Hematology/Endocrinology: 4:00-5:00Scribe: Ashley Holladay

Tuesday, October 20, 2009Proof: Teresa Kilborn

Dr. SteciukAnemias and HematopathologyPage1 of 6

Anemias and Hematopathology[S1]:
is his email.
Blood [S2]
Anemias and hematopathology- really broad topic.
We will be going over the anemias and just go over some of the anemias and give some non-neoplastic hematopathology along the way.
There are several major components. There are cellular components
Red cells, white cells, and platelets.
The red cells carry oxygen via hemoglobin
WBC react to infection. These are neutrophils, lymphocytes, monocytes.
Platelets are important to homeostasis and the coagulation pathway.
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.
The picture is a vial of blood that is spun down. Without being spun down it is all red. If it is spun down- clear/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.
Normal CBC Ranges [S3]
You do not have to memorize these numbers- just to give you the info.
RBCs- 4.5 million per microliter. Hemoglobin usually 14-16 g/dL. The life span of a RBC is about 120 days.
WBC- 4-10,000/ cubic ml. There are a lot less WBC. You can see this in the peripheral smears.
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.
Normal WBC Differential [S4]
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.
Nomenclature [S5]
If you have a low number of RBC- anemia
If you have a high number of RBC- erythrocytosis or polycythemia.
If you have a low number of WBC- leukopenia
If you have a high number of WBC-leukocytosis. If it is a more specific WBC. Neutropenia-low, neutrophilia- high. Platelets. Thrombocytopenia- low, thrombocytosis- high.
Anemia [S6]
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.
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.
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.
Clinical Manifestations of Anemia [S7]
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.
Classification of Anemias [S8]
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.
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.
You can also classify them according to their prevalence.
Pathophysiological Classification of Anemia [S9]
All of these are caused by decreased production of RBC.
You can have a defect in hemoglobin synthesis. That will cause to not be able to produce as many or functional red cells.
You can have a defect in DNA synthesis which will impair the body’s ability to produce red cells
You can have an isolated defect in hematopoietic differentiation for some reason.
Alternatively anemia of chronic disease is also an inability to make enough RBC.
Cont. [S10]
Increased destruction
If you have hemolysis (lysing the red cell).
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.
Membrane defects
Enzymatic defects
Abnormalities in the globin chain (sickle cell anemia)
Abnormalities of the production of heme itself
It increased destruction can also be caused by things outside of the red cells.
Mechanical destruction (microangiopathic hemolytic anemia)
Prosthetic cardiac valve
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
Drugs, toxins, burns
Anything that mechanically damages the red cell can cause extracorpuscular hemolysis and increased destruction
It can be an antibody mediated diseases, like autoimmune hemolytic diseases
Cont. [S11]
Reticulocytes are New Red Cells [S12]
Red cell- RBC
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.
RBC-Volume (size) Variation [S13]
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
Macrocytic- greater than 100 MCV. Macrocyte- big red blood cell.
Microcytic- less than 80 MCV. Microcyte- small red cell.
The MCV is a way to classify anemias.
Anemia [S14]
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.
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.
You can further classify those by their MCV of their size.
If the MCV is normal, you would think about aplastic anemia, mylothistic anemia, infection or renal disease.
If the MCV is low (this is the most common), you would think about iron disease, chronic disease, sideroblastic anemias and thalessemias.
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.
Anemia- worldwide major categories [S15]
Classification of anemias by prevalence.
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.
Thalessemia and sickle cell disease are also very common and will make up about 36% of anemias.
Anemia of chronic disease follows with about 18%.
All of the other causes of anemia combined are about 8%. These will be much lower on your index of suspicion.
Hemoglobin Molecule [S16]
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.
Iron Stores [S17]
We can look at iron stores to see what type of anemia it is.
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.
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.
3 % is in the muscle in the form of myoglobin.
Only 0.1% is floating around freely in the blood.
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.
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.
Iron Deficiency Anemia [S18]
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.
There are a lot of causes of iron deficiency anemia.
You can have decreased intake of iron
Longterm malnutrition
You can have an increased need for iron
Kids
Pregnant women
Any time you go through a rapid growth phase.
Any type of chronic blood loss could cause an iron deficiency.
Menstruation is a common cause. You will lose iron with the loss of blood and are unable to replenish it.
GI losses- colon cancer, inflammatory bowel disease or anything that bleeds into the GI tract will cause anemia.
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.
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.
You would have a small amount of ferritin (storage form) because you do not have a lot of iron.
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.
If you do a bone marrow biopsy and stain for iron- it will not be present.
Treatment- Give iron and address the underlying problem.
Sideroblastic Anemias [S19]
This is a problem with hemoglobin synthesis, and there are a variety of disorders.
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.
There are multiple causes
Hereditary
Drugs
Lead poisoning
Long term use of alcohol
You are not able to the iron (which you have plenty of) into heme.
Diagnosis- microcytic anemia just like iron deficiency.
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.
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.
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).
You treat the inciting agent if possible.
Thalassemias [S20]
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.
Looking at the peripheral smear, you have distinctive looking target cells.
There are genetic defects in the alpha chain. The severity depends on the degree of genetic deficiency.
It will result in a microcytic anemia in a peripheral smear with target cells.
You diagnose it with hemoglobin electrophoresis.
Flowchart [S21]
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.
Vitamin B12 and Folate Deficiency [S22]
Deficiency of folate can cause birth defects. This is why pregnant women take folate. It is important to catch it early.
B12 deficiency causes neurologic symptoms.
B12 deficiency doesn’t cause birth defects and folate deficiency doesn’t cause neurologic symptoms. Those things are exclusive.
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.
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.
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.
You treat this with B12 or folate.
Aplastic Anemia [S23]
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.
It can be idiopathic, caused by drugs, chemical, viruses. There are inherited forms **** anemia is an example.
Diagnosis- you see pan cytopenia. That is cytopenia of all 3 cell lines and diagnosis by bone marrow biopsy.
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.
Myelophthisic Anemia [S24]
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.
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.
Diagnosis by bone marrow biopsy.
Treatment- hopefully by being able to address the underlying causes, but this is usually a bad sign.
Anemia of Chronic Renal Failure [S25]
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.
When you have kidney failure, your kidney is no longer able to secrete erythropoietin and your marrow will not be making red cells.
You get a normocytic anemia, and the lab finding will be dominated by an elevated BUN and creatinin.