemias)

And hemoglobin F is alpha 2 and gamma 2.

19:11

S… Speaker 1 (5.2c Microcytic Anemias)

And again,

19:12

S… Speaker 1 (5.2c Microcytic Anemias)

there's no need for beta.

19:13

S… Speaker 1 (5.2c Microcytic Anemias)

So the key finding would be no hemoglobin A.

19:17

S… Speaker 1 (5.2c Microcytic Anemias)

And that concludes our discussion of microcytic anemias.

19:21

S… Speaker 1 (5.2c Microcytic Anemias)

The next section will deal with macrocytic anemia.

5.2c Microcytic Anemias

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