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99 Cards in this Set
- Front
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most common and important anemias associated with RBC underproduction
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nutritional deficiencies then renal failure then chronic inflammation
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pernicious anemia cause
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B12 (cobalamin) deficiency; autoimmune gastritis, failure of intrinsic factor production
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what are B12 and folic acid required for
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coenzymes for synthesis of thymidine (one of 4 bases found in DNA)
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anisocytosis
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variation in size
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poikilocytosis
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variation in shape
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characteristics of megablastic anemias
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macrocytic and oval; ample hemoglobin; lack central pallor, but MCHC not elevated; anisocytosis and poikilocytosis; reticulocyte count low; occasional nucleated RBC if severe in circulation; neutrophils larger than normal and hypersegmented; marrow hypercellular
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what secretes intrinsic factor
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parietal cells of fundic mucosa
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what frees B12 from binding proteins in food
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pepsin in stomch and binds to salivary proteins called cabalophilins or R-binders
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what occurs to bound B12 in duodenum
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released by pancreatic proteases and associates with intrinsic factor
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where is the intrinsic factor/B12 absorbed
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ilial enterocytes, where B12 associates eith transcobalamin II and secreted into plasma
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2 rxns that require B12
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1) methycobalamin serves as essential cofactor in conversion of homocysteine to methionine by methionine synthase (yields FH4) 2) isomerization of methylmalonyl coA to succinyl coA
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what builds up in urine and plasma with B12 deficiency
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methylmalonic acid and propionate
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neural effects may be caused by what due to B12 deficiency
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formation and incorporation of abnormal fatty acids into neuronal lipids = predisposes to myelin breakdown
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What is FH4 crucial for
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conversion of dUMP to dTMP (deoxyuridine monophosphate to deoxythymidine), immediate precursor of DNA
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autoantibodies in pernicious anemia
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75% type I-blocks binding of vit B12 to intrinsic factor; Type II-prevent binding og intrinsic factor-vit B12 complex to ileal receptor; Type III in 85-90%-recognize the alpha and beta subunits of the gastric proton pump
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where is the gastric proton pump normally localized
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microvilli of canalicular system of gastric parietal cell
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primary cause of gastric pathology in pernicious anemia
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NOT auto antibodies; autoreactive T-cell response initiates gastric mucosal injury and triggers formation of autoantibodies
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achlorhydria and loss of pepsin secretion
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B12 not readily released from proteins in food and can cause anemia
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exocrine pancreas fxn and B12
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with loss, can't release B12 from R-binder-B12 complexes
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anemia due to B12 with normal absorption causes
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pregnancy, tapeworms, hyperthyroidism, disseminated cancer, chronic infection
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atrophic glossitis
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tongue shiny, glazed, and 'beefy'; seen in B12 deficiency
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CNS and B12 deficiency findings
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demyelination of dorsal and lateral tracts, sometimes followed by loss of axons
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diagnosis of pernicious anemia
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1) moderate/severe megaloblastic anemia 2) leukopenia with hypersegmented granulocytes 3) low serum B12 4) elevated homocysteine and methylmalonic acid in serum
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elevated homocysteine levels risk factors
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increase artherosclerosis and thrombosis
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FH4 fxn
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serves as acceptor of 1-carbon fragments from cmpds such as serine and formimonoglutamic acid, then donates these 1-carbon units to various rxns
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most important metabolic processes involveing FH4
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1) purine synthesis 2) conversion of homocysteine to methionine 3) deoxythmidylate monophosphate synthesis
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3 major causes of folic acid deficiency
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1) decreased intake 2) increased requirement 3) impaired utilization
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daily required intake of folic acid
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50-200 ug; green veggies-lettuce, spinach, asparagus, broccoli; certain fruits, and animal sources (liver)
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cooking and folic acid
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destroys 95%+
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normal transport form of folate
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5-methyltetrahydrofolate
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how quickly can a defiency of folic acid appear
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reserves modest; can arise within weeks-months if intake is inadequate
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alcoholics and low folate
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low intake (intestinal absorption), trapping within liver, excessive urinary loss, disordered metabolism
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drugs that interfere with folate absorption
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anticonvulsant phenytoin and oral contraceptives
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folic acid antagonists
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methotrexate-inhibit dihydrofolate reductase and lead to deficiency of FH4
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diagnosis of folate deficiency
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decreased folate levels in serum or red cells; serum homocysteine levels increased, but methylmalonate concentrations normal; neurologic changes do NOT occur
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why should B12 deficiency be excluded b4 treating for folate deficiency
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folate therapy with B12 deficiency doesn't effect or can exacerbate neurological deficits of B12 deficiency states
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whom is iron deficiency common in the US
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toddlers, adolescent girls, and women of childbearing age
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heme iron vs nonheme iron absorption
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20% heme and 1-2% nonheme
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fxnal storage compartments for iron
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80% in hemoglobin; myoglobin and iron-containing enzymes like catalase and cytochromes contain the rest
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storage pool of iron
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hemosiderin and ferritin=make up ~15-20% total body iron
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transferrin
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transports iron in plasma; synthesized in liver; usually 1/3 saturated with iron (120 ug/dL in men and 100 ug/dL in women)
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free iron
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highly toxic
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ferritin
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ubiquitous protein-iron complex that is found at highest concentrations in liver, spleen, bone marrow, and skeletal muscles
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where is ferritin in liver
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stored within parenchymal cells (from transferritin)
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where is ferritin found in other tissues like spleen and bone marrow
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mainly in macrophages (from breakdown of RBCs)
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where is intracellular ferritin located
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cytosol and lysosomes
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basis of prussian blue stain to see hemosiderin
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potassium ferrocyanide
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what do blood ferritin levels correlate with
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body iron stores since this is where it is derived; below 12 ul/L in iron deficiency, can be up to 5000 ug/L
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where is iron absorbed
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proximal duodenum; no regulated pathway for iron excretion (1-2 mg/day lost in shedding of skin and mucosal cells)
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nonheme iron absorption
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1) most in Fe3+/ferric state and must be reduced to Fe2+/ferrous by ferrireductases like cytochromes and STEAP3 in lumin 2) Fe2+ transported across apical membrane by divalent metal transporter 1 (DMT1)
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2 pathways for iron that enters duodenal cells
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1) transport to the blood 2) storage as mucosal iron
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how does Fe2+ enter circulation
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1) transported from cytoplasm across the basolateral enterocyte membrane by ferriportin 2) newly absorbed Fe3+ binds rapidly to transferrin
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what is ferriportin transport coupled to
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oxidation of Fe2+ to Fe3+ via iron oxidases hephaestin and ceruloplasmin
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what regulates iron absorption and how
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hepcidin, made in liver; inhibits iron transfer from the enterocyte to plasma by binding to ferriportin and casuing it to be endocytosed and degraded; iron is then lost as cells are sloughed
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what other fxn dies hepcidin do
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suppresses iron release from macrophages-important in anemia of chronic disease
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TMPRSS6
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hepatic tansmembrane serine protease that normally suppresses hepcidin production when iron levels low; rare mutations cause microcytic anemia
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hemochromatosis
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systemic iron overload-low hepcidin
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secondary hemochromatosis causes
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diseases associated with ineffective erythropoiesis like B-thalassemia major and myelodysplastic syndromes
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causes of iron deficiency
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1) dietary lack 2) impaired absorption 3) increased requirement 4) chronic blood loss
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daily iron requirement (accounting for absorption percentage)
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~7-10 mg for men and 7-20 for women
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what is absorption of inorganic iron enhanced by
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asorbic acid, citric acid, aas, sugars in diet
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what is absorption of inorganic iron inhibited by
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tannates (in tea), carbonates, oxalates, and phosphates
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human breast milk vs cow iron
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breast milk ~.3mg/L; cow milk contains twice as much, but less bioavailability
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impaired absorption causes
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sprue, fat malabsorption (steatorrhea), chronic diarrhea
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most common cause of iron deficiency anemia in Western world
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chronic blood loss
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what type of anemia does iron deficiency cause
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hypochromatic microcytic anemia
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progressive loss of iron
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first lowers serum iron and transferrin saturation levels without producing anemia
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best way to see depletion of iron in bone marrow macrophages
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Prussian blue stains on smears of aspirated marrow
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central pallor of RBCs
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normally 1/3 of RBC diameter
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poikilocytosis
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small, elongated RBCs (pencil cells)
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Plummer-Vinson syndrome
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esophageal webs along with microcytic hypochromatic anemia and atrophic glossitis
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CBC specs in iron deficiency
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serum iron and ferritic low, TIBC high (elevated transferrin); transferrin saturation below 15%; low hepcidin levels; hgb and HCT low
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3 groups of chronic diseases that cause iron deficiency
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1) chronic microbial infections (osteomyelitis, bacterial endocarditis, lung abscess) 2) chronic immune diseases (RA, regional enteritis) 3) neoplasms (carcinomas of breast and lung, Hodgkin lymphoma)
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CBC specs in chronic disease iron deficiency
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low serum iron, reduced TIBC, abundant stored iron in macrophages; (also low erythropoietin)
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IL-6
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stimulates increase in hepatic production of hepcidin in chronic inflammation; inflammatory mediator
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red cells in chronic iron deficiency anemia
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normo or hypochromatic; and microcytic
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what can rule out iron deficiency as cause of anemia
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increased iron in marrow macrophages, high serum ferritin, reduced TIBC
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most cases of known etiology of aplastic anemia
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follow exposure to chemicals and drugs
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Fanconi anemia
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rare autosomal recessive disorder caused by defects in multiprotein complex that is required for DNA repair; marrow hypofunction early in lifealong with multiple congenital anomalies (hypoplasia of kidney and spleen, bone anomalies of thumbs or radii)
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inherited defects in telomerase
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found in 5-10% of adult-onset aplastic anemia; either short telomeres (more common) or telomerase mutations
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65% aplastic anemias
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idiopathic-no known cause
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two major etiologies of aplastic anemias
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1) extrinsic, immune-mediated suppression of marrow progenitors (T-cells) 2) intrinsic abnormality of stem cells
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expression analysis of remaining marrow stem cells in aplastic anemia reveal
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apotosis and death pathway genes up-regulated
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what finding should seriously question diagnosis of aplastic anemia
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spenomegaly
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RBCs in aplastic anemia
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usually slightly macrocytic and normochromatic; reticulocytopenia is the rule
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marroe in aplastic anemia
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hypocellular
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myeloid neoplam marrow
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hypercellular marrows filled with neoplastic progenitors
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what is pure RBC aplasia associated with
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neoplasms (thymoma, large grandular lymphocytic leukemia), drug exposures, autoimmune disorders, parvovirus infection
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parvovirus B19
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preferentially infects and destroys RBC progenitors; normally cleared 1-2 weeks and aplasia is transient; crisis in moderate/severe hemolytic anemias
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myelophthisic anemia
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marrow failure in which space-occupying lesions replace normal marrow elements (metastatic cancer, granulomatous disease, myeloproliferative diseases-spent phase)
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fibrotic marrow causes appearance of what in peripheral smear
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nucleated erythroid precursors, immature granulocytic forms (leukoerythroblastosis), teardrop-shaped RBCs (due to tortuous escape)
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chronic renal failure anemia is proportional to
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severity of uremia
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kidney failure anemia causes
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reduced erythropoietin, reduced RBC lifespan, iron deficiency due to platelet dysfxn, and increased bleeding
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hepatocellular liver disease anemia cause
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decreased marrow fxn; slightly macrocytic due to lipid abnormalities
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hypothyroid anemia
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mild normochromatic, normocytic anemia
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relative polycythemia results from
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dehydration; stress polycythemia or Gaisbock syndrome
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seconary polycythemia
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reponse to increased erythropoietin
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polycythemia vera
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myeloproliferative disorder associated with mutations that lead to erythropoietin-independent growth of RBC progenitors
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HIF-1alpha
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hypoxia-induced factor that stimulates transcription of erythropoietin gene
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