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Hematology/Endocrinology: 4:00-5:00
Tuesday, October 20, 2009
Dr. Steciuk
I.
Anemias and Hematopathology
Scribe: Ashley Holladay
Proof: Teresa Kilborn
Page 1 of 6
Anemias and Hematopathology [S1]:
a. [email protected] is his email.
II. Blood [S2]
a. Anemias and hematopathology- really broad topic.
b. We will be going over the anemias and just go over some of the anemias and give some non-neoplastic
hematopathology along the way.
c. There are several major components. There are cellular components
i. Red cells, white cells, and platelets.
ii. The red cells carry oxygen via hemoglobin
iii. WBC react to infection. These are neutrophils, lymphocytes, monocytes.
d. Platelets are important to homeostasis and the coagulation pathway.
e. The noncellular components, you have plasma, most of which has albumin and protein. But for our purposes, it
contains all of the coagulation proteins that are needed.
f. The picture is a vial of blood that is spun down. Without being spun down it is all red. If it is spun downclear/yellow plasma on top. On the bottom you get red cells. The red cells are what carry the oxygen with
hemoglobin. The hematocrit is the percentage of RBCs. You just measure the height of the tube and take the
percentage of the RBCs to get the hematocrit (about 40%). The other thing that we measure is the hemoglobin
to measure RBC or just the number of RBC.
III. Normal CBC Ranges [S3]
a. You do not have to memorize these numbers- just to give you the info.
b. RBCs- 4.5 million per microliter. Hemoglobin usually 14-16 g/dL. The life span of a RBC is about 120 days.
c. WBC- 4-10,000/ cubic ml. There are a lot less WBC. You can see this in the peripheral smears.
d. Platelets- 150-400,000/ cubic ml. These are less conspicuous because they tend to be small. The lifespan of a
platelet is about 7-10 days.
IV. Normal WBC Differential [S4]
a. This is a peripheral smear. Small red cells- RBC. You can see large neutrophil (WBC) in the top picture and
lymphocyte (WBC) in bottom picture. The smaller “dots” in the background are platelets. This picture just gives
you the normal differential.
V. Nomenclature [S5]
a. If you have a low number of RBC- anemia
b. If you have a high number of RBC- erythrocytosis or polycythemia.
c. If you have a low number of WBC- leukopenia
d. If you have a high number of WBC-leukocytosis. If it is a more specific WBC. Neutropenia-low, neutrophiliahigh. Platelets. Thrombocytopenia- low, thrombocytosis- high.
VI. Anemia [S6]
a. Anemia is a decrease in the oxygen carrying capacity of the blood. There are several ways to measure it. It is a
decrease in the total number of RBCs usually compared to a reference interval or a decrease in the hemoglobin
or hematocrit. Usually these go together.
b. There are a lot of causes for anemia. To figure out what the causes are, you need to have a good patient
history, medical history, medications, and a physical exam.
c. The general causes of anemia- you have a certain amount of RBC, and it is in flux, just like any physiologic
system You can get anemia by decreased production of RBC or increased destruction of RBCs. If you do not
make enough of it or if you destroy the ones you do have. You can also get anemia just by bleeding it out. If
you cut your wrist and bleed a lot out and you measure the hematocrit- it should be normal. But if you continue
to bleed and need saline to revive- the hematocrit will be lower in an hour because the body has added water
and saline into the intravascular system and diluted out the red cells. That allows the body to maintain volume
and blood pressure. That is the anemia of acute blood loss. It is not really a physiological thing, it is more just
dilution. That will be the same for all the cells. The platelets, lymphocytes, etc. will all be equally decreased.
VII. Clinical Manifestations of Anemia [S7]
a. Clinical manifestations of anemia are weakness, being tired, short of breath, pale, angular stomatitis, glossitis,
mucosal ulcers potentially. Koilonycia is spoon shaped nails. And you would get gastric atrophy. He will focus
more on laboratory manifestations.
VIII. Classification of Anemias [S8]
a. There are a lot of these and they are very complicated. You can look at the pathophysiology, and that is the
way we will look at it today.
b. A lot of clinicians like to classify anemias according to their red cell indices. You look at whether the red cells
are large, the amount of hemoglobin, etc.
Hematology/Endocrinology: 4:00-5:00
Scribe: Ashley Holladay
Tuesday, October 20, 2009
Proof: Teresa Kilborn
Dr. Steciuk
Anemias and Hematopathology
Page 2 of 6
c. You can also classify them according to their prevalence.
IX. Pathophysiological Classification of Anemia [S9]
a. All of these are caused by decreased production of RBC.
i. You can have a defect in hemoglobin synthesis. That will cause to not be able to produce as many or
functional red cells.
ii. You can have a defect in DNA synthesis which will impair the body’s ability to produce red cells
iii. You can have an isolated defect in hematopoietic differentiation for some reason.
iv. Alternatively anemia of chronic disease is also an inability to make enough RBC.
X. Cont. [S10]
a. Increased destruction
i. If you have hemolysis (lysing the red cell).
ii. If you have hemolysis due to something within the red cell, like a membrane defect or an enzymatic defect
within the red cell, that is referred to as an intracorpuscular hemolysis. Corpus- cell. (within the red cells).
These are defects intrinsic to the red cell that are going to cause hemolysis.
1. Membrane defects
2. Enzymatic defects
3. Abnormalities in the globin chain (sickle cell anemia)
4. Abnormalities of the production of heme itself
iii. It increased destruction can also be caused by things outside of the red cells.
1. Mechanical destruction (microangiopathic hemolytic anemia)
2. Prosthetic cardiac valve
3. Infections can cause destruction of the red cell even though there is nothing wrong with the red cell
itself, but it can cause the red cell to lyse
4. Drugs, toxins, burns
5. Anything that mechanically damages the red cell can cause extracorpuscular hemolysis and
increased destruction
6. It can be an antibody mediated diseases, like autoimmune hemolytic diseases
XI. Cont. [S11]
XII. Reticulocytes are New Red Cells [S12]
a. Red cell- RBC
b. Purple cell- no nucleus, a little bigger and darker than a red cell- reticulocyte. This is an immature RBC. It is
when a red cell is not fully matured, just let out of the bone marrow and into the peripheral blood. They usually
do not look this impressively different.
XIII. RBC-Volume (size) Variation [S13]
a. Normal MCV (mean corpuscular volume- this is a measure of the red cells) is normally between 80-100.
Normocytic- normal size of the red cell
b. Macrocytic- greater than 100 MCV. Macrocyte- big red blood cell.
c. Microcytic- less than 80 MCV. Microcyte- small red cell.
d. The MCV is a way to classify anemias.
XIV. Anemia [S14]
a. One way to classify what type of anemia a patient has is by looking at the red cell indices. You start by looking
at the reticulocyte count. If the reticulocyte count is high- it tells you that the bone marrow is putting out new red
cells and you do not have a problem with productions. This probably means you have increased destruction of
red cells.
b. If you have a low reticulocyte count- that means you have a problem producing RBC. If you have an anemia,
your bone marrow should be pumping out more reticulocytes. If it doesn’t, it means you have a problem
producing the red cells. If the reticulocyte count is low, you have a problem producing red cells. For one reason
or another your bone marrow is unable to get red cells out into circulation.
c. You can further classify those by their MCV of their size.
d. If the MCV is normal, you would think about aplastic anemia, mylothistic anemia, infection or renal disease.
e. If the MCV is low (this is the most common), you would think about iron disease, chronic disease, sideroblastic
anemias and thalessemias.
f. If the MCV is high (this is rare), you have big red blood cells but not enough of them, you think about folate or Vit
B12 deficiency.
XV. Anemia- worldwide major categories [S15]
a. Classification of anemias by prevalence.
b. The most common anemia is iron deficiency anemia. This is important ** It is about 38%. This makes sense
when you look at the causes of iron deficiency anemia. Iron deficiency is the most common cause of anemia.
Hematology/Endocrinology: 4:00-5:00
Scribe: Ashley Holladay
Tuesday, October 20, 2009
Proof: Teresa Kilborn
Dr. Steciuk
Anemias and Hematopathology
Page 3 of 6
c. Thalessemia and sickle cell disease are also very common and will make up about 36% of anemias.
d. Anemia of chronic disease follows with about 18%.
e. All of the other causes of anemia combined are about 8%. These will be much lower on your index of suspicion.
XVI. Hemoglobin Molecule [S16]
a. The hemoglobin molecule is made up of 4 globin chains. There is an iron atom within each of the globin chains,
and that is what is responsible for carrying oxygen. There are two alpha and two beta chains and there is an iron
in each globin chain.
XVII. Iron Stores [S17]
a. We can look at iron stores to see what type of anemia it is.
b. The vast majority of the iron in your body is present in hemoglobin- 2/3. It is floating around in your blood
attached to heme.
c. 305 is in the storage stage in the ferritin molecule or the hemosiderin molecule. Ferritin is the more dynamic
and hemosiderin is a more long term granule with little structure.
d. 3 % is in the muscle in the form of myoglobin.
e. Only 0.1% is floating around freely in the blood.
f. Ferritin is a storage form that is important to measure. It can be found circulating in the blood but it is not part of
hemoglobin.
g. Transferrin is what you actually transport the iron around in a way that is rapidly usable to the body. If the body
needs to get iron from one place to another it will use transferrin to get it there. Transferrin=transport.
XVIII. Iron Deficiency Anemia [S18]
a. Iron deficiency anemia is a the most common. It is classified by decreased production and an inability to make
hemoglobin. Hemoglobin has 4 iron atoms. If you don’t have enough iron, you can’t make enough hemoglobin
and you get less RBCs.
b. There are a lot of causes of iron deficiency anemia.
i. You can have decreased intake of iron
1. Longterm malnutrition
ii. You can have an increased need for iron
1. Kids
2. Pregnant women
3. Any time you go through a rapid growth phase.
iii. Any type of chronic blood loss could cause an iron deficiency.
1. Menstruation is a common cause. You will lose iron with the loss of blood and are unable to
replenish it.
2. GI losses- colon cancer, inflammatory bowel disease or anything that bleeds into the GI tract will
cause anemia.
iv. Any hemolytic process- even if the hemolysis is intravascular, you still lose the iron because the body is not
able to absorb it rapidly enough.
c. To diagnose iron deficiency anemia- peripheral smear. The RBCs are small and look empty and do not have a
lot of volume. If they are small, it is a microcytic anemia.
d. You would have a small amount of ferritin (storage form) because you do not have a lot of iron.
e. You will have high levels of transferrin. Transferrin is what carries the iron. Your body will sense that it is low on
iron and try to pump out the amount of iron it is able to move out of its stores. Your transferrin will go up as
your body tries to get the iron to bone marrow. You end up with a low transferrin saturation because you have a
lot of transferrin but not a lot of iron to put it on.
f. If you do a bone marrow biopsy and stain for iron- it will not be present.
g. Treatment- Give iron and address the underlying problem.
XIX. Sideroblastic Anemias [S19]
a. This is a problem with hemoglobin synthesis, and there are a variety of disorders.
b. Sidero=iron, blast= big cell. In sideroblastic anemia, you are unable to incorporate iron into heme. You will
have enough iron there, but cannot get it into heme.
c. There are multiple causes
i. Hereditary
ii. Drugs
iii. Lead poisoning
iv. Long term use of alcohol
d. You are not able to the iron (which you have plenty of) into heme.
e. Diagnosis- microcytic anemia just like iron deficiency.
Hematology/Endocrinology: 4:00-5:00
Scribe: Ashley Holladay
Tuesday, October 20, 2009
Proof: Teresa Kilborn
Dr. Steciuk
Anemias and Hematopathology
Page 4 of 6
i. You will have a high ferritin because you do have a lot of iron and your body will take in more and more but
there is some blockage somewhere.
ii. You will have a low transferrin and an increased transferring saturation. You will have enough iron and
transferrin but just not getting into the marrow.
f. Looking at the bone marrow, you will see ring sideroblasts. These are early erythroid precursor blasts with lots
of iron around them. There is a ring of iron around (blue).
g. You treat the inciting agent if possible.
XX. Thalassemias [S20]
a. In your normal hemoglobin molecule you have 4 globin chains, 2 alphas and 2 betas. In thalassemias you have
a genetic defect that prevents you from getting enough alpha chains.
b. Looking at the peripheral smear, you have distinctive looking target cells.
c. There are genetic defects in the alpha chain. The severity depends on the degree of genetic deficiency.
d. It will result in a microcytic anemia in a peripheral smear with target cells.
e. You diagnose it with hemoglobin electrophoresis.
XXI. Flowchart [S21]
a. This is a chart that shows that Vit B12 and folate are important for DNA synthesis. This is all you need to know
from this slide- don’t memorize the chart. If you don’t have folate, you can’t make DNA. Red cells turn over a
lot, so this is one of first places where you see problems with DNA synthesis.
XXII. Vitamin B12 and Folate Deficiency [S22]
a. Deficiency of folate can cause birth defects. This is why pregnant women take folate. It is important to catch it
early.
b. B12 deficiency causes neurologic symptoms.
c. B12 deficiency doesn’t cause birth defects and folate deficiency doesn’t cause neurologic symptoms. Those
things are exclusive.
d. Otherwise these are very similar. They affect all of the hematopoetic lines. They cause a macrocytic anemia.
That means that the red cells are large. This has to do with the maturation of the red cells. This is pretty
unique. Not many conditions cause a macrocytic anemia.
e. The peripheral smear shows this, but it is hard to tell by just looking at the smear that they are macrocytic. Cell
counters, cell size and monitors and meters to tell the size of the RBC. The neutrophil on the slide has 6 lobes.
If you know this, you know it is B12 or folate deficiency. It is very specific and can be diagnosed by just seeing
one cell that has 6 neutrophilic lobes. Folate and B12 are important to DNA synthesis. It will not just affect red
cells, it will also affect platelets and WBCs so you will be able to recognize it.
f. MMA (methylmalonic acid) and homocysteine tests can be used to help figure out which one of these is the
problem if you are trying to differentiate between the two.
g. You treat this with B12 or folate.
XXIII. Aplastic Anemia [S23]
a. This is a decreased production of red cells. This is a problem with hematopoietic differentiation. In the normal
bone marrow (top), you see some fat, some hematopoietic precursors. If you have aplastic anemia (bottom),
you see a lot of fat and basically an empty marrow. That is what someone with aplastic anemia looks like. They
don’t have any cells in their marrow. It is a bone marrow failure involving all 3 cell lines. You see
thrombocytopenia, leucopenia and anemia.
b. It can be idiopathic, caused by drugs, chemical, viruses. There are inherited forms **** anemia is an example.
c. Diagnosis- you see pan cytopenia. That is cytopenia of all 3 cell lines and diagnosis by bone marrow biopsy.
d. The treatment is to take away whatever agent is causing it if you can find it. Otherwise you should have a bone
marrow transplant or the patient would die.
XXIV. Myelophthisic Anemia [S24]
a. This is a lot like aplastic anemia functionally, but you see a marrow that is full rather than an empty marrow. But
it is not full of normal marrow elements. You see a carcinoma or fibrosis or abnormal cell due to a storage
disorder. You could see a lymphoma where a cancer is filling the marrow and it pushes all of the marrow
elements out so there is no place in the marrow for the normal hematopoesis to occur. So you get cytopenia.
b. If you have a fibrosing process, the little amount of red cells that are there, have a hard time getting out, and
they get deformed as they are trying to squeeze their way out. And you get these funny looking shapes- tear
drop cells- forming as the red cell is trying to squeeze its way out of a packed marrow.
c. Diagnosis by bone marrow biopsy.
d. Treatment- hopefully by being able to address the underlying causes, but this is usually a bad sign.
XXV. Anemia of Chronic Renal Failure [S25]
a. The kidney is responsible for sensing the blood volume. Part of that is sensing the number or red blood cells
and therefore responsible for secreting erythropoietin. Erythropoietin tells the marrow to make red cells.
Hematology/Endocrinology: 4:00-5:00
Scribe: Ashley Holladay
Tuesday, October 20, 2009
Proof: Teresa Kilborn
Dr. Steciuk
Anemias and Hematopathology
Page 5 of 6
b. When you have kidney failure, your kidney is no longer able to secrete erythropoietin and your marrow will not
be making red cells.
c. You get a normocytic anemia, and the lab finding will be dominated by an elevated BUN and creatinin. It will be
dominated by the renal failure and the patient will have an anemia.
d. You treat this patient with erythropoietin.
e. Cyclists often dope their blood with erythropoietin. It is a common way to dope because you can increase the
number of red cells and therefore their oxygen carrying capacity so that they can climb mountains better.
XXVI. Anemia of Chronic Diseases [S26]
a. It is hard to know what is really going on in this situation. In many chronic diseases (like arthritis, tuberculosis,
anything associated with long term inflammation), you get anemia. Inflammation causes an increase in the
number of acute phase reactions including lactoferrin, and ferritin (all of which tie up iron and prevent it from
being incorporated into red blood cells).
b. The reason this is important is because it is very common. 3rd most common behind iron deficiency and sickle
cell and thalassemia. It contributes to about 18%. It is common because a lot of people have chronic disease.
c. It is diagnosed by looking at the blood and seeing a microcytic anemia. You can tell it apart from iron deficiency
because you have increased ferritin, decreased transferrin and decreased transferrin saturation. You have a lot
of iron but are not able to move it around. It is tied up in long term storage.
d. If you look in the bone marrow, where you could have long term storage, you have a lot iron there, so you do not
have decreased iron. It is just tied up because of the inflammation.
e. Treat the underlying condition or treat with iron or erythropoietin.
XXVII. Hemolysis [S27]
a. Hemolysis is characterized clinically by jaundice, palor, dark urine- acute hemolysis presents this way.
Hemolysis is almost always a process by which a red cell is destroyed. You will get reticulocytosis if your
marrow is okay and you do not have enough cells, you will try to get red cells out. You will get reticulocytosis
because the marrow will want to push out as many new cells as you can. This will characterize all of the
disorders of increased destruction.
b. You will also get elevated LDH and indirect bilirubin. You will have a decreased haptoglobin. These lab tests
will help you diagnose hemolysis.
c. Peripheral smear- you will have reticulocytes, spherocytes, schistocytes and nucleated red blood cells.
XXVIII. Reticulocytes… (Histology) [S28]
a. Reticulocytes are new cells. A nucleated red cell is even more immature than a reticuloctye. The last thing a
red cell does before it leaves the marrow is push its nucleus to the outside. The red cell precursors start with a
nucleus, and then they push their nucleus out into the marrow and then leave and go into the blood stream. If
your body is just trying to get erythrocytes out as fast as it can in a real severe anemia or hemolytic process, you
will see nucleated red cells. You can tell this from a lymphocyte because they are almost perfectly round.
b. Schistocytes look like torn up red cells. They are red cells that have been torn apart by different processes.
c. Spherocytes. If you have a really small red cell with not a lot of membrane. The red cell starts off with a lot of
membrane and folds down to become biconcave. If you take a lot of that membrane and start pinching it off, the
cell will try to round up because a sphere has the least surface area. If you don’t have a lot of membrane you
will try to minimize your surface area when you have a hemolytic process.
XXIX. Hereditary Spherocytosis [S29]
a. This is a hemolytic process- increased destruction. It is an intracorpuscular defect inherent to the red cell. It is
a genetic deficiency in the structural protein of red cells that are required to maintain their shape (spectrin, etc.).
When you have defects here you are unable to maintain that biconcave shape and you get a round cell. As the
red cell goes through the spleen, it will recognize that the RBCs are somewhat mis-shapen and it will take off
little bits of membrane until all of the red cells in the circulation have this round shape because they have lost
the membrane. They will all look like spherocytes instead of your typical hemolytic process where just a few are
spherocytes. This is because all of these have that defect in the cytoskeleton that causes the spleen to destroy
them.
b. You will get red cell destruction in the spleen. It is a hemolytic anemia. You get a lot of spherocytes in the
peripheral blood. This typically presents in infants. These spherocytes are sensitive to high levels of sodium, so
we use that test for it.
c. Treat this by splenectomy. You take out the spleen and there is now nothing to destroy the mis-shapen red
cells. These patients do fine for the rest of their lives.
XXX. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency [S30]
a. G6PD- increased destruction caused by an enzyme deficiency. Hereditary spherocytosis- problem with the
skeleton of the red cell. G6PD is a problem with an enzyme within the red cell. G6PD is necessary for the
production NADPH which fights free oxygen radicals. If you have a lack of NADPH because of a G6PD
Hematology/Endocrinology: 4:00-5:00
Scribe: Ashley Holladay
Tuesday, October 20, 2009
Proof: Teresa Kilborn
Dr. Steciuk
Anemias and Hematopathology
Page 6 of 6
deficiency, your red cells are subject to oxidative damage. So if you are exposed to an oxidative insult, you get
severe hemolysis. Many things can cause acute exacerbations.
b. Usually these are African Americans and people of Mediterranean descent. Antimalarials are notorious to
cause this and fauva beans have also been the cause.
c. Diagnosis- you get hemolytic anemia and you can test for G6PD enzyme activity.
d. Treatment- avoid the agent that is causing.
XXXI. Sickle Cell Anemia [S31]
a. This is increased destruction disorder. This is a disorder of globin synthesis. It is a genetic defect in the globin
chain sequence. It causes structurally abnormal hemoglobin and the RBCs to sickle. The sickle shape gets
caught in the peripheral circulation that causes vasoclusion.
b. It is most common in African Americans. You get anemia and peripheral smear with sickle cells.
c. Treatment with transfusion, red cell exchange, hydroxyuria. Hydroxyuria is a drug that works by increasing the
amount of fetal hemoglobin which is unaffected by sickle cell disease.
XXXII. Porphyrias [S32]
a. This is a combination of increased destruction and decreased production because of an abnormality in heme
synthesis.
b. It is a group of disorders that have problem in the enzymes that make heme. It presents with a very clinical
picture.
i. Photosensitivity
ii. Pale complexion
iii. Mis-shapen and fluorescent teeth
iv. Anemia and hemolytic anemia
v. It is thought that these people are the basis for the legend of vampires.
XXXIII. Paroxysmal Nocturnal Hemoglobinuria [S33]
a. PNH is increased destruction caused by a genetic defect that is acquired in life as a clonal abnormality in your
red cell hematopoietic precursors. You lose a gene PIGA (phosphoinositol glycan) that anchors membranes to
the surface of red cells.
b. It anchors. Two of the cells that it anchors are CD55 and CD59. They are responsible for prevented
complement mediated destruction of red cells. If you lose this PIG A gene, you lose CD55 and CD59 on the
surface of your cells. The red cells become susceptible to complement mediated lysis. For some reason this
tends to happen at night. The complement attacks the red cells at night. These people end up with massive
hemoglobinuria but only at night.
c. The diagnosis is confirmed by cytometry (looking for these decreased surfaces of the red cells.)
d. There is no cure for this. All you have is supportive therapy.
e. This is as far as he got today- he will pick it up on the next lecture.
END [44:41]