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318 Cards in this Set
- Front
- Back
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Decreases in tissue O2 tension that attend anemia usually trigger increased erythropoeitin production except in the case of what disorder?
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Chronic renal failure
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Explain why in the case of chronic renal failure decreases in tissue O2 tension do not stimulate increased erythropoeitin production.
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If there is a decrease in tissue O2 tension in patients with chronic renal failure there will be a lack of appropriate response in increase in erythropoeitin production because erythropoeitin producing cells in the kidney are lost.
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How do you know when your marrow is increasing its production of RBCs
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You observe reticulocytosis
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What are reticulocytes?
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Newly formed RBCs
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What types of anemias will show reticulocytosis?
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Anemia due to blood loss or RBC destruction
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If the onset of anemia is slow, what are some of the compensatory mechanisms that the body will exhibit to compensate for the decreased O2 carrying capacity of the blood?
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1. Increase in plasma volume
2. Increase in cardiac output 3. Increase in respiratory rate 4. Increased RBC 2,3 bisphosphoglycerate levels |
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What are two symptoms that are common to all anemias?
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Pallor and lassitude
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What are 3 symptoms characteristic of Hemolytic Anemias?
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Hyperbilirubinemia, jaundice, and pigment gallstones
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Anemia due to what process is associated with inappropriately high levels of iron absorption in the gut?
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Ineffective hematopoiesis
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What are some of the Intrinsic Hereditary causes of hemolytic anemia?
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Membrane abnormalities, Enzyme deficiencies, Dsorders of hemoglobin production
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List three membrane abnormalities that can lead to hemolytic anemia:
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spherocytosis and elliptocytosis (membrane skeleton proteins) & abetalipoproteinemia (membrane lipids)
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List two hereditary enzyme deficiencies that could lead to hemolytic anemia:
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G6PD and Glutathione synthetase
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How does iron deficiency lead to anemia?
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Through underproduction, because Fe is essential for hemoglobin production and effective erythropoeisis.
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How long is the average life span of an RBC?
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120 days; 4 months
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What are two key clinical features that hemolytic anemias are almost invariably associated with?
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Erythroid hyperplasia within bone marrow and increased reticulocyte count in the peripheral blood
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When is extramedullary hematopoesis seen?
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In severe hemolytic anemias
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Which organs are involved in extramedullary hematopoesis?
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Spleen, liver, and lymph nodes
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What job does haptoglobin do?
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Binds and clears free hemoglobin
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Which mode of destruction in hemolytic anemias is more common: Intravascular or Extravascular hemolysis
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Extravascular hemolysis= Macrophages
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What causes most Alpha Thalassemias?
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Gene deletion
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What causes most Beta Thalassemias?
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Errors in mRNA transcription, processing, or translation
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What are the two results that contribute most to the pathogenesis seen in Beta Thalassemias?
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Reduced HbA formation and Red Cell Hemolysis
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What causes the propensity for red cell hemolysis in Beta Thalassemia?
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Unpaired alpha chain formation in RBCs that aggregate and precipitate leading to membrane damage and removal through extravascular hemolysis. ***Erythroblasts are also susceptible through intramedullary destruction
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What is a special characteristic cell seen in Beta Thalassemia? And what is responsible for its characteristic appearance?
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The Target Cell; it looks like a target because there is a large increase in the surface to volume ratio, which leads Hb to collect in the center of the cell
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Explain why it is common to see cardiac failure in patients with Beta Thalassemia?
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Due to secondary hemochromatosis from chronic increased iron absorption (iron overload)
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Describe why there is a marked increase in iron absorption in patients with Beta Thalassemias.
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This is because ineffective hematopoiesis occurs, which is associated with low levels in Hepcidin. Hepcidin is the key player as it is a negative regulator of iron absorption.
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What two factors contribute most to the iron overload seen in patients with Beta Thalassemia Major?
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1) Increased iron absorption due to low levels of hepcidin
2) The administration of necessary blood transfusions |
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What lab test is needed to make a diagnosis of Beta Thalassemia minor?
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Gel electrophoresis
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Describe the clinical observations that are diagnostic of Beta Thalassemia.
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1) A peripheral blood smear showing microcytic hypochromic anemia
2) Poikilocytosis (marked variation in cell shapes) 3) Reticulocytosis 4) Electrophoresis shows profound reduction or absence of HbA and increased levels of HbF. HbA2 may be normal or increased. |
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Name the conditions associated with the deletion of:
1) 4 alpha globin genes 2) 3 alpha globin genes 3) 2 alpha globin genes 4) 1 alpha globin genes |
1) Hydrops Fetalis (fetal death)
2) HbH disease (moderately severe) 3) Alpha Thalassemia Trait ( Like B-trait) 4) Silent Carrier |
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What molecule is responsible for protecting RBCs from oxidative damage?
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Reduced Glutathione (GSH)
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What enzyme deficiency, associated with GSH production, is responsible for a hemolytic anemia?
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Glucose-6-Phosphate Dehydrogenase (G6PD)
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Is the G6PD mutation linked to the X or the Y chromosome?
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X-linked
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What U.S. demographic is most effected by G6PD deficiency (10% Carrier Rate)?
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Black Males
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What is different about G6PD in G6PD deficiency?
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It has a shorter half life than normal
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How does the shorter half life of G6PD lead to hemolytic anemia?
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RBCs lack protein synthesis ability, so as the cell ages it has an increased rate of enzyme loss without the ability to replenish it, leaving it more susceptible to oxidative damage
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When are signs and symptoms of G6PD deficiency first able to be noticed?`
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Only when the patient is exposed to an environmental factor that produces increased oxidative stress!!! (i.e. INECTIOUS AGENTS-most common- and DRUGS)
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What type of drugs are most often the culprits for producing increased oxidative stress?
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Anti-malarials, sulfonamides, nitrofurantion, phenacetin, aspirin in large doses, and vit K derivatives
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What is the typical intracellular inclusion body seen under the microscope when looking at G6PD deficiency?
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Heinz body = oxidized Hb that denatures and precipitates
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Are Heinz bodies damaging agents?
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Yes, they can damage the cell membrane sufficiently to cause intravascular hemolysis
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What is a "characteristic cell" seen in G6PD under the microscope?
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The Bite Cell
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What is mechanism is responsible for creating the bite cell?
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RBCs without GSH that undergo mild oxidative damage still suffer from loss of deformability and Heinz bodies. Splenic phagocytes create the "bite cell" when they attempt to "pluck out" the Heinz body
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What do the changes seen from Heinz Bodies and Bite Cells predispose the RBCs to?
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Becoming trapped in the splenic sinusoids and subsequent destruction by phagocytes (Extravascular Hemolysis)
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What is the gene mutation associated with Paroxysmal Nocturnal Hemoglobinuria (PNH)?
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PIGA mutation
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What is the gene PIGA required for in our meyloid derived cells?
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It is required for synthesis of the membrane protein anchor Phophatidylinositol Glycan (PIG)
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What is the PIG anchor in PNH responsible for?
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It is responsible for anchoring a compliment inactivating protein to the membrane of RBCs....without it RBCs are susceptible to compliment mediated lysis
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Why is hemolysis nocturnal in PNH?
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Because the it is believed that the blood becomes acidic during sleep due to CO2 retention and this favors hemolysis
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How is the PIGA mutation associated with PNH transmitted genetically?
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X-linked mutation
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Which myeloid lineages are effected in PNH?
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All myeloid lineages are effected
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Why are PIG deficient stem cells allowed to predominate?
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Because an autoimmune mediated event selects for them by preferentially targeting normal cells
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What do we use the Direct Coombs Antiglobulin Test for?
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To detect antibodies or complement on a patient's RBCs
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Which type of antibodies cause Warm Antibody Immunohemolytic Anemias(WAIA) (binding RBCs @ 37)?
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IgG, and rarely IgA (you see a lot of G-strings and A's when its warm outside)
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What causes hemolysis in WAIA?
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Hemolysis usually results from the opsinzation of RBCs by autoantibodies
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What type of characteristic cells are seen in WAIA?
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Spherocytes- resulting from membrane removal during attempts at phagocytosis
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Which type of antibodies are involved in Cold Antibody Immunohemolytic Anemias (CAIA)?
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IgM antibodies (We wear MITTENS when its cold outside)
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What are the conditions required for IgM to bind RBCs?
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There must be lower temperature because the antibodies are low affinity binding. The temp must be about 30 degrees which you find in the extremities.
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Is RBC hemolysis intra- or extra-vascular in CAIA?
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Extravascular once the RBCs return back to the warmer proximal areas from the periphery
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What additional phenomenon is seen with CAIA?
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Reynauds phenomenon as a result of the agglutination of RBCs in the capillaries of exposed parts of the body
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What is the name for altered RBCs in Microangiopathic Hemolytic Anemia that will try to trick you with the name of cells found in HS and WAIA?
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SCHISTOCYTES....not spherocytes
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What are some other characteristic cells found in MHA?
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Burr cells, helmet cells, and triangle cells
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When does MHA become a problem?
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When small vessels become partially obstructed and RBCs can become sheared
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Describe the main malfunction occurring in hereditary spherocytisis.
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There is a defect in the RBC membrane that renders cells spheroidal, less deformable and vulnerable to splenic sequestration and destruction. Cytoskeleton proteins ankryn, band 3 and spectrin are most commonly involved.
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What are characteristic features of Hereditary Spherocytosis?
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Anemia, splenomegaly and jaundice
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What is the mutation that produces sickle cell anemia?
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A substitution of the amino acid valine for glutamic acid at the six position of the Beta chain produces HbS.
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Name the most common form of familial hemolytic anemia.
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Sickle Cell anemia
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What condition leads to autosplenectomy and when in the patient's life is it seen?
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Sickle cell anemia; it begins in childhood and is complete by adulthood
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Where is the body's major source of functional iron found?
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80% is found in the hemoglobin- the rest is found in myoglobin and iron containing enzymes
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Where are the body's iron storage pools found?
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Hemosiderin and Ferritin-bound iron found in the liver, spleen, bone marrow, and skeletal muscle
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What is the one of the most reliable methods of quantifying the body's iron stores?
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Sampling the bone marrow
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How is iron transported in the blood?
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Transferrin
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The body has no regulated pathway for iron excretion, so how does it regulate iron balance?
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Through regulating dietary absorption of iron
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Which form of iron is more absorbable: heme iron or nonheme iron?
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Heme iron (associated with animal meat products)- this is why there is a less iron deficiency anemia in developed countries
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Where in the body is iron absorbed?
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In the duodenum
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Describe how Hepcidin regulates the iron absorption in the duodenum.
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Hepcidin made by the liver binds to ferroportin in the basolateral membrane of the duodenum and induces its internalization and degradation; thus when hepcidin levels are high ferroportin levels fall and less iron is transferred out of the enteroctes to transferrin
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When would we see microcytic, hypochromic RBCs and increased numbers of platelets in a peripheral blood smear?
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Iron deficiency anemia
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What are some of the diagnostic criteria of iron deficiency anemia?
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micropocytic microchromic red cell indices, low serum ferritin and serum iron levels, low transferrin saturation, increased total iron binding capacity, and response to iron therapy
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What is the underlying cause of anemia of chronic disease?
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Inflammation-induced sequestration of iron wthin the cells of the mononuclear phagocyte (reticuloendothelial) system
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In what setting are anemias of chronic disease most commonly observed?
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Hospitals in hospitalized patients
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List three chronic type conditions that can lead to anemia of chronic disease.
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1) Chronic bacterial infection
2) Chronic immune disorders 3) Neoplasms |
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Anemias of chronic disease can present with microcytic hypochromic cells and look like iron deficiency anemia, but what features would tell you that it is not anemia due to iron deficiency?
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Increased storage iron in the bone marrow, high serum ferritin concentration, and reduced total binding iron capacity- all attributed to circulating levels of Hepcidin
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Explain why there are high hepcidin levels found in anemias of chronic disease and how it contributes to the anemic condition.
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Elevated hepcidin levels are cause by pro-inflammatory cytokines, which enhance the synthesis of hepcidin by the liver; high levels of circulating hepcidin inhibit ferroportin and block the transfer of iron from the mononuclear phagocyte storage pool to the erythroid precursors.
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Gel Electrophoresis is particularly important in diagnosing which RBC disorders?
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Those with abnormal hemoglobins (e.g. Sickle cell anemia, Beta/Alpha Thalassemia)
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What RBC disorders is Coombs test used to identify?
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Immunohemolytic anemias
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Explain the value of obtaining a reticulocyte count; what does it tell you about the patients condition?
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Reticulocyte counts are used to distinguish between anemias caused by red cell destruction (hemolysis; high retics) and decreased production (marrow failure; low retics)
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Explain the distinctions that can be drawn from the various iron indices (serum iron, serum-binding iron capacity, transferrin saturation, and serrum ferritin concentrations)
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These are used to distinguished between hypochromic microcytic anemias caused by iron deficiency, anemia of chronic disease, and thalassemia minor
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Why would one take measurements of serum and red cell Folate and B12 concentrations?
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To identify the cause of an observed megaloblastic anemia
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What diagnosis is supported by increased concentrations of plasma unconjugated bilirubin and haptoglobin?
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Hemolytic anemia
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What physical abnormality does Polycythemia (erythrocytosis) denote?
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An increase in blood concentration of RBCs
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What are two forms that general Polycythemia (erythrocytosis) can take?
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Relative (dehydration and loss of blood volume) or Absolute (increase in RBCs due to autonomous proliferation or increase in erythropoietin)
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Leukopenia most commonly results from a decrease in which type of cells?`
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Granulocytes
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What is the condition called when there is a reduction in the number of granulocytes in the blood?
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Neutropenia, or agranulocytosis when the reduction is severe
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The mechanisms that cause neutropenia are divided into which two categories?
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1) Inadequate, or ineffective, granulopoiesis
2) Accelerated removal or destruction of neutrophils |
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What are some of the causes of inadequate or ineffective granulopoesis?
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aplastic anemia, cancer chemotherapy inducing temporary aplastic anemia
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What are some of the causes of accelerated removal or destruction of neutrophils?
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Immune mediated injury of neutrophils, increased peripheral utilization in some bacterial infections, an enlarged spleen which leads to sequestration and accelerated removal
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What is the main clinical feature that you would expect to be associated with neutropenia?
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Problems with chronic infection; particularly lesions with invasion of the oral mucosa
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Basophilic leukocytosis is often associated with what myeloproliferative disease?
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CML (chronic myelogenous leukemia)
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How does EBV DNA exist in the cells in which it takes a latent form?
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As an extrachromosomal episome
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Which form of EBV causes infected B cells to undergo polyclonal activation and proliferation; active or latent?
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Latent; this is the form that the infection takes most of the time (unproductive)
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Explain which branch of the immune system is responsible for limiting polyclonal proliferation of B-cells infected with EBV and which cells, in particular, are most important.
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Cell mediated response is very important; CD8+ T cells and NK cells key players
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In what disease do we see atypical lymphocytes?
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EBV
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Are the atypical lymphocytes found with EBV T-cells or B-cells?
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Cytotoxic CD8+ T-cells
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What characteristic-looking cell do some EBV infected cells imitate and what is the disease associated with the real characteristic cell?
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Reed Sternberg cell; Hodgkins lymphoma
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Explain why organs become enlarged in EBV.
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Atypical Lymphocytes; these are the culprits of most of the histological changes IN EBV infection. Heavy infiltration causes many problems and enlargements
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What what is the general mechanism behind follicular hyperplasia of a lymphnode in chronic non-specific lymphadenitis? (*seen in rheumatoid arthritis, toxoplasmosis, and early stages of HIV infection)
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Processes that activate B cells, which enter into B-cell follicles and create the follicular (germinal center) reaction.
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Which form of lymphadenitis can be can confused with follicular lymphomas?
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Follicular Hyperplasia
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In chronic non-specific lymphadenitis what is the general mechanism responsible for parafollicular hyperplasia?
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Reactive changes within the T-cell regions on the lymphnodes
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What type of infections will show parafollicular hyperplasia most often?
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Viral infections (e.g. EBV)
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What therapeutic Tx can cause parafollicular hyperplasia?
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Vaccinations (e.g. smallpox) and drugs (e.g. phenytoin)
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When do we see chonic non-specific lymphadenitis involving Sinus Histiocytosis?
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Often encountered in lymphnodes draining cancers and may represent an immune response to the tumor or its products
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What is the general mechanism responsible for producing Sinus Histiocytosis?
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Hypertrophy of lining endothelial cells and an infiltrate of macrophages
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Give the basic description of a leukemia.
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Tumors that primarily involve the bone marrow with spillage of neoplastic cells into the peripheral blood
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Give the basic description of a lymphoma.
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Tumors that produce masses involved in lymph nodes or other tissues
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Explain why we find clinical overlap in the presentations of lymphoid neoplasms and lymphoid leukemias originating in the bone marrow.
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This is because lymphoid neoplasms can spill over into the peripheral blood creating a leukemia type picture. At the same time leukemias of lymphoid origin can infiltrate nodes and other tissues creating the histological picture of lymphoma
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How do we distinguish lymphoid neoplasms from other diseases?
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Based on the appearance and molecular characteristics of the tumor cells; in other words for the purposes of diagnosis and prognostication it is most helpful to focus on what the tumor cell is and not where it resides in the patient
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What are the two types of recognized lymphoma?
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Hodgkin and Non-Hodgkin lymphoma
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What are the characteristic cells demonstrated in Non-Hodgkin lymphoma?
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Reed-Sternberg cells, but when these are found in nodes they are usually greatly outnumbered by neoplastic inflammatory cells.
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Both pre-B and pre-T-cell lymphoblastic tumors usually take on the clinical appearance of an Acute Lymphoblastic Leukemia (ALL) at sometime in their course, but which typically progresses to a leukemic phase more rapidly?
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Pre-T-cell
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The pathophysiology, laboratory findings, and clinical features of ALL closely resemble what other major type of leukemia?
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Acute myelogenous leukemia (AML)
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What is the principle pathogenetic problem in an acute leukemia?
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A block in differentiation
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Explain the mechanism of pathogenesis and the manifestation of clinical symptoms associated with acute leukemia.
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Accumulation of immature leukemic blasts in the bone marrow suppress the function of normal hematopoietic stem cells by physical displacement and other poorly understood mechanisms. Bone marrow failure results and this accounts for the clinical manifestations of the symptoms.
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Describe the main idea behind the therapy associated with acute leukemia.
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The therapeutic goal is to reduce the leukemic clone sufficiently to allow normal hematopoiesis to resume.
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Even though they seem to present similarly, why is it of such great importance that we distinguish ALL from AML?
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Because their courses of Tx and responses to therapy differs greatly.
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In ALL, blasts compose what percentage of of marrow cellularity, by definition?
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25%
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Leukemia refers to cancer found where?
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In the blood and bone marrow.
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Lymphoma refers to cancer found where?
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As a discrete tissue mass, usually in the lymphnodes
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Are acute leukemias usually populated by immature or mature cells?
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Immature cells; precursor cells; blast cells
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Are chronic leukemias usually populated by immature or mature cells?
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Predominantly mature cells.
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What lab technique is employed to determine if a leukemia is of lymphoid or myeloid origin?
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Flow cytometry
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If a leukemia is of lymphoid origin how do we determine whether it is a B-cell or T-cell leukemia?
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Flow cytometry and immunophenotyping for CD markers
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What are the main differentiating features between lymphoid and myeloid leukemia?
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The presence of Auer rods and small granules, which will be present in cells of myeloid origin ***If a myeloid leukemia lacks granules it is virtually impossible to tell the difference between lymphoid and myeloid under the microscope
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Which more commonly involves the CNS, AML or ALL?
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ALL
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What disease is the translocation 12:21 associated with? Who most commonly presents with the disease?
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Pre-B-cell ALL (the most common ALL); most commonly found in kids
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Who presents most often with pre-T-cell ALL and what symptom is commonly associated?
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Adoclescent males; a mediastinal (thymic) mass
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The 9:22 translocation is seen in what two diseases? Which has a worse prognosis?
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9:22 translocation makes Philadelphia Chromosome and it is found ALL and CML. ALL associated with this translocation indicates a poor prognosis for treatment.
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What characteristic features is the FAB AML classification M0 most commonly associated with?
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Minimally differentiated blast cells that are indistinguishable from pre-lymphocytes. Can only tell the difference through lab testing.
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What characteristic features is the FAB AML classification M1 most commonly associated with?
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There is some maturation but not much. May see granules or Auer rods.
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What characteristic features is the FAB AML classification M2 most commonly associated with?
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These cells are generally observed with more maturation towards the neutrophil lineage and are commonly seen with Auer rods. There is a characteristc translocation (8:21) that is associated with a good prognosis that you must know
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What characteristic features is the FAB AML classification M3 most commonly associated with? (*promyelocytes are the largest cells in the neutrophil lineage and in this case they are filled wtih collections of Auer rods)
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The most predominant cell block is at the promyelocyte stage. It is also known as Acute Promyelocytic AML. Auer rods are often present in clusters. There is a T(15;17) RAR alpha-PML translocation, which causes the arrest of cells at the promyelocyte stage of development.
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What are some of the other unique features of M3?
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DIC- this is an urgent leukemia that needs treatment right away. Often occurs in younger patients. The RAR alpha/PML fusion protein is targeted by retinoic acid therapy(Atra), which helps overcome the block in differentiation by the fusion protein.
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What characteristic features is the FAB AML classification M4 (monocytic lineage) most commonly associated with?
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Chromosome 16 abnormalities that cause eosinophilia. Both myeloid and monocytoid elements are present. Associated with previous therapies for other malignancies!!! (alkylating agents & topoisomerase inhibitors)
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What characteristic features is the FAB AML classification M5 (monocytic lineage) most commonly associated with?
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MLL gene on chromosome 11. Predominantly myelocytoid with tissue infiltration and organomegaly present. Associated with previous therapies for other malignancies!!! (alkylating agents & topoisomerase inhibitors)
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What characteristic features is the FAB AML classification M6 most commonly associated with?
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Erythroleukemia- Leukemia of blasts that are destined to become RBCs. Dysplatic erythroid cells intermixed with myeloblasts. Very characteristic large dysplastic cells.
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What characteristic features is the FAB AML classification M7 most commonly associated with?
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Megakaryoblastic. Down syndrome children patients are at risk.
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What are the four WHO classifications for AML
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I. AML with recurrent chromosomal rearrangements
II. AML with multilineage dysplasia III. AML therapy related IV. AML Not Otherwise Specified |
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What are 4 chromosomal abnormalities associated with the WHO Class I AMLs
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1) T(8;21)- (FAB M2)- good prognosis
2) Inv 16- (FAB M4)- good prognosis 3) T(15;17)- (FAB M3)- intermediate prognosis 4) 11q23 (MLL) (FAB M4, M5)- poor prognosis |
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Describe the prognosis of AML with (WHO class II) and without multilineage dysplasia.
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With = very poor
Without= poor |
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Explain the prognoses for AML Therapy Related illnesses.
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If due to alkylating agents = very poor
If due to topisomerase inhibitor = very poor |
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What is the WHO class IV (AML Not Otherwise Specified) category used for?
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It is used sort of as a catch all for AMLs that cannot be fit into one of the other classes. Here the FAB subclassifications become useful M0-M7.
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At the present time AML classification is far ahead of the treatments we have for the diseases. With this in mind how do the treatments vary for the various AML diseases that are classified by the WHO and FAB?
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Except for the case of M3, which is given directed treatment with synthetic retanoic acid, the treatments for AML across the board are mostly the same, because our methods of classification are much more sophisticated than our levels of treat
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Are Myelodysplastic Syndromes (MDS) created from a block in myeloid maturation like AMLs or something else?
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Something else ---> ineffective differentiation/ hematopoiesis ---> creates morphologically abnormal cells
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In what settings do we see a MDS arise?
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Idiopathic (uknown), Therapy realted (e.g. alkylating agents, radiation)
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What was the old term for MDS and why was it called that?
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Preleukemia; because it has a propensity for progressing to AML
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Why do we see cytopenias with MDS and its inefective hematopoiesis?
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Because this is a disease with the bone marrow where cells have trouble differentiating and surviving. Cells often die before making it out. The marrow is trying to make up for this loss of cells, but is doing so INEFFECTIVELY, and so is increasing its proliferation, but in an unorganized manner.
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How is the average patient population that suffers from MDS different than that of AML?
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MDS generally effects older patients (rarely seen in a child, normally 65 or so) and AML is usually observed with younger patients.
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What is the most common cause of death in patients with MDS?
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Death from infection due to neutropenia
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What leads to the progression of MDS to AML?
|
The increase in the number of blasts
|
|
|
What are common cytogenetic finding associated with MDS that we need to know?
|
Monosomy 5 and monosomy 7.
|
|
|
How are myloproliferative disorders defined?
|
Abnormal proliferations of cells in marrow
|
|
|
What is a characteristic cell seen in Myelodysplasia and in another congental disorder?
|
Pseudo Pelgar-Hewit cells and Pelgar-Hewit cells
|
|
|
What is the main difference between AML and CML?
|
With AML we see a preponderance of blasts in the peripheral blood, WHICH IS NEVER NORMAL!!!. With CML there is obvious maturation of the increased cells.
|
|
|
What are four features of blast cells?
|
1) Large
2) Open lacey chromotin 3) Nuceoli 4) High nuclear to cytoplasmic ration |
|
|
What is the most common acute leukemia in adults?
|
AML; can show problems with anemia and bleeding due to low mature RBCs and platelets
|
|
|
What is most characteristic about the marrow, with regard to cellular maturation, observed in AML?
|
A block in maturation is observed
|
|
|
What is a general treatment idea for adults with AML?
|
Treat with combo chemo to initially and follow up with consolidation chemo or marrow transplant
|
|
|
What is the most dangerous aspect of Acute Promyelocytic Leukemia (M3)?
|
Consumption of clotting factors and DIC
|
|
|
What causes APML (M3)? and why does treatment work?
|
A balanced translocation t(15;17); this puts a retinoic acid receptor next to PML protoncogene, and treatment with All Trans Retinoic Acid is a potential cure. The retinoids promote differentiation and releases the block (arsenic trioxide also promotes differentiation). Must follow up with consolidation Tx.
|
|
|
What does Acute Promyelocytic Myelogenous Lukemia (M3) look like under the microscope?
|
They have PROMINENT, PURPLE, PRIMARY granules.
|
|
|
Who has the highest chance of presenting with ALL? and who fares better with this diagnosis?
|
AML is the most common leukemia in CHILDREN and incidence also increases after the 5th decade of life. Children fare better than adults. Children about 90% cure, adults pretty miserable.
|
|
|
Where does this leukemia like to spread to?
|
Sanctuary sites like the brain and testes. Sanctuary because there is a blood-tissue barrier, such as the BBB.
|
|
|
Acute Leukemia pearls?
|
Differentiative abnormality; block in maturation
|
|
|
AML pearls?
|
Auer rods, most common acute leukemia in adults, myeloblasts
|
|
|
M3 (Promelocytic) Leukemia pearls?
|
t(15;17), RAR-alpha/PML, all-trans retinoic acid, DIC
|
|
|
ALL pearls?
|
most common leukemia in children, sanctuary sites like spinal cranial axis, requires long term of treatment
|
|
|
Myelodysplasia pearls?
|
>50% have chromosomal abnormalities, macrocytosis, older people, alkylating agents and radiation
|
|
|
Compare Small Lymphocytic Lymphoma and Chronic Lymphocytic Leukemia.
|
These two disorders are morphologically, phenotypically, and genetically identical. They differ only in the extent of peripheral blood involvement.
|
|
|
What is the arbitrary marker that distinguishes SLL from CLL?
|
If the peripheral blood lymphocytosis exceeds 4000 cells/mm3, the patient is diagnosed with CLL
|
|
|
What is the most common leukemia of adults in the western world?
|
Chronic lymphocytic leukemia (CLL)
|
|
|
What are some buzz words to think of when talking about SLL/CLL?
|
Proliferation center, absolute lymphocytosis (effacing of lymphnode architecture takes place), smudge cell
|
|
|
What type of neoplastic cells are involved in SLL/CLL?
|
SLL/CLL is a neoplasm of mature B-cells expressing the pan B-cell markers CD19, CD20, and CD23 and surface immunoglobulin heavy and light chains. Less common tumors derived from naive B-cells that have not undergone a follicular center reaction appear to have a substantially worse prognosis.
|
|
|
What are the main problems associated with SLL/CLL?
|
Lymphadenopathy, hepatosplenomegaly, hypogammaglobulinemia (which increases susceptibility to bacterial infection), autoimmune hemolytic anemnia, thrombocytopenia, some more chronic cases transform to more aggressive tumors that resemble either pro-lymphocytic leukemia or diffuse large B-cell leukemia. These are correlated with poor prognoses.
|
|
|
Describe the cellular involvement in Follicular Lymphoma.
|
The tumor cells resemble normal follicular center B-cells. The predominant neoplastic cells are centrocyte-like and have cleaved nuclear contours. Mitoses are infrequent and single necrotic cells are not seen
|
|
|
Describe a key abnormal protein expression finding associated with the B-cells involved in Follicular Lymphoma.
|
BCL2 is characteristically expressed, although it is a protein that is absent from normal follicular B-cells
|
|
|
Name the key translocation observed in the majority of cells in Follicular Lymphoma.
|
t(14;18), this translocation fuses the BCL2 gene on chromosome 18 to the IgH locus on chromosome 14 and leads to the inappropriate expression of BCL2 protein, which functions to prevent apoptosis
|
|
|
Explain how Mantle cell lymphoma arises.
|
Most Mantle cell tumor cells have a t(11:14) translocation that fuses the cyclin D1 gene on chromosome 11 to the IgH locus on chromosome 14. This translocation dysregulates the expression of cyclin D1.
|
|
|
How can Mantle Cell Lymphoma can be distinguished from CLL/SLL?
|
By the presence of cyclin D1 and the absence of proliferation centers.
|
|
|
What is a key characteristic tissue involvement of this disease that is not often seen in lymphomas?
|
Involvement of the gastrointestinal tract, sometimes in the form of multifocal submucosal nodules that grossly resemble poylps.
|
|
|
Do these tumors have a good prognosis?
|
These tumors are aggressive and incurable, and are associated with median survival of 3 to 5 years.
|
|
|
This lymphoma is the most important type of lymphoma in adults, as it accounts for ~50% of adult NHL. What is it?
|
Diffuse Large B-cells lymphoma.
|
|
|
Describe the type of B-cells that are found in Diffuse Large B-cell lymphoma.
|
The tumors uniformly demonstrate somatic hypermutation of immunoglobulin genes, consistent with mature B-cells originating from a follicular or post-follicular center B-cell
|
|
|
Name the Acute Leukemias of Myeloid origin.
|
Myelodysplastic Syndrome (MDS), Acute Myelogenous Leukemia (AML; M0-M7)
|
|
|
Name the Acute Lymphoid Leukemias
|
B-ALL and T-ALL
|
|
|
What are the chronic leukemias of lymphoid origin?
|
CML, ET, Pvera, Myelofibrosis.
These are actually Myeloproliferative disorders and not leukemias, except for CML |
|
|
What are the chronic leukemias of lymphoid origin?
|
B-cell: CLL/SLL, Hairy cell, Myeloma
T-cell: ATCL, LGL, MF/SS |
|
|
What type of cells are found in CLL/SLL?
|
Mature B-lymphocytes
|
|
|
What are the characteristic cells seen in CLL/SLL?
|
Smudge cells, or basket cells
|
|
|
What does the lymphnode look like in CLL/SLL?
|
It is effaced by lymphocytes. Complete take over of cells stuck back to back with one another and the normal architecture of the lymphnode seems abscent.
|
|
|
Describe the types of immunologic dysfunction is observed in CLL/SLL.
|
Autoantibody formation that can lead to hemolytic anemia and thrombocytopenia. Hypogammaglobuilinemia which leaves the patient susceptible to infection
|
|
|
Is the course of CLL/SLL agressive or asymptomatic?
|
Some people can go their whole lives and die from other causes and not know they had this disease, while other forms can be very aggressive.
|
|
|
What are the names for the disease with an agressive course that CLL/SLL can progress to?
|
Prolymphocytic leukemia or Diffuse Large B-cell lymphoma (Richter)
|
|
|
What type of cells are involved in Hairy Cell Leukemia?
|
Mature B-Cells
|
|
|
Describe two main organ features that are associated with the rare disease Hairy B-cell Leukemia.
|
Massive! Splenomegaly and pancytopenia (monocytopenia most pronounced)
|
|
|
Explain what characteristic result is found upon bone marrow biopsy in a patient with Hairy Cell Leukemia and why.
|
DRY TAP- which is an inability to aspirate cells due to extensive reticulin fibrosis.
|
|
|
What is an old stain used to identify hairy cells, that is no longer in use but is a buzz word for the boards?
|
TRAP stain- Tartrate Resistant Acid Phosphate
|
|
|
Describe the cells involved and the cause of a very common adult leukemia found in the Asia and the Carribean.
|
This is Adult T Cell Leukemia/ Lymphoma. Here we see a malignancy of MATURE CD4+ T CELLS showing the characteristic Flower cell (pathognomonic) or clover leaf morphology in peripheral blood. It is caused by HTLV-1.
|
|
|
What is a malignancy that we are likely to see on the wards that sounds like the name of a fungus, but isn't? What type of cells are involved?
|
Mycosis Fungoides/Sezary Syndrome- this is a malignancy of MATURE CD4+ T CELLS
|
|
|
Compare how the anatomical involvements differ in Mycosis fungoides and Sezary Syndrome.
|
MF- only involves skin- can lead to an ulcerative tumor
SS- shows exfoliative erythroderma and Leukemic Sezary cells |
|
|
What are the collections of lymphocytes seen just under the epidermis of the skin in MF called? (*USMLE buzzword)
|
Pautrier's microabsesses
|
|
|
What specific type of T-cells are involved in Large Granular Lymphocytic Leukemia?
|
MATURE CD8 T CELLS or NK CELLS
|
|
|
Describe the demographic usually involved with Large Granular Lymphocytic Leukemia and another condition that is likely to be presented with it.
|
This is an indolent disease that is usually found in elderly patients and has an increased incidence of concurrent rheumatologic disorders.
|
|
|
What is the name of a plasma cell neoplasm that we are likely to see here in the African American population?
|
Multiple Myeloma
|
|
|
Describe what the plasma cells produce as a result of Multiple Myeloma. What is it called?
|
The plasma cells in Multiple Myeloma produce a single homogenous immunoglobulin or it fragemnts. This is clonal and the same is produced by all plasma cells. This is call the M component. Excessive free light chains produced by the plasma cell are called Bence-Jones proteins (responsible for renal failure)
|
|
|
In this malignancy most people present with mulitfocal bone lesions composed of plasma cells that contribute to what is called a pathological fracture.
|
Multiple Myeloma
|
|
|
What is the most common cause of death in Multiple Myeloma?
|
Infection because of a decreased production of normal Ig
(*Bence Jones proteins are toxic to renal tubules and can cause renal failure) |
|
|
Describe what is likely to be seen on a bone marrow biopsy of a patient with Multiple Myeloma.
|
Sheets of plasma cells.
|
|
|
Name the disease that presents with a characteristic M spike in a serum protein electrophoresis (usually due to IgG).
|
Multiple Myeloma
|
|
|
What should you know about Plasmacytoma?
|
It is a solitary lesion of bone or soft tissue and it usually progresses to Multiple Myeloma.
|
|
|
What does MGUS stand for?
|
Monoclonal Gammopathy of Undetermined Significance
|
|
|
What is a key finding of MGUS?
|
M protein without other symptoms. This is the most common cause of monoclonal gammopathy (M spike).
|
|
|
Is MGUS malignant or benign?
|
MGUS usually follows a benign course and rarely progresses to MM
|
|
|
With blood disorders what is basophilia a Buzzword for?
|
CML or myeloproliferative disorders
|
|
|
What lab test is used to help distinguish between infection and CML?
|
Leukocyte alkaline phosphatatse
|
|
|
Describe the 4 treatments that we have for CML.
|
1) **Imatinib-bcr/abl tyrosine kinase inhibitor- revolutionized Tx
2) Allogeneic transplant 3) IFN-alph and cytarabine (old methods) 4) Hydroxyurea for WBC |
|
|
What is the only way to cure CLL?
|
Allogeneic transplant, but risk for GVHD increases with increasing age.
|
|
|
Does Hairy cell Leukemia more commonly effect women or men?
|
MEN in the 6th decade of life
|
|
|
How do we treat Hairy cell?
|
Cladrabine which send >95% pts into remission
|
|
|
Name the prototypical plasma cell dyscrasia and its clinical presentations.
|
Multiply Myeloma with its M-spike, Hypercalcemia, Anemia, Renal incufficiency and lytic bone lesions
|
|
|
CLL pearls?
|
smudge cells, most common leukemia in adults, long natural history
|
|
|
CML pearls?
|
philadelphia chromosome t(9;22), blast crisis, imatinib, basophilia
|
|
|
Hairy cell pearls?
|
older men, splenomegaly, dry tap, TRAP +, cladarabine
|
|
|
Myeloma pearls?
|
Hypercalcemia, lytic bone lesion, anemia, MGUS?, Thalidomide, know what plasma cells look like.
|
|
|
What are the two major categories of lymphoma?
|
Hodgkin and Non-hodgkin
|
|
|
What distinguishes HL from NHL?
|
Reed Sternbeg cells which indicate Hodgkin Lymphoma
|
|
|
What is the first test that one does in order to find out if a neoplasia is of lymphocytic origin?
|
CD45+ stain
|
|
|
What are the T-cell markers that we look for in lymphoma? (T-cells have tiny markers)
|
CD3, CD4, CD5, CD8
|
|
|
What are the B-cell markers that we look for in a lymphoma? (B-cells have big markers)
|
CD20, CD79a
|
|
|
What is the translocation invovled in Anaplastic Large Cell Lymphoma?
|
(2;5) alk
|
|
|
What is the translocation invovled in Burkitt's Lymphoma?
|
(8;14) c-myc
|
|
|
What is the translocation invovled in Mantle cell lymphoma?
|
(11;14) cyclin D1
|
|
|
What is the translocation invovled in Follicular cell lymphoma?
|
(14;18) BCL-2
|
|
|
What are the curious finding of cellular markers on Reed Sternberg cells?
|
CD45 -, but CD15 positive, CD30
|
|
|
What cells are Reed-Sternberg cells derived from?
|
B-cells
|
|
|
Describe some of the key features that make up the Hodgkin Lymphoma- Nodular Sclerosis.
|
FIBROUS BANDS divide the tumor into nodules, LACUNAR CELLS
|
|
|
What virus is associated with 75% Hodgkin lymphomas?
|
EBV
|
|
|
Describe the translocation, protein over-expression, and progression of Follicular cell lymphoma.
|
t(14;18), BCL-2 over expression, can progress to diffuse large B-cell lymphoma
|
|
|
What does Follicular Lymphoma look like under the microscope?
|
Many back to back lymphoid follicles filled with small lymphocytes
|
|
|
What is a characteristic cell the we see with Follicular Lymphoma?
|
Buttock cell
|
|
|
Name the one small cell lymphoma that is aggressive that we learn about. What translocation is it associated with and what protein is over expressed?
|
Mantle Cell lymphoma, t(11;14), cyclin D1 overexpression
|
|
|
Which lymphoma did we learn about that is commonly found in extra nodal sites (usually mucosa MALTOMAS) with a t(11;18)?
|
Marginal Zone lymphoma
|
|
|
What other general class of disease in Marginal Zone lymphoma commonly associated with?
|
Autoimmune disease
|
|
|
What bacteria can be associated with MALTOMAS in the gut?
|
H. pylori
|
|
|
What contributes to Waldenstrom Macroglobulinemia?
|
Lymphoplastic Lymphoma when malignant plasma cells secrete large amounts of IgM. These large amounts of IgM thicken the blood an cause hyperviscosity syndrome.
|
|
|
What type of problems does Waldenstrom Macroglobulinemia and hyperviscosity syndrome cause?
|
Visual impairments, neurologic problems, bleeding, cryoglobulinemia
|
|
|
What NHL makes up 20% of all cases of NHL, is associated with BCL-6 mutations and has 2 rare subtypes associated with oncogenic viruses?
|
Diffuse Large B-cell Lymphoma
|
|
|
Describe the histology of DLBCL as seen under the microscope.
|
There is a diffuse pattern of infiltration, the B-cells are 4 times the size of a normal lymphocte and the cells tend to have prominent nucleoli
|
|
|
How long is the doubling time for the cells in Burkitt Lymphoma?
|
Cells can double in only one day.
|
|
|
Describe the classic histology of Burkitt B-cell lymphoma seen under the microscope.
|
Starry sky pattern created by benign histiocytes ingestin nuclear debris and apoptotic cells
|
|
|
What NHL T-cell lymphoma can commonly get mistaken for HL because of similar appearance of Reed Sternberg cells? What translocation is associated and implies a better prognosis?
|
Anaplastic Large Cell Lymphoma (ALCL). t(2;5) ALK mutation.
|
|
|
What is another name for Extranodal NK/T Cell Lymphoma and what virus is it almost guaranteed to be associated with? How does it present?
|
"Lethal midline granuloma". It is almost always associated with EBV. Its an aggressive malignancy that is very destructive and often affects the nose and face.
|
|
|
What T-cell lymphoma are we most likely to see that is called a wastebasket category for lymphomas that are unable to be classified?
|
Peripheral T cell lymphoma, unspecified. These are heterogenous cells with no specific morphological characteristics and in general they have a worse prognosis that B-cel neoplasms
|
|
|
What is a special term to describe how Hodgkin Disease appears by incidence of age on a graph?
|
Bimodal appearance. This is because we see two peaks at when HL is most likely to show up. Around age 24 and 50/60.
|
|
|
Do younger or older patients tend to have a better prognosis with HL?
|
Younger people tend to have a better prognosis.
|
|
|
How does HL usually present in the clinic?
|
Most often it will present with adenopathy, but patients can also present with "B" symptoms.
|
|
|
What do the "B" symptoms associated wtih HL include?
|
Fevers, Night sweats, and weight loss
|
|
|
In HL how do we dictate Tx of the disease? What system is used?
|
STAGING SYSTEM. Earlier stages may be treated by radiation alone, and later stages may involve combo chemotherapy
|
|
|
How is STAGE 1 of HL determined?
|
Single lymphnode region or single extralymphatic site involved
|
|
|
How is STAGE 2 of HL determined?
|
Two or more lymphnodes on the same side of the diaphragm
|
|
|
How is STAGE 3 of HL determined?
|
Both sides of the diaphragm involved
|
|
|
How is STAGE 4 of HL determined?
|
Diffuse involvement of extralymphatic (liver, BM, etc.) sites and nodal disease
|
|
|
In NHL how do we dictate Tx of the disease?
|
Treat according to cell type and can be thought of as grade
|
|
|
Compare the dictation of Tx in HL vs. NHL.
|
In HL we Tx according to stage, whereas in NHL we Tx according to cell type and can think of diseases in terms of grades (i.e. Low, Intermediate, High grade)
|
|
|
Compare the incidence of NHL with that of HL according to age.
|
Whereas HL shows a bimodal curve with regard to incidence with increasing age, NHL simply shows increasing incidence with increasing age
|
|
|
What type of Tx was HL the protoypic disease for developing?
|
Combination chemotherapy
|
|
|
If you find that you have a LOW GRADE NHL what do you know about it? (Follicular small cleaved cell = prototype)
|
Not classically curable due to low doubling time, long natural history, can progress to higher grade lymphomas with certain transformations and translocations, follicular involvement
|
|
|
If you find that you have a INTERMEDIATE GRADE NHL what do you know about it? (diffuse large cell lymphoma = prototype)
|
A little more aggressive than low grade and it grow a little faster, thus it is potentially curable with combination chemo therapy and monoclonal antibody to CD20. Lymphnode involvement is diffuse instead of follicular
|
|
|
If you find that you have a HIGH GRADE NHL what do you know about it? (Burkitt = prototype) ***BEWARE OF TUMOR LYSIS SYNDROME!!!
|
Treatment is complicated and completed over many months, high cell turnover ---> Burkitt's has highest cell turnover of any cancer
|
|
|
Explain what happens in Tumor Lysis Syndrome. (*must hydrate and use allopurinol in patients with rapidly dividing tumors)
|
With rapidly dividing tumors there are generally many and they are sensitive to chemotherapy. If many cells die at once and release their cellular contents into the circulation uric acid levels, K+, LDH, CPK, and Phosphorous levels increase. Ca++ goes down because it comes out with P. Precipitated CaP and uric acid can precipitate in the kidney and cause renal failure.
|
|
|
Describe the primary and secondary jobs of Von Willebrand Factor (vWF).
|
The primary job of vWF is to bind platelet to vessel walls at sites of injury. Its secondary job is to help platelets bind to other platelets along with the help of fibrinogen.
|
|
|
Compare the role GPIB/IX/V and GPIIb/IIIa.
|
GPIB/IX/V holds platelets to endothelium via vWF and GPIIb/IIIa holds platelets together via both vWF and fibrinogen
|
|
|
Why is GPIIb/IIIa important for us to know about from a pharmacological point of view?
|
We have drugs that inhibit GPIIb/IIIa for people with acute coronary syndromes and help prevent platelet aggregation and clotting. In the arterial system, the platelet system is what causes thrombosis
|
|
|
What would make us suspect that a patient has a disorder of primary hemostasis?
|
Problems with superficial bleeding. Gums, mucosal surfaces, easy bleeding, bruising, lots of menstrual bleeding
|
|
|
What are the two primary lab tests we use to assess the Primary Hemostatic Process?
|
PFA and Platelet aggregation test
|
|
|
Name the drugs that interfere with Primary Hemostasis (Interfere with platelet function).
|
Aspirin, NSAIDS, Clopidrogel/ticlopidine; GPIIb/IIIa inhibitors- abciximab, tirofiban, eptifibatide
|
|
|
Which part of the extrinsic pathway initiates the common pathway?
|
Factor VIIa; this acts on Factor X which is the beginning of the common pathway
|
|
|
What coagulation factor starts the beginning of the Common Pathway?
|
Factor X
|
|
|
Which portion of the Common Pathway in the Coagulation Cascade works to feed into the intrinsic pathway?
|
Thrombin goes to the intrinsic pathway
|
|
|
Which test do we use to evaluate the integrity of of the Extrinsic Pathway pathway of Secondary Hemostasis?
|
PT (prothrombin time), which takes an extrinsic tissue factor added to plasma to clot and measures the integrity of the Factor VII extrinsic system. Normally takes ~13 sec to clot
|
|
|
What reaction starts the beginning of the Extrinsic Pathway of Secondary Hemostasis?
|
Tissue Factor converting Factor VII ---> Factor VIIa
|
|
|
What does PT measure the integrity of?
|
The Factor VII extrinsic coagulation system
|
|
|
What is the protoypical drug that affects the Extrinsic pathway? And what special equation comes with it?
|
Warfarin: the equation is:
INR= (PTpatient/ PTcontrol)^isi INR= international normalized ratio ISI= international sensitivity index |
|
|
What aspect of the Common Pathway leads into activating the intrinsic pathway?
|
Thrombin
|
|
|
Name the lab test that we use to evaluate the integrity of the Intrinsic Pathway.
|
aPTT (activated partial thromboplastin time); therapeutic range 1-1.25 X
|
|
|
What are some of the drugs that we use to affect the Intrinsic coagulation pathway?
|
Heparin, Low molecular weight Heparin (LMWH), Hirudin
|
|
|
Explain which coagulation factors use Vitamin K, what it does, and how it does it.
|
Factors II, VII, XI, and X use Vitamin K. Vitamin K activates these clotting factors and it does it through gamma-carboxylation
|
|
|
How does Warfarin work?
|
It inhibits the action of Vitamin K to activate clotting factor III, VII, XI and X.
|
|
|
Which clotting factors are made in the liver?
|
ALL OF THEM!...and some endothelial cells make Factor VIII too.
|
|
|
What is the most common congenital bleeding abnormality?
|
Von Willebrand's disease
|
|
|
Von Willebrand factor is involved with platelet binding to endothelial cells and platelets binding to other platelets (primary hemostasis). So, why is it that some people with vWF disease have a prolonged aPTT when that is a test of Secondary Hemostasis?
|
This is because vWF binds Factor VIII and stabilizes it in circulation. Without vWF Factor VIII has a shorter half life and this affects the Intrinsic pathway which is part of Secondary Hemostasis. Thus aPTT is affected.
|
|
|
How is a patient with vWF disease treated pre-surgically to help insure that they do not have problems with bleeding?
|
They are given Desmopressin (DDAVP) in advance. This can raise levels of vWF in the blood by increasing the amount released from endothelial cell organelles (Weibel-Palade bodies)
|
|
|
Von Willebrand's Disease vWD pearls?
|
Most common congenital coagulopathy (~1% pop), usually autosomal dominant, prolonged bleeding time and prolonged aPTT, DDAVP to Tx
|
|
|
What is a deficiency of coagulation factor VIII called (most common abnormality in the intrinsic system)?
|
Hemophilia A
|
|
|
What is a deficiency of a coagulation factor that looks just like a deficiency of Factor VIII and is also involved in the intrinsic system?
|
Hemophilia B, which is a deficiency of Factor IX
|
|
|
What is similar about how Hemophilia A and B are passed down through generations?
|
They are both X-linked, thus men are usually the only ones to suffer from the disease
|
|
|
Hemophilia pearls?
|
Hemophilia A and B are X-linked, characterized by "deep" bleeding, prolonged aPTT, Coagulation Factor concentrates are used to treat
|
|
|
Liver disease would significantly decrease the production of the majority of all your clotting factors, affecting both the extrinsic and intrinsic pathways. Which factor level in the blood would be most effected, and subsequently which pathway and lab test?
|
Factor VII because it has the shortest half life; the Intrinsic Pathway; PT lab test
|
|
|
Contrast the clotting that occurs in veins with the clotting that occurs in arteries.
|
Venous Thrombosis most often occurs through relation to clotting factors, whereas Arterial Thrombosis most often is intimately related w/ platelets as it is a high flow system
|
|
|
What are the two naturally occurring anticoagulant systems that we care about right now?
|
Protein C/ Protein S system, Antithrombin system
|
|
|
What are the jobs that Thrombin does?
|
1) Fibrinogen ---> Fibrin
2) FXI ---> FXIa (activates intrinsic system) 3) Platelet activaiton |
|
|
Explain how Thrombin, which has many coagulative properties, acts as an Anticoagulant.
|
Thrombin binds thrombomodulin on endothelial cells. This complex then activates Vit. K dependent Protein C. Activated Protein C uses Protein S as a co-factor and together they Inhibit Factors V and VIII, which are co-factors in the Common and Intrinsic pathways respectively. Thus thrombin acts as an anticoagulant.
|
|
|
What is the most common cause of venous thrombosis?
|
Protein C resistance, which is usually related to a mutation in Factor V called "FACTOR V LEIDEN"
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What are the disorders that we are most likely to see causing Hypercoagulable states?
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Protein C deficiency (rare), Protein S deficiency (rarer), Activated protein C resistance by Factor V (Factor V Leiden)
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Describe the role of Antithrombin in anticoagulation.
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Antithrombin binds Thrombin, Factor Xa, and Factor XII and inhibits them
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How does Heparin work?
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It binds to Antithrombin and enhances its activity
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What mutation concerning prothrombin can lead to hypercoagulation?
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Prothrombin mutation 20210, which can lead to overproduction of prothrombin
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If you have a congenital disorder of hypercoagulation what are the most likely conditions to have?
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Factor V Leiden mutation and Prothrombin mutation 20210
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What are some non-congenital causes of Arterial Thrombosis?
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Heparin associated thrombocytopenia, Antiphospholipid antibodies, Cancer, Myeloproliferative disorders
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Explain the mechanism by which Antiphospholipid (anticardiolipin) antibodies cause inappropriate coagulation. Who suffers from this condition most?
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Antiphospholipid antibodies displace anticoagulation factors at the mucosal surface and, thus promote inappropriate coagulation. This is more often seen in women.
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Explain the rationale behind the mixing test used in the detection of anticardiolipin antibodies.
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In vitro the ACL antibodies inhibit clotting. In vivo they promote it. Patient is found with a prolonged PTT. Mix blood with another person. If it clots the prolonged PTT was due to lack of clotting factors. If it doesn't clot ACL antibodies should be suspected of inhibiting the reaction.
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Explain the mechanism by which Heparin causes Heparin associated Thrombocytopenia.
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Heparin causes immunoactivation of plateles and the become sticky and can aggregate to cause thrombosis
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