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378 Cards in this Set
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3A intro and approaches to anemias
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3A intro and approaches to anemias
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WW causes of anemia?
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iron deficiency- other nutritional deficits (vit A- B vit)- malaria- hookworm- HIV-AIDS- TB
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what effects does anemia have on childrens' development
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slower
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what is anemia and what three things may be abnormal
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reduced red cell mass lower Hb- lower Hct- or lower number of RBCs
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what factors may influence the hematocrit?
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dehydration may influence total volume. or leukemia may increase WBC proprtion
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what two internal factors determine a rbc survival/what three external factors?
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internal: maintain shape and osmotic integrity. external: antibodies- toxins- spleen- bleeding
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would the hemoglobin binding curve be shifted left or right in a person adapted to live at high altitude?
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it should be shifted RIGHT
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why do red cells need active metabolism
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they need it for glutathion/free radical reductase and to make hemoglobin
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what is the methemoglobin raction? why do rbcs need a metabolism?
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to put Fe in ferrous (+2) vs ferric (+3) state to bind o2
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how long do normal rbcs last?
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120 days
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what organ produces the hormon for more rbcs and what is the stimulus/response?
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kidney makes EPO to signal bone marrow to make more RBCs- stimulus is hypoxia OR anemia
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what are four possible causes of anemia
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kidney disorder- loss of EPO sensitivity in marrow- a decreased production/release of RBCs from marrow- or shorter than normal RBC survival (lost vs destroyed)
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what are three classifications of anemia
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decreased RBC production- hemolysis (RBC degradation)- or bleeding
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what color do reticulocytes appear/how are they different from RBCs
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reticulocytes are slightly bluish
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what does the supervital stain do?
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stains RNA dark in reticulocytes. special stain just for them
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why do you not get iron def anemic with hemolytic anemia but you do with bleeding?
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you are not iron deficient in hemolytic because the iron stays in your circ when the RBCs are destroyed- whereas when bleed it leaves
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what's a normal reticulocyte count
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0.5-2%
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if a pt is anemic with low reticulocytes then they
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have a marrow or erythropoietin disorder- eg low iron
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if a pt is anemic with high reticulocytes then they
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have a helathy marrow- trying to compensate for bleeding or hemolysis
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why use a corrected reticulocyte count
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(if marrow working high- could get uncorrected 10%- 20%) this is corrected for lowered number of RBCs in anemia. if the corrected number is below 2% the marrow has some degree of insufficiency
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what are fundamental building blocks of hemoglobin needed in marrow
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iron- folate b12
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what might cause low EPO
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kidney disease
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what might cause deficiency of red cell precursors
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low iron- folate- or b12. basically- if the marrow isn't working
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what might cause a fatty marrow with low reticulocyte count- low WBC and platelets? what's this called and how do you treat it?
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this is called aplastic marrow (low cellularity)/marrow hypoplasia. could give blood transfusion. could be caused by radiation. usu idiopathic although can react to drugs also
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what are two location classifications of anemia?
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intrinsic (lacking normal RBC- usu inherited eg sickle cell) or extrinsic (splenomegaly- prosthetic heart valve)
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which are the most common causes of anemia?
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iron deficiency- hemolysis- bleeding
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what are words for smaller- bigger than normal RBCs?
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microcytic- macrocytic
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what are steps in workup of anemia
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blood smear for RBC shape- reticulocyte count- histoy (Aids- bleeding family)- phys exam for underlying disease
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what four things may anemia symptoms be attributed to?
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low O2 to tissues- a cardiac/pulmonary response- hypovolemia of blood- or underlying dz
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at what hb level do you experience symptoms with exercise? symptoms in daily living?
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8-10 exercise- <8 dialy living
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what results from low O2 delivery in anemia
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pallor of skin nailbeds conjunctivae- fatigue- light headedness
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what are cardiovascular symptoms
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rapid pulse- dyspnea heart failure
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what are 5 symptoms of hypovolemia (eg on a battlefield)- would you get these with an ulcer or GI bleed
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pale- cold- rapid HR- low BP- dizziness. less likely with slow belld bc more time to compensate
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with what type of anemia might you see jaundice and why?
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hemolytic anemias due to breakdown of heme (bilirubin)
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why might symptoms of acute anemia be unrelated to hemoglobin?
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could be related to underlying cause eg blood in stool colon cancer or battlefield shock/hypovolemia due to loss of blood
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3b morphology of anemia
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3b morphology of anemia
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what is a normal WBC
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4k to 11k per ul
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What's most practical way to classify anemias
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by their size (MCV)
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platelets normal value
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150k to 400k per ul
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red blood cell normal
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3.8 to 5.3 mill Female 4.3 to 5.8 mill male
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hemoglobin normal
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11.8- 15.5 g female 13.5 - 17.5 g male
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mcv normal
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80-100 fl
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hematocrit
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36-46
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where is the proper place to evaluate a wright blood smear
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between the head and tail
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what is polycythemia
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when there are too many red blood cells?
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what is RDW suggestive of?
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High variation in size even if the mean cell volume is normal
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spherocyte
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suggests 2 dzs: spectrin dfect causing hereditary spherocytosis or autoimmune hemolytic anemia if older pt. have a LOT of hemoglobin in spherical cells
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schistocyte
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fragmented- helmet or wedge-shape
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macroovalocyte
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large and oval.
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what are four causes of microcytic anemia
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iron deficiency- chronic inflammatiory anemia- THALASSEMIA- sideroblastic anemia
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what is basophilic stippling and what diseases does it suggest?
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it is bluish pallor due to persistence of RNA- it suggests high reticulocyte production eg thalassemia vs. iron deficiency. iron deficiency are more hypochromatic
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what is increased diameter of central pallor called?
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hypochromasia- usua ssoc with iron deficiency
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what is typical presentation of iron disease
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microcytic hypochromic anemia
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what are four causes of normocytic anemia
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sickle cell- hemolytic anemia- blood loss anemia- chronic disease (also microcytic if severe) or very mild iron deficiency
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what is the only RBC morphologic clue specific for certain disease
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sickle cell but can't exclude just having TRAIT
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how do polychromatic blood cells look compared to normal
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sort of more blue- like a reticulocyte- stains RNA blue
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what might you see in TTP and why?
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microangiopathic hemolytic anemia
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what are three causes of macrocytic anemia
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B12 deficiency- folate deficiency- and myelodysplastic syndrome
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what is a clue to macrocytic RBC presence
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If they are bigger than nuclei of a lymphocyte
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what are hypersegmented neutrophils indicative of?
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b12/folate deficienct
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what are hypo-lobated hypo-granulated neutrophils suggestive of?
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myelodysplastic syndrome
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What exactly is myelodysplastic syndrome
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on the way to leukemia - abnormal cell maturation but not cancer yet
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what is a leptocyte
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an unusually flattened RBC
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what is likely diagnosis with low RBC and hypochromasia- microcytic RBCs
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iron deficiency anemia
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what is likely diagnosis with low RBC- high MCV- progressive fatigue macrocytic- multisegment polynuclear-
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b12 deficiency/folate
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what is likely diagnosis for MCV 90- mean cell hematocrit 37- low RBC- abundance of reticulocytes? spherocytes- hyperchromatic-
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autoimmune unless younger kid because hereditary spherocytosis
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3C Iron flow- deficiency- and anemia of inflammation
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3C Iron flow- deficiency- and anemia of inflammation
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put these in order from most iron to least iron: transferrin/cytochrome- hemoglobin- ferritin/hemosiderin- myoglobin
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hemoglobin- ferritin/hemosiderin- myoglobin- cytochromes/transferrin
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what has highest Fe turnover
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transferrin bound iron
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where is most iron absorbed
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duodenum (1mg/d)
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what protein carries iron in the bloodstream and what three places can it go?
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transferrin and it can go to the liver- bone marrow to make RBCs
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what is DMT1
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the iron entry protein - takes across the membrane
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what is transferrin
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the carrier protein (its receptor is located on the sirface of red cells
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where are transferring receptors located?
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on surface of rbcs
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what is ferritin and what cells is it found in?
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in enterocytes - storage form in the blood - binds Fe2+ then goes in circulation until it gets to cells where it bigns to receptor and is phagocytosed
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what is the difference in stability between low iron and high iron regarding stability of the transferrin receptor mRNA
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at low iron- the transferrin receptor mRNA is more stable based on iron regulatory proteins (IRP) while ferritin i degraded
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why is pregnancy associated with anemia
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baby needs iron
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what groups should you consider for iron deficiency anemia
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pregnant- young kid (too much milk)- picky eater; growing kid- menstruating woman. RAPID GROWTH=INCRESED DEMAND
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what are the two types of iron sources named- which is better absorbed- what facilitates absorption
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heme and iron of plants. 15% heme iron is better absorbed THAN 3%plant. Vit C enhances iron absorption
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what three factors can cause decreased absorption of iron
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tannins/bran/fiber/calcium - disrupted mucosa as in crohn's - or achlorhydia from PPIs- surgery
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why might diverticuli or hemhorrhoids or NSAIDS be associated with anemia
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these increase blood loss
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what is angular stomatitis? koilonychia- what color are the sclerae?
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koilonychia=spoon nails- sclearae are bluish- pallor of conjunctiva. angular stomatitis=rash at corner of mouth.
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what are two signs of reduced iron store (early)
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decreased marrow iron- decreased ferritin
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what four signs of depleted iron stores
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increased TIBC- low plasma iron- low transferrin sat- and elevated soluble transferrin receptor (IS THIS DUE TO mRNA stability?)
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what stage would be associated with decreased Hb and decreased MCV>
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true iron deficiency anemia
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why is RDW elevated in iron deficiency anemia
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new red cells are small and older are bigger. also might see higher platelets
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would you expect to see normal- low or high reticulocytes in iron deficiency anemia
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high reticulocytes bc lot of turnover due to EPO. also see high RDW and hypochromasia
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what are the names for the diseases of decreased globin synthesis
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the thalassemias
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what shapes of RBCs are suggestive of decreased globin synthesis
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pencil or teardrop shape common
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what are five possiblities if you have microcytic anemia
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iron deficiency- lead poisining- sideroblastic (problem putting iron into red cells) anemia- chronic inflammation- or thalassemia
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how is iron deficiency usually treated
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1)oral ferrous sulfate to replete stores (2mo past correction)- slow release form fewer Sfx but may have lower absorption. can also give parenteral iron or IV infusion.
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what developmental effect of iron deficiency
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development and behavior changes- lower immunity- work performance- developmental effects
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with what chronci diseases is anemia associated?
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chronic infection- lupus- cancer- trauma- ulcerative colitis- regional enteritis
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what process is defective in anemia associated with chronic dz?
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transfer of iron from reiculoendothelial macrophages to transferrin is broken. so the STORAGE iron is GREATER. Ferritin is ELEVATED unlike in deficiency anemia. also reducied EPO and shorter RBC lifespan
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what is hepcidin
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a protein made in liver- antimicrobial activity- increased in inflammation and with high iron levels. it's like an antiiron protein which binds ferroportin- degrades it- preventing iron's door from the gut form opening
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what does inflammation do to hepcidin levels and why?
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it increases them because it's antimicrobial. any acute infection may cause anemia
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Diff btwn iron def and anemia of chronic infect
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TIBC high in iron def- ferritin/bone marrow Fe low. Whereas TIBC maybe low in ica- ferritin/bone marrow iron HIGH.
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3D B12 and folate deficiency
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3D B12 and folate deficiency
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what are morphologic characteristics of megaloblastic anemia
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increased N/C ratio and increased hypersegmentation of neutrophils. immature nuclei in RBCs
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describe N/C ratio
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it decreases as cells mature. if you're B12 deficient- the nucelus gets bigger
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what are five causes of megaloblastic anemia
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folate deficiency- cobalamin- acute megaloblastic anemia- drugs- inborn error. all lead to imbalance in nucleus to cytoplasm
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How are b12 and folate dificencies related in megaloblastic anemia
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they both result in decreased DNA synthesis- causing rapid cytoplasm maturation and slow nuc maturation and effect eryhtrocytes
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what is vit b12 bound to in the body
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intrinsic factor or Rbinders (temp) OR transcobalamin II (uptake in cells)
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why is vitamin B12 necessary for DNA synthesis
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it's a cofactor for mTHF to THF rxn which is requred to convert dUMP to dTMP nucleotide. basically it converts RNA precursor into DNA precursor. protein synthesis is OK
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what do R proteins/binders do
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may dispose of B12 analogs. compete with IF
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how do you get b12
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it lives in dirt- synth by a bacteria- cows wat and as we eat them we get b12. we can also get it from eatting dirt. usu NOT nutritional deficiency
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what is cobalamin
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vit b12
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how do you absorb b12
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parietal cells make intrinsic factor (along with stomach acid)- helping transport through bowel system. IF competes with R-binders- not as good at binding in the stomach's acidity but better at end of digestive sys because proteases cause its release from R-binders in the small bowel. essentially: two chances for IF to bind B12
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what might pernicious anemia- a gasterectomy- zollinger-ellison syndrome-
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these are all gastric causes of cobalamin deficiency. ZE is a type of cancer where you generate too much stomach acid and you never neutralize Rbinders.
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what causes pernicious anemia
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autoimmune against parietal cells- lack of intrinsic factor causes b12 deficit- pernicious anemia
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what are intestinal causes of cobalamin deficit
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ileal resection (crohn's)- blind loop syndrome- fish tapeworm. vegetarianism a MINOR cause
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what are key proteins in B12 transsport
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IF- pancreatic enxymes destroy R binders- transcobalamine II transporter- liver storage
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what is the schllings test
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basically- this test asks- at what level can you correct their defect - eg give radioactive B12 and IF- see if corrects- if so- IF deficit
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what is pernicious anemia and what types of pts may be comorbid with it?
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An IF deficit. diabetes- thyroid- hypotparathyroid- ulcerative colitis- vitiligo- OR autoantibodies may cause this
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what are signs of megaloblastic anemia
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tired- CHF (due to increased output demand)- pallor- jaundice- epithelial lesions (tongue!!) think rapidly dividing cells
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ethnic groups prone to pernicious anemia
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northern europeans and african americans
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what is combined systems disease
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sensory/proprioceptive defect and unable to walk bc can't feel feet
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why are there neurologic symptoms associated with cobalamin deficiency
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demyelination causes combined systems disease (irev) can't feel feet- paresthesias
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how do you treat cobalamin deficiency (what should you NOT do)
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DON't transfuse. Instead treat with B12. you CAN give folate- but WON'T solve neurologic deficit. Folate solves anemia ONLY.
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why DON't give transfusion
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their anemia occurred REALLY slowly- their heart is pumping a TON- and then you give MORE blood- you may trigger acute heart failure. SO MUST CHECK B12 in megaloblastic anemia
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what are only two things you should give RBCs for
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active bleeding and low hemoglobin- OR iron deficiency anemia without too much volume
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what symptoms are not adequately treated by high dose folate
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neurologic aren't treated
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how are vit b12 and folate associated
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b12 catalyzes activation of THF (folate)
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what could you be concerned about in old age- poverty- alcoholism- hemodialysis- preemies- or goat's milk anemia- pregnancy
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FOLATE deficiency
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what dz is nontropical and tropical sprue assoc with
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folate deficiency
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what drugs might cause folate deficiency
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methotrexate- 5FU- hydroxyurea- anticonvulsants- OCs. ALL impair DNA maturation
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what are inborn errors of cobalamin
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imerslund grasbeck- congenital IF deficit-
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what are inborn errors of folate metabolism
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congeinital folate malabsorption DHF reductase deficit- homocysteine
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what is the RBC count in megaloblastic anemia?
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depressed- because they are rapidly dividing.
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ileal reseaction- blind loop syndrome- or a fish tapewrom result in
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pernicious anemia
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3I Neoplasia 3
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3I Neoplasia 3
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what type of gene results in growth stimulation subsequent to a loss of function
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tumor suppressor
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what's an oncogene
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requires only 1 hit to turn on tumor
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what is Ras an example of?
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It's a cytosolic protein that carries downstream signals from the EFGR tyr kinase- and if mutant can cause cell proliferation
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How can FISH be used to demonstrate oncogenic activity of a Ras translocation?
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HSR 9homologous staining region
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region of gene amplification
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**What is the EGFR gene product duplicated and what ELSE must be mutant to cause cell proliferation
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Would a Ras mutation causing cancer be expected to increase or decrease GTPase activity?
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DECREASE bc active form is GTP bound
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What's the active form of Ras
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Ras-GDP
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What does Myc do and would it be expected to be over or underactivated in cancer?
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oncogene. overactive. normally it makes repressors of the cell cycle, so no block in the G to S transition.
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what is myc
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a protein that activates the cell cycle and represses cell cycle repressors- when it's active it's an oncogene. Ras phosphorylates and activates myc
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Describe the mechanism of Burkitt's lymphoma from the myc gene
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Basically chromosomal translocation changing regulator of myc causing increased expression of c-myc and speeds cell cycle- less differentiation- more telomerase- less adhesion
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what type of genes are associated with point mutations- amplifications and translocations
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oncogenes
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what type of genes are associated with methylation and why?
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tumor suppressor
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what is the inheritance pattern for hereditary retinoblastoma?
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autosomal dominant
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is hereditary more likely to be uni- or bilateral and why?
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bilateral (hit earlier in life)
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is the RB1 gene likely to be a tumor suppressor or oncogene?
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Tumor suppressor because require two hits to one cell to develop cancer - even in hereditary form
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What two ways might the RB1 protein be mutatn
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Most are due to erroneous transcript production- but 10% of sporadic may be due to hypermethylation and thus inactivation of DNA
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what does methylating do to DNA
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it inactivates it
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what do CpG islands mean for DNA and would they have greater effect on tumor promoters or suppressors
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these are locations for methylation of DNA and they should have a greater effect on suppressors
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What other strategy might turn off a perfectly functional RB1 gene?
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cdks phosphorylate to inactivate
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what do cyclins (cdks) do to rb
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they phosphorylate it- removing the rb block on the G to S transition
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are cyclins and cdk4s oncogenes or tumor suppressors?
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they are oncogenes if broken in phosphoyrylate on
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What are 3 DNA tumorviruses
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adenomvirus- polyomavirus- and papillomavirus
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How are tumorviruses associated with cancer?
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their oncoproteins bind to Rb OR p53 and inhibit them (mimic cyclin or cdk4)
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What does the RB1 protein normally do?
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It represses transcription factors that tend normally to move through the cell cycle
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3J Hemoglobinopathies
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3J Hemoglobinopathies
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How many O2 can one heme subunit bind? How many can one hemoglobin molecule then bind?
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1..4
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Is the curve higher affinity if shifted right or left?
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left
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What allosteric modifiers shift the curve right to give the molecule less affinity
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heat acidity, 2,3 BPG which a product of glycolsis
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What does 2-3 BPG do to O2 affinity of hemoglobin and why?
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It should decrease it. A byproduct of glycolysis??
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What type of mutation are hemoglobinopathies caused by?
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null product so deletional or nondeletional but prevent expression
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What type of mutations are thalassemias
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nondeletional - just misformed product
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are deletional mutations more common in a or B genes?
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deletional more common in alpha genes but of course there are two genes, not one like B
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describe some ways in which B genes can be modified
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can be Bo or B+, if B+ has some level of transcript present
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What three steps in mRNA processing might lead to defective B globin?
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splicing and polyadenylation and the 3'UTR must mediate stability
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why is HbA2 important?
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If it's elevated above 3 then likely to have some kind of thalassemia - it's the
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Any significant phenotype with a thal (hint: B4)
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HbH is a disease due to 4Bs associating soluble, but are destroyed at a greater rate than normal
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3M hemoglobinopathies and thalassemias
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3M hemoglobinopathies and thalassemias
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Look closely at the Hb electrophoresis and make sure oyu understand
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What is a thalassemia
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What characterizes thalassemia and what predicts their severity
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what type of anemia si produced in thalassemia
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where are hotspots for thalassemia? assoc with what dz?
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What is deficient in a thalassemia and what stocks up as a result
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what is HbH? what is the a genotype?
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What is deficient in B thalassemia and how is the resultant product DIFFERENT from in a-chain
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SO you can't get a+ but you can get B+? weird
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what is cooley's anemia?
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Bo/Bo
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When you measure the weird hemoglobins- do you use the same measurement tests?
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What is notable about the spectrum of thalassemias
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What do splenomegaly- microcytic yet hypochromatic RBCs- normal iron but elevated bilirubin- poor growth and endemic area suggest
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woop woop severe B thalassemia
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Why does a chain preciptiation lead to prodound anemia? what can you say about blood iron levels?
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How does hepatosplenomegaly result in B thalassemia
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what causes cardiac- hepatic- endocrine tissue damage?
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iron overload due to ineffective erythroid progenitors
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what cell shapes are specifically associated with B thalassemia
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what does anisocytosis mean
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variation in cell sized
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what characteristic morphology of b-thalassemia trait
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microcytic hypochromic
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DOES THE a TRAIT LOOK DIFFERENT?
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What two causes of low MCV will you see commonly>
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Iron deficiency anemia and thalassemia
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What allows you to distinguish B thalassemia form iron deficiency
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What is the HbA2 level in thalassemia? In iron deficiency?
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High in thalassemia and low in iron def.
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would you expect thalassemia to have higher or lower retics?
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What's the difference between major and minor B thalassemias?
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What is standard of care for B thalassemia
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what does desferal do?
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3L hematopathology Lymphoma Overview
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3L hematopathology Lymphoma Overview
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What is the difference between reactive disorders and neoplastic disorders
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neoplastic are clonal
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what's the difference between leukemia and lymphoma
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leukemia is disseminated in blood whereas lymphoma is solid masses in organs but this distinction not definite
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what difference between acute vs chronic leukemia/lymphoma
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acute=blast cells, chronic=mature lymphocytes. may somewhat correlate with speed of disease
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what is a lymphoma
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a nodular tumor of one of the lymhoid organs eg speeln, thymus lymph node
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describe where lymphocytes and plasma cells are found in the normal lymph node
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medulla=plasma, cortex=lymphocytes,
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what is a secondary lymph node
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one where the germinal center has been activated and B cells are proliefarting
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what is the difference between hodgkin and nonhodgkin lymopha
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hl is a different type of lymphoma which spreads from node to node. NHL is mostly Bcell tumors but some T cell tumors and plasma
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how do you distinguish size of lymphocytes
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small cell are size of normal lymphocytes while large cell are size of histiocyte nuclei
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what is the immunophenotype and why is it used?
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it's the molecules expresse don the surface of the cell and it tells you what type of progenitor cell population your B cell came from
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how can immunophenotype distinguish bening and neoplastic?
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on an immunoplot there are all molecules of one type (eg all with k chain, eg)
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what molecule marks immature B cells
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Tdt (and cd19)
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what marks mature B cells
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CD20 (and cd19)
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what do CD10 and BCL6 identify? what is NOT expressed by these cells?
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germinal center cells. BCL2 should NOT be expressed in these cells unless there has been a translocation
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What cell type is CD3 specific for?
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immature T cells
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What call type is CD19 specific for?
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B cells
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What does surface Ig say about a cell?
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it can tell you whether the cell population is clonal or not
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would you be concerned about B cells expressing CD5?
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CD5 is normally on T cells. B cells expressing CD5 likely malignant
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What information does a genotype of a lymphoma give you?
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tells you about its mechanism of disease
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why are mature B cells more prone to neoplasm than T cells?
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they undergo two additional rearrangements that T cells do not
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what is a normal cell counterpart in the context of a lymphoma?
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normal cell counterparts are identified based on morphologic characteristics, geno
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what are type B symptoms of a lymphoma?
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fever chills night sweats
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What are kappa and lambda chains
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they are part of the immunoglobulin chain and may indicate clonality of a cancer type
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what does it say if cancer found in bone marrow
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bad sign since normally there is not hematopoeisis in the bone marrow
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What are two causes of microcytic anemia
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iron deficiency or B thalessemia
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How can you tell the difference between Iron deficiency and B thalessemia
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Iron level diagnostic Higher retics and higher A2 in B thal
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How can you tell between Bo and ao
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Look and see if she has any A2 hemoglobin. If yes, then B major (Bo) if no then a thalessemia
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treatment
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chelator of excess iron and packed RBCs
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What are three forms of B thal
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minor (trait), intermedia (above 50%) major - Bo/Bo
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What is different between sickle cell trait and sickle cell disease
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they nly have one abnormal B globin gene an dit's benign
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What is the mutation in sickle cell disease
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missense resulting in a Glu to val subsitution
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Why do you see problems if HbS is a normal O2 transporter?
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when HbS is deoxy, it forms polymers which can disrupt cell shape
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Describe what causes aggregation of HbS
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the change of acidic acid to a nonpolar Val, causing trend toward aggregation
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What is the log jam model of SCD? What is added currently?
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that the sickled cells can't get through small vessels, ADDED=rheology-flow, rbc dehydration, cell adhesion
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How does delay time affect HbS formation? What affects delay time?
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slight changes in conc of hemoglobin has a huge impact in how fast RBCs sickle so if they're more dehydrated they sickle faster
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What is relationship between NO and HbS
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Burst cells allow their hemoglobin to scavenge NO which can no longer relax vessels
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Explain some organ consequences of sickle vasoocclusion
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skin ulcers, neuro=stroke, pulm hypertension, MI, immunologic problems because spleen infarcts
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What are four SCD crises?
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acute chest (fat emboli); splenic sequestration=fatal anemia; aplastic crisis secondary to parvovirus=anemia, vasoocclusive crisis
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What are treatments
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underlying cause eg infection, oxygen, last resort RBC transfusion
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Why might inducing fetal y globin be a good treatment
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hydroxyurea increrases Y glbon because it makes sure that the hemoglobin is excluded from polymer
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what's important for chronic SCD re: prevention
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folate; vaccination, penicillin
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What are Hb, MCHB, MCV in SCD?
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anemic mild but normal other two. Weird cell morphology only
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What type of Hb might be elevated in SS
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HbS
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What are key differences in HbA levels between sickle cell trait and scd?
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SS can't produce hemoglobin A. AS can make 60% HbA and 40%HbS. If not this split, there's something else going on!!!
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3N Hemolytic anemias
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bilirubin
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What 3 factors to consider a hemolytic anemia
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stable/dropping Hb despite more RBC production and no bleed
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How can reticulocytes be used to monitor hemolytic anemia?
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if theyre hight be hemolytic anemia
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What forms bilirubin?
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Bilirubin is formed from heme breakdown
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What binds free heme and what two organs may be involved in its disposal (hint the second one is if there are no blood binders)
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haptoglobin and hemoplexin. Albumin binds ferri heme. These three are processed in the liver, but if binding capacity exceeded, start excreting in urine
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Why is decreased serum haptoglobin and increased bilirubin suggestive of hemolytic anemia
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these are breakdown and transport proteins for heme. Also increase retics
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What are five non-immune mediators of hemolyisis?
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microangiopathy, hypersplenism, infection, toxins, and venoms
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What type of RBCs show up in hemolytic anemias
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schistocytes=fragmented red cells
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How does the Coombs (DAT) test work?
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BOUND antibodies are tested by this by adding antisera which would measure these antibodies and clump
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What's the difference between indirect and direct Coombs test?
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indirect is for circulating antibodies if all of your RBCs have been destroyed, you can still find the Ab in the serum
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Where do spherocytes come from?
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Spherocytes CAN come from phagocytic cells chomping off bits of the membrane, OR due to internal protein defects
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What is autoimmune hemolytic anemia a common sequelae of?
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cold, illness
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List four symptoms of autoimmune heolytic anemia
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jaundice, anemia, splenomegaly, reticulocytosis
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what's an appropriate treatment for autoimmune hem anemia
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In whom are cold reactive anti-red cell antibodies found?
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IgM antibodies are produced which can cause mild to moderate hemolysis by fixing complement to RBC surface The Coombs test will be positive for complement.
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What is heriditary spherocytosis a disease of?
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normally spectrin and ankyrin give its shape, but can have mutations, get trapped in spleen and destroyedcomplications gallstone from bilirubin, red cell aplasia, leg ulcers
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Why is splenectomy treatment for spherocytosis?
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because then you remove the thing that's destroying the RBCs
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what is g6pD? Why do certain drugs given to G6PD patients induce hemolysis?
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Sex-linked Enzymoptahy that causes hemolysis in response to infection OR drugs. Primaqine (fava beans) antimalarial caused soldiers to hemolyze. RBCs with Heinz bodies are destroyed in the spleen.
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3N Nonhodgkin's Lymphoma
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What is the progenitor cell of small B cell NHL?
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What is the most common NHL
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Follicular lymphoma 45%
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What are clinical features of FL? (eg, how fast, involvement?)
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cervical lymphadenopathy, BM involvement hematogenous spread stage IV disease, indolent, liver and spleen involvement
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How is the spleen affected in follicular lymphoma?
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Painless diffuse splenomegaly (manifest as early satiety) in contrast to aggressive lesions which form masses
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What peripheral blood features are seen in 10% of patients?
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small celaved cells (centrocyte) and
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What is the prognosis for FL? What potential problem?
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indolent slow-growing so hard to eradicate but may transform
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Where do FL come from (what were they doing before?)
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They were in the GC
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Describe a neoplastic FL lymh node
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It can be nodular or
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What cell morphologies are predictive of aggressive behavior?
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centroblasts and diffuse nodules
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What characteristic bone marrow growth pattern is diagnostic of FL?
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paratrabecular groth rather than just rampaging through the whole bone
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What is different about immunophenotype on B cells in FL?
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They express BCL2+ and are kappa or alambda restricted
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How do FL cells behave diferently in germinal centers than normal B cells
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they don't grow fast but they don’t die due to persistence of BCL2
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What's a cytogenetic hallmark of FL?
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t14 -t18
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What are clinical features of CLL/SLL (Blood symp, BM involvement, immune dysregulation?)
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frequent blood involvement common cause of adult leukemia, indolent to aggressive, interstitial bone marrow involvement, TWO TYPES (1 and 2)
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How swiftly does it progress/transform?
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Richter's transformation possible with poor prognosis, some indolent some rapid, hard to tell who's who?
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What are morphologic characteristics of CLL/SLL
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not known origins, but has smudge cells which are in peripheral smear
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What cells are characteristic of CLL/SLL
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erase normal architecture of follicels, bu has pseudoproliferation centers vs follicles, can have diffuse marrow growth unlike FL
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What is unique about the immunophenotype of CLL/SLL
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They are B cells but they express Cd5+ which is a T cell marker
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What may act as tumor suppressor in CLL/SLL (better progrnosis)
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there may be miRNAs which act as tumor suppressors (13q)
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Which form of CLL/SLL does better? Why?
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Distinguish btwn group 1 (unmutated grIgV, less mature) VS group 2 hypermutated Zap70-, have traversed germinal center, have hypermutated IgV. Group 2 are LESS AGGRESSIVE
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What are three types of marginal zone lymphomas?
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Nodal, extranodal (MALT), or splenic. From B cells that have TRAVERSED the germinal center
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What can MALT be associated with
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Assoc with chronic infection-helico, campylo, skin borrelia, orbit chlamydia. The spleen MAY be assoc with hep C
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What's MALT prognosis?
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indolent slow-growing so hard to eradicate but may transform
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What are two histologic features of MALT
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Larger than normal marginal zones with a tropism for invading/destroying epithelial structures
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Immunophenotype of MALT?
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Nothing significant but they are Cd10-, BCL6-, BCL2+
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Two key factors of MALT biology (antigen, spread)
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first clonal expansion due to inflammatory stimulus, then can become stimulus independent by translocation
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What translocation in MALT?
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Normally upregulation of NFKB which causes accum of B cells in MALT lymphoma. t11.18 Cells grow too much and don't die.
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How to treat MALT? 1st and 2nd
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1st treat underlying infection (cut off chronic inflmmation). ANTIBIOTICS. OR 2nd can treat spread from mucosa to mucosa (tumor spread) readiation chemo
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what is characteristic MALT spread pattern
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mucosa to mucosa infrequent marrow involvement
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3S Multiple myeloma
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What cells is multiple myeloma from?
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MM comes from plasma cells and is associated with the bone marrow
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What is unique about the epidemiology of multiple meloma?
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Most common in AA and increasing
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Immunophenotype of MM (remember this is different from other B cells and is not technically a lymphoma)
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CD138 syndecam as well as NCAM to stick to marrow
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Where do you find MM?
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bone marrow and also lymph nodes
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pathology of MM
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Flame cells (express IgA) and Mott cells (large glops of fat like a pearl necklace around the cell)
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What are clinical features of MM?
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MM cause extensive bone remodeling and anemia due to marrow replacement. Osteopenia/hypercalcemia. lytic bone lesions in axial skeleton! Painful. Anemia due to marrow replacement
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what chromosomal activating mechanism for MM?
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deletions of 13q
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What is paraprotein and how does it have its effects?
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aka M (for monoclonal) protein, oversecreted antibody by the cancerous cell, usually these are IgG or IgA, cause renal failure due to cast nephropathy, anemia, immunodeficiency bc only make one kind of Ig
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amyloidosis
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when the paraproteins bind together in plaques and settle out in some organs
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How does MM have its effects?
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Light chains can pass through the urine alone (called Bence Jones protein, measure of disease severity). Can block renal tubules in "tubular casts" also die of immunodef
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what is bence jones protein
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light chain in urine and marker of MM progress/recurrence
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Describe what's unique about two pathogetic mechanisms of DLBCL
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two ways: either progression of another lesion or de novo
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What two lymphomas are aggressive type
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Burkitt's and DLBCL
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What is typical presentation of DBLCLs and how does this affect their grading?
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They tend to present at a single site, quick growth, so pain. Better prognosis
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What lymphomas is associated with fish flesh (discuss architecture)
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DLBCL is fishflesh, cells not set up to organize
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which type of DLBCL does better
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the germinal center B cells (GCB) do better than activated B cells (ABC)
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Describe the malignancy of Burkitt's lymphoma, is it curable?
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it is very rapidly malignant and curable bc of this
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Where is Burkitt's lymphoma (nodal or extranodal)
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i think both, wherever
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Describe each of the three variants of Burkitt's lymphoma
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endmeic, sporadic, immundeficiency
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What is link between EBV and Burkitt
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the endemic forms usually have EBV in them - EBV drives B cell proliferation always found in african variants. other two have lower association with EBV
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What disease may develop with ct14:18 and what gene is activated?
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Burkitt. c-myc is activated causing cyclin activation
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what are the main differences between endemic, sporadic, and immunodeficient burkitt's?
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endemic is in africa facial, viral associated, sporadic may be associated abdominal masses more common, immunodeficient=HIV assoc
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why is burkitt's both an emergency and rapidly responsive to treatment?
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it doubles quickly but this also means it's very responsive to therapeutic agents
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What cells produce the histologic pattern seen in BL and what's the pattern called?
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starry sky pattern and they are called tingible body macrophages
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What tumor might have hgih Ki67 and why?
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BL because it's very proliferative
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what's the difference between follicular lymphoma a Burkitt's in terms of proliferative drive?
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FL has low proliferative drive but has BCL2+ which means it's lost ability to apoptose, whereas BL has high proliferative drive due to myc translocation
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how does overexpression of cMYC happen and what cancer is this specially associated with?
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BL is associated with cMYC translocation in fron to fthe light an dheavy chain loci
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3T Hodgkin lymphoma
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What are key differences in lymphoma and leukemia
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lymphomas tend to have focal masses and staging. leukemias present with bone marrow failure. diagnostic difference-lnode bipsy vs bone marrow aspirate
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What are two similarities between HL and NHL
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painless lymphadenopathy, constitutional symptoms BUT different prognoss, spread pattern, prognosis much better for HL
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what's diff btwn acute and chronic
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depends if neoplastic block comes before blast or after
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what' s unique about age spread in Hodgkin
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bimodal (15-30) and greater than 50. mostly a disease of young adults
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what are diagnostic features of HL
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orderly spread, unifocal, reed sternberg owl cells, effaced architecture of LNs, pleomorphic infiltrate,
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where do reed sternberg cells come from
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B cells
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cytokine soup
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Reed Sternberg cells secrete cytokine soup to cause the other cells to come in night sweat symptoms predispose to constitutional symptoms
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what two classifications of HL and describe the more common
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Classical 95%, with four subtypes: nodular sclerosis, lymphocyte rich or poor, or mixed cellularity
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which HL classification has diffuse or nodular growth, rs cells, mononuclear/lacunar CD45-, static IgH genes
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classical HL. (nodular lymphocyte predominant HL)
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which subtype of classical HL is strongly associated with fibrosis
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nodular sclerosis
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Which type of HL is most common in young? second most common?
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young is 70% - and nodular sclerosis, good survival. females, mediastinal.
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Describe the pathology of HL
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fish flesh appearance (custanrd, eg yolk), with a lot of fibrosis, also look for reed sternberg cells
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What determines staging of disease
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how many regions in the body and whether they are on the same or different sides of the diaphragm
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What is early stage treatment
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radiation OR chemo alone, combo.
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what are chemos used for HL
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MOPP or ABVD but toxicity includes 2ndary AML, pulmonary fibrosis. sterility. more often ABVD
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what late stage treatment
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chemo ALWAYS very bulk
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3V Bone Marrow Overview
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3V bone marrow overview
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What are anemia polycythemia
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anemia too few RBCs, polycythemia too many
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what is the difference between thrombocytosis/thrombocytopenia
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cytosis too many platelets, penia too few
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what's the difference between leukocytosis/ leukoopenia
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cytoisis=toomany, penia too few
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how is bone marrow used in cancer
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as a measure of disease progress (stage IV)
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where do you withdraw bone marrow/complications
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posterior superior iliac spine
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what marrow is associated with cellular trabeculae
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cancer of follicular lymphomas
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describe organization of bone marrow normally
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normally the myeloid cells are clumped close to the trabeculae and the erythroid and megakaryocytes are closer to the center
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why might you be unable to identify FL or HL fmor a bone maarrow smear
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FL: lose paratrabecular organization of cancers, HL can't see the fibrotic regions because they don't aspirate
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Describe patterns of chromatin transition and granules within the cytoplasm
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chromatin goes from tiny spots to circles or lines, while the NC ratio increases
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What cells can be confused with megakaryocytes and how to tell difference
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osteoclasts - but these are true multinucleate
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what can be confused with lymphocyte
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osteoblasts - but can tell apart byprotrusional nuclei and polygonl cytoplasm
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what are 2 different categories of bone marrow failure anemia
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pancytopenia/isolated OR inherited/acquired
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what can ethanol toxicity result in
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acquired decreased erythropoeisis
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what does bone marrow look like in failure
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marked hypocellular marrow (lots of fat) in aplastic anemia
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why wouldn't you expect to see increased lymphopoeisis in bone marrow
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normally reactve lymphopoeisis occurs only in peripheral blood
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if you see a neutrophil with a Dohle body, what's in it and what can you condlude about origins of neutrophilia
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Dohle body is proteins, vacuoles, and RNA and these usually arise from sickness
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what is MPD
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myeloproliferative disorder, espansion of all cells or just a few eg (polycythemia vera RBC expansion)
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what is the diagnosis if you have 20% of more blasts in your blood
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AML/ALL which cause clonal expansion of different cell lines
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Difference between Myeloproliferative disease, leukemia,
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MPD is clonal expansion of hematopoeitic stem cell lines (1 or more) including differentiationwhereas leukemia is block in differation and decrease in apoptosis leading to oncrease of progenitor cells in blood and LOW regular cells in blood
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What type of lymphocyte do you see in EBV
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wedge shaped downey cells - they're NK cells or monocytes
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what infiltrate in cml
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neutrophils
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basophilic stippling=dohle body
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