Hi, my name is Carrie Thompson, and

I am an associate professor here at

Mayo Clinic, and a consultant

in the division of hematology.

I'm also internal medicine program

director for the residency.

Welcome to my talk on anemia!

The objectives of today's

discussion will be to

describe an approach to anemia that

I like to use: the size of

the red blood cells.

We'll talk about iron replacement as

well, because that's something that

comes up very commonly in

practice.

We'll recall the laboratory values

seen in hemolysis

and lastly, talk about the

differential diagnosis of

macrocytosis.

Let's start off with some

definitions.

What is anemia?

Well, it's a decrease in the red

blood cells and that can be

measured in different ways: either

the hemoglobin concentration

or the hematocrit, which is

a calculated value, or

the red blood cell count.

I personally use the hemoglobin

concentration.

Now you can use either hemoglobin

or hematocrit.

Most people don't use red blood cell

count, but the truth is, the three

of them usually decrease in parallel

in anemia

other than thalassemia.

Remember this one because in

thalassemia,

the red blood cell count can

actually be increased as

opposed to decreased.

Alright, so what are the normal

ranges?

For men, it's 13.6

to 16.9; and

women slightly less,

11.9 to 14.8.

There may be a couple circumstances

where those normal values are a

little bit different.

For example, somebody living

at high altitude would be

expected to have a slightly higher

hemoglobin.

There's a couple other really

helpful red blood cell indices

that are calculated with every

complete blood count that you get,

and these are really useful when

you're working up anemia.

So I think it's worthwhile reminding

us of what these are.

First one is MCV, and that stands

for mean corpuscular

volume. It really tells you what

the size of the red blood cell

is. Is it small?

Is it average?

Is it big?

And as you'll see in the upcoming

slides, that's how I

classify types of anemia.

So this one's really important to

look at.

The MCHC stands

for mean corpuscular hemoglobin

concentration, and that's

the average hemoglobin concentration

in every red blood cell.

Why is that one important?

Because in iron deficiency, it's

low, but in

spherocytosis, or in cases of red

cell agglutination, that one

can be elevated.

And then lastly, I want to mention

RDW, or the red cell distribution

width.

So this tells us how much

variability there is

in different red blood cell sizes.

Another term

that you may hear

when an

hematopathologist is describing a

lot of variability is

anisocytosis.

So that just basically is a fancy

word for meaning a high RDW

and that is elevated in iron

deficiency anemia.

What

are reticulocytes?

That's another thing that we often

use as part of our workup for

anemia.

Those are the baby red blood cells.

So they usually spend most of their

time in the bone marrow and only

circulate in peripheral blood for

a day before they reach their

final maturity of a red blood

cell.

But during that process,

they change.

They have some ribosomal material

that allows a hematopathologist,

or a lab tech, to stain for

them and actually count the

number of reticulocytes.

So that can be helpful because

if there's a lot of reticulocytes,

it tells us that our bone marrow is

responding.

If the reticulocytes are low,

that may be anemia where the bone

marrow is not working properly for

one reason or another,

such as myelodysplastic syndrome

or a nutritional deficiency,

including iron deficiency.

Alright, now I'd like to talk you

through what is my approach to

anemia.

And what's really

important is looking through old

records, finding not just the

history and the physical of the

patient that you're evaluating,

but also the history and trend of

those blood counts.

So is this anemia brand new?

It just happened over the last

month? Thinking of something acute

like blood loss, or is this

something that's been slowly and

steadily causing problems

and finally reaches clinical

concern when

the number is low enough?

And that may be something like a

chronic condition,

such as myelodysplastic syndrome

or vitamin B12 deficiency that

can take some time to develop.

You usually have the luxury of

looking through all of these lab

values, getting a complete history,

doing further workup.

But there are times where you want

to just bypass all

of those steps and go straight to a

bone marrow biopsy, and

that's if you see blasts in the

peripheral blood.

Now, usually you're gonna have more

than just anemia as a problem

on your complete blood count, and

the patient will be symptomatic. But

very rarely, somebody could just

present with macrocytic anemia.

The other time is severe

pancytopenia. Obviously, there's

something sinister going

on, whether that's a systemic

disorder, or a bone marrow disorder.

And generally you're

gonna go straight to a bone marrow

biopsy in those situations.

Alright, I like to think through

things in an algorithmic way

and this is how I start

with anemia. So very, at the very

top, anemia is detected on

your CBC.

So next step, you're going to

perform that history and physical.

Again, that's of the patient.

But also really looking back at

those former records to determine

how quickly this problem has come

on.

And then, as I mentioned, I like to

use the MCV, that's the size

of the red blood cells to classify

the anemia.

So that's either microcytic, where

the cells are small, defined

as a cut off of less than 82.

Their normal size, 82 to

95, or macrocytic,

where the cells are too big and

that's an MCV greater than

95.

I'm going to just

give us a case to work through and

kind of round our discussion.

So this is a 45 year old

female who comes to see

you for evaluation of fatigue

and low back pain for the last three

months. Pretty common complaints.

Her past history is fairly

unremarkable.

No real chronic medical conditions

other than migraines.

And she's developed menorrhagia in

the last year or so.

On exam, she's

a bit pale, but otherwise

unremarkable.

And here's her lab tests: her white

count is normal at 5.2,

hemoglobin is low, it's 8 grams

per deciliter, and platelets are

290.

Next, we're gonna look at those red

blood cell indices that we

discussed.

The MCV is 67.

That's low. This is microcytic

anemia.

And the RDW is just a little bit

high. Again, that is the

variation in

the size of the red blood cells.

So that's a little bit elevated at

17.

So the question is, what's the next

best step in evaluation?

What are you going to order?

Is it A.

Reticulocyte count, B.

Serum iron TIBC percent

saturation, C.

ESR and CRP, D.

Ferritin, or E.

all of the above?

So think about what you would do in

practice and you may

be surprised to find out

that D.

Ferritin is actually the correct

answer. That is the first

test that you need to work up this

woman with microcytic anemia.

So this

is the next part of our algorithm

where we're working up patients who

have microcytic anemia, again,

based on that MCV classification.

First step, check your serum

ferritin, and if the ferritin

is low, you're done.

You have diagnosed the patient.

They have iron deficiency anemia.

You're done in figuring out why

they're anemic, but you always have

to search for the cause

of iron deficiency.

And so we'll talk about that in the

next upcoming slides,

but then you'll replace iron and

follow their CBC.

So the only thing that causes

a low ferritin

is iron deficiency.

Now how about if the ferritin is

normal or elevated?

Then you're going to go back to that

history that you have from the blood

counts.

Is this microcytosis chronic?

Meaning, this has been going on for

years. Every CBC you look

at over the last 10 years has shown

a low MCV.

If yes, then you're thinking about a

hemoglobinopathy like thalassemia

and checking a hemoglobin

electrophoresis

would be the next laboratory study.

If no, then this

may be one of the anemia of chronic

disease or chronic inflammation

that a third of the time can present

with microcytosis,

rather than what we usually think of

as a normocytic anemia.

So the ESR and CRP can be

helpful. As well, of course,

looking at the patient as a whole,

what kind of systemic illnesses

do they have currently?

Alright. Let's spend a little more

time diving into iron deficiency

anemia because it is so common.

I mentioned the ferritin

is the test that will get you the

diagnosis and I know some

of you are thinking, wait a second,

what about those patients who have

inflammation?

Isn't, isn't ferritin an acute phase

reactant?

Yes. Hold on. We'll get there.

I'll show you the table that that

can help us here.

For those who you have

a diagnosis, the ferritin is

10 and you you know for

sure they have iron deficiency,

you have to do that next test

to workup the patient to discover

why are they iron deficient

and that can be really two

categories.

The first one is blood loss,

and the most common is G.I.

bleeding. That can be upper or lower

and often times can be subclinical,

especially in the elderly

population.

Menorrhagia and so that was actually

the key

to the case that I just shared with

you, that 45 year old female

who had low back pain and

menorrhagia and microcytic anemia.

Multiple pregnancies can be a cause,

as well as one of my favorites is

the frequent blood donor.

So I have actually seen some

patients in my clinic, where

referred for workup of iron

deficiency anemia, and

it's fairly easy

to ask their history.

Have you donated blood as

they come in with their tote or

t-shirt that says

I've donated six gallons of blood.

Though other cause

of iron deficiency anemia beyond

blood loss is decreased

iron absorption,

and that can be in a couple

different situations.

Those who are strict vegans,

who don't take iron supplements,

post-bariatric surgery,

and celiac disease.

So patients who have

either malabsorption from

bariatric surgery or celiac disease,

one clinical pearl to point out,

is that they may malabsorb more than

just iron.

They can have multiple nutrients

that are important for red cell

production, such as B12

deficiency.

And so sometimes those patients may

trick you and they actually may have

not microcytosis, but they may

be normocytic because they have

concurrent iron deficiency

and B12, and so two

different populations of cells,

one that's small, one that's large

from those various nutritional

deficiencies.

And because the MCV is an average,

it averages out to normal.

How do you treat iron

deficiency? I get asked this a lot.

It doesn't have to be fancy.

I usually just prescribe ferrous

sulfate over the counter.

It's the cheapest oral preparation.

It provides 66 milligrams

of elemental iron per tablet

and while some say, well, my

patients can't tolerate that.

I always ask, what dose are you

giving them?

If they're trying to get them

to be BID or TID dosing,

that's far too much.

The G.I. side effects are going to

be excessive.

So what I tell patients

to do is take one

tablet on an empty stomach

because we know that increases

absorption and take it right before

dinner, because generally

that's--patients tend to have an

empty stomach.

So, again, better absorption.

And if there is some nausea

or abdominal upset, that happens

when the patient's sleeping, so it's

pretty well tolerated.

In fact, there is

some data that shows that absorption

may be increased

if patients take an iron

tablet every other day instead

of every day.

So I figure that most patients are

going to forget every now and again,

especially an over the counter

iron tablet.

And so telling them to take it once

a day means that probably I'll get

in at least every other day.

It does take three months

to completely replace

that iron even after the anemia

has resolved.

So it's important to follow

the patient, not just the CBC,

because that will increase within

weeks, but follow that ferritin

level in six months of replacement

is what you should aim for.

Now, when should you use

IV iron?

There's certain circumstances, so

for those patients who are not

absorbing oral iron

such as celiac disease,

they may need IV iron because all

the oral iron in the world, they're

just not going to absorb through

their G.I. tract.

Those who have high iron

requirements, for example,

patients with chronic G.I.

bleeding that cannot

be fixed through endoscopic

approaches and will have ongoing

G.I. blood loss, they may not be

able to keep up with the amount of

iron that they need for their bone

marrow production, and so IV iron

may be needed or a failure

of oral iron.

Sometimes this is because patients

can't tolerate it or

other reasons.

Alright, so

for those who get all of these fancy

tests in the blood.

Let's talk about what they mean.

And so there's three different rows

here. Normal range; the second

one is iron deficiency; and then the

last one is anemia of chronic

disease or chronic inflammation.

So these can get a little

bit tricky.

If you look at the first column

there at serum iron, so

it's noteworthy that in both

iron deficiency and anemia

of chronic disease, the iron is

going to be low.

TIBC, or the iron binding

capacity, will differentiate

where it is high in iron deficiency

and low in anemia of chronic

disease. As well as the percent

saturation will be low in iron

deficiency, high in anemia

of chronic disease.

So here's the ferritin.

Iron deficiency, again, I've

mentioned the low ferritin is

diagnostic and low can

be less than 12 for sure.

Slam dunk.

But actually, if you go up to a

ferritin of 41, you still

have really good sensitivity and

specificity, almost 90%

for iron deficiency.

So you can be a little more liberal

with your cut offs.

It's the patients who have a

ferritin between 40-100

where sometimes it's a little more

challenging. That patient may have

anemia of chronic inflammation, and

that ferritin is an acute phase

reactant.

However, for those who are truly

iron deficient, it's pretty

hard to get a ferritin much above

100. So those patients who have a

ferritin of 300, and

you can pretty much rule out iron

deficiency.

I wanted to mention

thalassemia as this is another

cause of chronic microcytosis.

So if you have a patient who has had

a low MCV for a long time,

or you're thinking blood, blood loss

but just have not been able to find

a source, think thalassemia.

Look at the patient's ethnicity.

Remember that thalassemia is quite

common in countries

in the Mediterranean as well as

parts of Africa.

Look for a family history.

This is a genetic disorder.

Splenomegaly may go along with this

disorder as well.

The laboratory findings, you'll

have hypochromia and microcytosis,

just like iron deficiency.

But you'll also have some other

unique findings: target cells,

some teardrop forms, and basophilic

stippling.

Those things you should not see in

iron deficiency.

I mentioned that red blood cell

count can be elevated

despite having anemia,

and the iron stores will be normal

or increased.

How do you make the diagnosis?

Through hemoglobin electrophoresis.

That will diagnose your beta

thalassemia, and if that's

normal, then you may have to go to

molecular techniques to look for

alpha thalassemia.

Alright, so that covers microcytic

anemia.

Let's move on to the big category

of normocytic anemia, where the MCV

is normal.

So the first step is rule out

treatable causes.

So on the left hand side, there is

nutritional anemia.

Check your ferritin and homocysteine

levels.

That's looking for iron deficiency

and B12 deficiency.

And you may be thinking about wait,

iron deficiency causes microcytosis.

B12 causes macrocytosis.

Remember that MCV is an

average value and so, you can

have multiple different nutritional

deficiencies, which averages

out to a normocytic

anemia.

Oh, I'll skip over the middle for a

moment and go to the right.

The anemia of renal insufficiency.

Recall that erythropoietin is

a hormone produced in the kidneys

and that gives a signal to the bone

marrow to make red blood cells.

If that erythropoietin,

or EPO, level is low, which

can happen in acute or chronic

kidney injury, then the

EPO level is not available

to stimulate the bone marrow to make

more red blood cells.

So check the serum creatinine and,

of course, check an EPO level.

In the middle is the one that

is a little more tricky, hemolytic

anemia. So you're going to look for

your laboratory studies of

hemolysis.

That includes your haptoglobin,

which would be low; your lactate

dehydrogenase, which should be

elevated; your indirect

bilirubin should be elevated; and

your reticulocyte count.

Remember, those baby red blood

cells should be elevated

as long as the bone marrow has all

the necessary nutrients to make red

blood cells.

Continuing the algorithm here,

we've got our lab tests at the top

that we just talked about.

Let's say they're not suggestive of

hemolysis. They're normal.

OK. Then we're in the big category

of anemia of chronic disease.

Sometimes it can be a primary bone

marrow disorder, so you're going to

use the whole picture of the

patient, the history, and look at

that peripheral blood smear to

decide if patient needs further

workup from a hematologist or if

this is something that you can

watch.

Alright, let's go back to that

hemolysis. Let's say all of these

tests are suggestive

of hemolysis.

Well, then you're gonna look at your

peripheral blood smear.

The peripheral blood smear is so

helpful to hematologists.

So if you see spherocytes

on the peripheral blood smear,

that's consistent with autoimmune

hemolytic anemia or hereditary

spherocytosis.

And I'll show you on upcoming

slides what those cells look like.

And you can do your Coombs' test, or

DAT, and that would

be positive in generally most cases

of autoimmune hemolytic anemia.

If you see schistocytes on the

peripheral blood smear, that's a

problem. That generally happens with

disorders that are quite concerning,

often serious.

Usually these patients are in the

hospital.

So that's suggestive of

microangiopathic hemolytic

anemia and causes include

TTP, HUS,

DIC, or valvular hemolysis,

and obviously you would get a

hematology consultation.

In fact, when I get a consult

in the hospital service where

somebody has anemia,

and usually a little bit of

thrombocytopenia, if a peripheral

blood smear hasn't been done, the

first thing I do is call the CBC

lab and ask them to add on a smear

to see if there are schistocytes.

As soon as I get

those results, then I can triage.

Do I need to go see that patient

right away if schistocytes are

present, or can I kind of prioritize

them with the rest of my workflow

for that day?

So again, we mentioned renal

insufficiency or erythropoietin

deficiency.

So you would look at the patient's

GFR, and check an EPO level,

or anemia of chronic inflammation is

obviously a huge category,

and one that, unfortunately, we

don't have excellent treatment for.

Back to hemolysis,

I mentioned these laboratory studies

and I want to emphasize checking

that peripheral smear.

Besides the

spherocytes that we talked about was

autoimmune and the schistocytes that

are suggestive of microangiopathic

hemolytic anemia,

there's a few other causes

of hemolysis that are worth

mentioning.

Certain drugs can lead to this,

particularly in patients, who are

G6PD deficient, PNH,

which is a rare bone marrow

disorder, but that can

present also with

hemolysis and clots in unusual

locations, and then some congenital

disorders as well.

Alright, this is what a peripheral

blood smear looks like under the

microscope in somebody with

autoimmune hemolysis.

So in panel A, you

can see these red blood cells look

quite a bit different than what you

would expect in iron deficiency,

where where the cells are really

pale. These look a little more

fluffy and and they

look a little more generous.

Panel B is

the stain looking for reticulocytes.

And so the ones that have all

of the staining within them

are reticulocytes, or those baby red

blood cells.

So what's happening in this patient

is that they are making

auto-antibodies against the red

blood cells.

They're getting eaten up in the

periphery and

the bone marrow is responding

by making more of the baby red blood

cells or reticulocytes.

Alright, this is

a fun picture of

cells called bite cells.

And if you look at the second panel,

just look where those arrows are

pointing. It literally looks like

somebody took a bite out of those

red blood cells and that's what you

see in oxidative

stress with G6PD deficiency.

In this particular example,

it was caused by starting Dapsone

for the patient.

Alright, these are the ones that

scare me,the schistocytes.

So you can see the arrow pointing to

one schistocyte.

There's quite a few others

schistocytes on that peripheral

smear. That's indicative of again,

of microangiopathic hemolytic

anemia.

Or you can shorten it by saying

MAHA.

And those are disorders such as TTP,

DIC, valvular disease, all

really significant disorders.

Alright, let's switch

gears. I'm going to put us back into

context with another case.

This is a 51 year old man who comes

for evaluation of fatigue.

He follows with his cardiologist,

but he hasn't seen you, his primary

care provider, for three years.

Past history significant for morbid

obesity, status post gastric

bypass 10 years ago

now. Hypertension, hyperlipidemia,

type 2 diabetes, coronary artery

disease, peripheral vascular disease

and peripheral neuropathy.

It's quite concerning that he hasn't

seen his primary care physician in

three years with this past medical

history.

Here's his medications: Metformin,

Metoprolol, Lisinopril, Simvastatin,

Aspirin, Acetaminophen, and a

multivitamin.

Social history:

he lives alone.

He has a 35 pack year smoking

history, but he quit back when he

had his bypass surgery.

Has an occasional beer, maybe once

or twice a month, and he works in

sales.

Here's his labs: so

his white count is low, 2.9,

hemoglobin is 8.3, so

he has anemia. Platelets are 145

and the MCV is slightly elevated

at 104, so he has a macrocytic

anemia.

Other studies: his calcium level is

normal at 8.2, albumin is

fine, creatinine 1.1,

LDH is 240 with

an upper limit of normal of 222,

AST, ALT, and total bilirubin

are fairly unremarkable,

though, that bilirubin is just a

smidge above normal.

If you're working

up this patient's macrocytic anemia,

and you're doing a peripheral blood

smear, what would you most likely

see?

A. hypersegmented neutrophils,

B. blasts, C.

Rouleaux, D.

dysplastic changes, or E) burr

cells or echinocytes.

What do you think?

Yeah, A.

hypersegmented neutrophils.

So this patient has

pancytopenia. It's subtle, but he

certainly is low on all three cell

lines and macrocytosis.

So the most likely diagnosis is

vitamin B 12 deficiency

due to malabsorption given his

history of gastric bypass surgery.

Hypersegmented neutrophils are

classic, classic finding that we

see in vitamin B12 deficiency

and you can see that on this

depiction of a peripheral smear

below.

Alright, back to

an algorithm and this one is for

macrocytic anemia.

So when we start at the top, we ask

what kind of medications is the

patient taking, and

are they using alcohol in excess?

So there are multiple medications

that interfere with DNA

synthesis within the cells,

and that will cause the cells to be

a bit larger than usual or

macrocytosis.

So if you identify those,

then you found your cause.

Manage the meds and manage the

alcohol.

No?

Then you would be looking for

nutritional deficiencies, and

homocysteine and vitamin

B12 level could be checked.

If the homocysteine and B12 levels

are normal, then you're gonna look

at how big those red blood cells

are.

Are they just a little bit big, 97

to 100?

You're gonna think about myelodysplastic

syndrome or other causes, but

if they're greater than 110, that's

really pointing you towards

myelodysplastic syndrome.

And that patient should get worked

up with a bone marrow biopsy.

Alright, how about a B12 and folate

deficiency? Let's go into a little

more detail.

If you're checking homocysteine,

please know that that can be

elevated with either B12

or folate deficiency.

But methylmalonic acid

is what can help distinguish between

those two disorders.

So if that's high, that is most

likely due to B12 deficiency.

Remember, chronic kidney disease,

though, can slightly increase the

MMA, so you need to take that into

account.

If methymalonic acid is normal,

then significant cellular level

B12 deficiency is unlikely.

One thing to point

out is that folate deficiency is

actually very uncommon in

the United States because many of

our foods are fortified with folate.

So let's talk about other things

besides B12 and folate

deficiency in the differential

of macrocytosis.

I mentioned medications.

Remember, anything that interferes

with DNA synthesis.

So many forms of chemotherapy,

for example, methotrexate for

the patients on chronic methotrexate

for rheumatoid arthritis. 6-mercaptopurine for

patients with ulcerative colitis,

those types of things.

Many anti-HIV drugs have

the same effect.

Alcohol use,

about 80 grams of alcohol

per day will lead to

macrocytosis, and that's equivalent

to about a one bottle of wine

or four to five beers per day.

That is reversible macrocytosis

if somebody stops alcohol.

Liver disease from any cause, not

just alcohol, will lead to

macrocytosis.

Reticulocytes,

those baby red blood cells we've

been talking about, they're a little

bit bigger than mature red blood

cells. So for somebody who has

hemolysis and a really brisk

reticulocytosis, for example,

their MCV may be actually a little

bit high.

Significant hypothyroidism

will lead to macrocytosis.

We mentioned B12 and folate

deficiency.

Copper deficiency is

another one that can lead to

macrocytosis.

We see this in malabsorption,

or sometimes patients who have a

zinc excess will have

copper deficiency.

And then lastly, nitrous oxide

abuse. I've never seen that, but

it's always fun to have as a

differential on rounds.

Alright, let's finish things up

talking about pancytopenia, which

sometimes you will see

with when you're working up anemia.

You'll note that the it's not just

a problem with the red blood cells.

The white cells are low and the

platelets are low.

There's a lot of different causes

for this, but some

of these are important to know

about.

Particularly, autoimmune disease

can cause pancytopenia. Many,

many different drugs, including very

common drugs that we use, such as

antibiotics.

As well as many, many

others, particularly in those

hospitalized patients.

Infections.

Parvovirus is one to always think

about with pancytopenia.

But then many other viral infections

can lead to this, too, including

HIV, EBV, CMV

and then bacterial infection,

particularly in sepsis.

Nutritional B12, folate,

copper, we just talked about that

with macrocytosis, but that

can affect more than just the red

blood cells. That can affect the

white cells and the platelets as

well.

And then, of course, any kind of

malignancy that is invading

the bone marrow, really crowding out

the normal ability of the bone

marrow to make the precursor

cells such as leukemia,

lymphoma, multiple myeloma,

or solid tumors that have

metastasized to the bone marrow.

So that wraps things up.

Here's my summary.

So the CBC is such an important

and a very common laboratory

study. It gives us clues towards

many different disease processes.

Many of these are hematological

based, such as a primary

bone marrow disorder.

But many other systemic illnesses

will cause anemia or other

cytopenias.

Those other CBC parameters

are really helpful to review

to help you work up the patient

with anemia. We talked about the

MCV, the RDW,

white cell differential, etc.

And don't forget about a peripheral

smear because that can give you

other helpful information that

you won't get from an automated CBC.

Thank you very much.