Pathology - Dr. Morgan Sneha Patel
P040509 Ashis Barad
WHITE CELL DISORDERS
He started off with some jokes about hematology and then started on page 535 of the notes. I tried to keep the outline format that Dr. Morgan used in his notes, but there are spots where he just goes off for a long time (these are the bulleted areas in the scribe). I tried to make it as easy to read as I could, but if you have any questions just ask.
I. Leukopenia
A. Neutropenia
1. Decrease in the absolute number of neutrophils below the normal range of 2,500-7,000 neutrophils/mm3. You will notice however, that some of these normal ranges will vary a lot depending on the patients age, especially in pediatrics. However, for the purposes of this class we will only be concentrating on the normal adult range of 2500 -7000.
· He stressed that it is very important to know the absolute numbers of the different types of WBC's. This is especially important when looking at a CBC report that often gives percentages of the different WBC's . A normal percentage of neutrophils might be about 60 -70 %, but it doesn’t really mean a lot because when the WBC count increases or decreases, the percentage may increase or decrease with it. The percentage is only important when the WBC count is within the normal range.
· For example: A patient can have a WBC count of 50,000 (which is very high) and a %age of neutrophils of only 10% (which is a whole lot below the normal %age range). This low percentage does not however mean that a patient has neutropenia because 10% of the total WBC count is 5,000, which is within the normal range of 2500-7000.
· The point: IGNORE percentages. The first thing to do when interpreting a CBC report is to multiply the WBC count (Segmented + Band Neutrophils) by the different percentages of cell types to give an absolute number.
a. Cyclic Neutropenia: a benign syndrome of low neutrophils that is more common in blacks. It has no clinical significance, other than the fact that their neutrophil count is low. They do NOT have an increased risk of infection. You diagnose this when a patient comes in with an absolute neutropenia and their past medical records show no history of repeated infections. To make sure of the diagnosis, you should have the patient come back again in a couple of weeks and see if their neutrophil level has returned to normal. If it has then you are probably dealing with a cyclic neutropenia.
b. Severe Persistent Neutropenia: aka-Agranulocytosis – which is usually a misnomer, because you hardly ever see an absolute neutrophil count of 0. Syndrome in which the neutrophil level is <2500 and it stays that way. This DOES predispose to infection. Initial symptoms include malaise, chills, fever, onset of infection, and easy fatigability. If the patient does not have enough neutrophils, he will have a difficult time warding off bacterial infections. This is a major cause of death in cancer patients on chemotherapy because one of the major side effects of chemotherapeutic drugs is neutropenia. Remember that neutrophils have the shortest lifespan and thus their numbers drop very quickly and stay down for a long time until the patient's bone marrow starts to regenerate.
2. Etiology of Neutropenia
a. Inadequate or ineffective granulopoiesis
i. Aplastic Anemia: if everything in the bone marrow is wiped out, the neutrophil count will also drop.
ii. Leukemias and Lymphomas: especially when a lymphoma involves the bone marrow and it crowds out the normal bone marrow. Would see a pancytopenia, along with a neutropenia and thrombocytopenia.
iii. Myelosuppressive drugs including chemotherapeutic drugs
iv. Megaloblastic anemia: B12/folate deficiency inhibits DNA synthesis, therefore there is not only a decrease in RBC's but also a decrease in the WBC's and platelets.
v. Myelodysplastic syndromes: acquired syndromes usually in elderly, in which we see cytopenias and morphological abnormalities.
b. Accelerated removal/destruction of neutrophils
i. Seen with a lot of immunological syndromes like Felty's syndrome (rheumatoid arthritis, splenomegaly, neutropenia, and leg ulcers). There may be a decrease in neutrophils.
ii. In Felty's syndromes, the decrease in neutrophils is specifically due to sequestration due to splenomegaly. These individuals may also produce autoantibodies that can react against neutrophils, which can cause an additional decrease in neutrophils. In any of the autoimmune diseases and any of the causes of splenomegaly, it is possible to see a neutropenia.
c. Decreased production/increased destruction
i. Drug effects of chloramphenicol and sulfonamides
ii. Viral infections
Question from student: How does megaloblastic anemia cause neutropenia?
Megaloblastic anemia is where there is a deficiency in B12 or folate, which are both necessary for DNA production. This deficiency will therefore interfere with any mitotically active cells, including the stem cells of the bone marrow. Without them, there is no proper production of neutrophils, erythrocytes, platelets, . . . In addition, because neutrophils are so short-lived (1-2 days), they are very strongly affected.
B. Lymphopenia
1. A decrease in absolute numbers of lymphocytes. The normal adult range is 1000-4000 lymphocytes/mm3. Children normally have more lymphocytes, both in their bone marrow and their peripheral blood. Their normal range is up to 8000 lymphocytes/mm3.
2. Etiology
a. Bacterial infections and sepsis cause lymphopenia, just like viral infection cause neutropenia,. Therefore, it is possible to look at the absolute numbers of neutrophils and lymphocytes and get an idea as to whether the cause of the infection is viral or bacterial.
b. TB
c. Uremia
d. Lymphomas.
II. Reactive Leukocytosis: an increase in leukocytes. The term leukocytosis does not tell you anything about the kind of WBC that is increased, just that there is a general increase in the WBC count. Therefore, again you must multiply the percentages of each individual WBC type with the number of WBC's to find out which of the WBC types is increased (it can be more than one). See Robbins, Table 15-1, p648. It gives the different causes for leukocytosis.
A. Neutrophilia (aka-Neutrophilic leukocytosis or Granulocytic leukocytosis (not really a good term because it refers to any type of PMN granulocytes, not just neutrophils)): a significant increase above the normal range of neutrophils (segmented and bands). The absolute number for this is above 8000.
1. Etiology
a. Bacterial infection - the most common one and the most important one. With bacterial infection, you see a left shift and reactive changes including toxic granulation, cytoplasmic vacuolization, and Dohle bodies.
What is a Left Shift?
· It is NOT an increase in the number of bands, but rather an increase in the number of cells less mature than bands in the peripheral blood. The number of neutrophils and bands increase quickly with any physiologic stress because they hang around in the marginal pool at the edges of blood vessels and in the spleen.
· Therefore, a bacterial infection can be noted with the presence of reactive changes along with presence of granulocytes less mature than band forms (which are usually found in the bone marrow and NOT in the margins of the blood vessels or peripheral blood or the spleen). There is hyperplasia of granulocytic elements, as neutrophils and earlier forms of neutrophils get pushed out into the peripheral smears in an attempt to deal with the stress.
See Robbins Fig 15-2, pg 648: Examples of different mechanisms associated with neutrophilia
· Types of white blood cell pools in our body
-The precursor pool is in the bone marrow. This pool is ready to become hyperplastic whenever needed, in order to produce more neutrophils.
-The storage pool includes the more mature elements that are found in the bone marrow. These can get kicked out into the peripheral blood as well, when needed.
-The marginal pool is found at the margins of blood vessels and the spleen
-The circulating pool, is also found in the blood vessels. The circulating neutrophils from this pool can enter tissues to fight off infections.
· Mechanisms-The first 3 mechanisms are examples of physiological leukocytosis, where you may see an increase in bands and/or neutrophils, but they are not specific for infection.
- Increased release of marrow storage pool cells: This can happen with endotoxemia such as with sepsis, acute infection, hypoxia, or glucocorticoid use. In this case, cells from the storage pool have gone out into the circulation. Therefore we see an increase in both the marginal pool and the circulating pool. This would give an increase in the number of circulating neutrophils. But, we don’t see a left shift. Acutely there is no stimulus to the precursor pool, although if these problems become more of a chronic thing, there eventually may be a stimulus to the precursor pool to increase and cause a left shift.
-Demargination of neutrophils: This can happen with acute infection, exercise, and especially epinephrine (from a stressful situation). The WBC count may go up a little. However, there is also a shift from the marginal pool into the circulation. Therefore, you see an increased percentage of bands. This is NOT specific for acute infection.
-Decreased extravasation into tissues: With more chronic stress, you get release of glucocorticoids. In this case, you see an increase in bands and neutrophils in the peripheral blood.
-Expansion of marrow precursor pool: This is due to chronic infection, inflammation, tumors, rebound from neutropenia, and malignant disorders in the myeloproliferative syndromes. In these cases, we have an increase in the precursor pool and an increase in the storage pool within the bone marrow, so you see a granulocytic hyperplasia with an increased cellularity of the bone marrow and expansion of the cells in the peripheral blood. A TRUE LEFT SHIFT would be seen because of the hyperplasia of the bone marrow, thus granulocytes less mature than band cells will be found in the blood.
(contd from above: “Etiology of Neutrophilia”)
b. Physiologic Stress Leukocytosis
c. Leukemoid reaction: This is when the white cell count becomes very high (almost to the point that is associated with leukemias >100,000). Also see immature granulocytes (also a sign of leukemia, particularly chronic granulocytic leukemia, which has maturing granulocytes). However, the big difference between a leukemoid reaction and a leukemia is that a leukemoid reaction is reactive. The main differential diagnosis of a leukemoid reaction is chronic granulocytic leukemia.
d. Leukoerythroblastosis: the presence of immature precursors (not necessarily blasts) of the WBC’s, especially neutrophils and erythroid cells in the peripheral blood. Therefore, there is an increase in granulocytic band cells and also nucleated blood cells are present on the peripheral smear. This also tells us that there is either hyperplasia in the bone marrow of neutrophils and erythroid precursors or that there is an extramedullary hematopoeisis where the immature precursors are leaking out into the blood. DDx of leukoerythroblastosis includes chronic granulocytic leukemia, which can also have circulating red cell precursors.
Slides of examples of reactive changes in neutrophils:
-Cytoplasmic vacuolization: This is often not seen until there is sepsis. In other words, when the microorganisms or the bacteria actually are circulating in the blood. Many times, you may actually see the microorganisms in the cytoplasmic vesicles of the neutrophils. This is a much better indicator of bacterial infection (especially sepsis) than just an increase in band forms because we know that the cells are actually reacting to something.
-Toxic granulation: See pretty normal looking bands and neutrophils with faintly staining cytoplasmic granules. When these cells react to an antigenic stimulation such as a bacterial infection, the granules increase in number and they become darker. This is because they are becoming more metabolically active. (Similar to Robbins, Fig 15-3, pg 649)
-Dohle body: blue blobs usually found at the periphery of the cells are clusters of rough endoplasmic reticulum and ribosomes. This only tells you that these cells are synthetically active. (Similar to Robbins, Fig 15-3, pg 649)
So, there are 3 main signs of a Bacterial Infection: cytoplasmic vacuolization, toxic granulation, and Dohle bodies.
B. Eosinophilia: the absolute increase in the number of eosinophils above 500/mm3. There is no such thing as eosinophilopenia – because normally it is possible to not see any eosinophils on a blood smear when a 100 cell differential count is done. With a machine count it is possible however, to get a low eosinophil count, but there is no clinical significance in having a low eosinophil count.
1. Etiology
a. Allergies such as hayfever and asthma. At this time of year a lot of people have eosinophilia.
b. Allergic drug reactions
c. parasitic infections (textbooks make a big deal about this, but in the US it is rare to find eosinophilia due to parasitic infections, because we don’t have problems with parasites like they do in 3rd world countries. When there is eosinophilia associated with parasitic infections, it is usually diagnosed very early on. However, it does need to be included in the DDx for eosinophilia).
d. Many skin disorders
e. Idiopathic eosinophilic syndromes include Loeffler’s syndrome which presents with endocarditis, eosinophilic infiltrates in the lungs and GI tract, and eosinophilic gastritis. Not very common.
f. Eosinophilia can also be seen with acute and chronic leukemias.
C. Basophilia: an increase in the absolute number of basophils above 100/mm3. This is rare.
1. Etiology
a. Myxedema
b. Chronic Myelogenous Leukemia (CML): Basophilia is used to distinguish between a leukemoid reaction and CML because basophilia is not seen with leukemoid reaction.
c. Ulcerative colitis, . . .(He said to read the rest)
D. Monocytosis: greater than 1000 monocytes/mm3
1. Etiology
a. chronic infections such as TB and bacterial endocarditis
b. chronic inflammation such as chronic vascular disease, inflammatory bowel disease, metastatic tumors, and myelodysplastic syndromes.
Monocytosis is nonspecific but can be an indicator of chronic infections or inflammation.
E. Lymphocytosis: greater than 4,000 lymphoctes/mm3 in adults and greater than 8,000 in children.