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Pathoma Ch 5 RBCs
Terms in this set (88)
-reductions in RBC mass is ---
-how to measure RBC mass
sx are weakness, fatigue, dyspnea, pale conjuntiva and skin, headache , lightheadedness, angina, prexisting CAD
-Hb, Hct, RBC count are used as surrogates for RBC mass
-MCV <80 b/c it undergo 1 extra division due to decreased production of hemoglobin
-MCV > 100
list microcytic anemias: (4)
-anemia of chronic disease
In what kinds of cases could Hct and Hb be falsely low?
Pregnancy - increased fluid volume, normal RBC mass
Trauma, etc. - after being given fluid replacement
What size are RBCs if there isn't enough Hb? Why?
The MCV is <80, because RBCs will undergo an extra division to maintain an adequate Hb concentration in the cell.
-Heme is made of
-Iron + protoporphyrin
-Where in the gut is iron absorbed?
-transporter that move iron from enterocyte into blood
Extracellular(in blood) Fe is bound to __.
Intracellular Fe is bound to __
how to prevent iron radicals?
by keeping iron bound, to prevent fenton reaction
What is the normal % saturation of transferrin molecules?
What cells are the main storers of iron?
Macrophages and liver cells
Why would a gastrectomy decrease iron absorption?
Iron is best absorbed in the Fe2+ state, acid maintains Fe2+ state instead of Fe3+
What are the stages of iron deficiency?
1. Depletion of storage iron (dec ferritin, inc TIBC)
2. Depletion of serum iron (dec % saturation)
3. Normocytic anemia
4. Microcytic, hypochromic anemia (hypochromic = less red, more central pallor)
What is koilonychia?
Spoon shaped nails from iron deficiency
What is the red cell distribution width (RDW)?
Range of sizes of RBCs
Iron deficiency anemia
Esophageal web - dysphagia
Atrophic glossitis - beefy red tongue
What is the acute phase reactant that keeps iron sequestered in inflammatory states? What does it do?
Limits iron txfer from macrophages to erythroid precursors
Suppresses EPO production
What will the lab findings be in anemia of chronic disease?
Dec % saturation and serum iron
Increases free erythrocyte protoporphyrin (FEP) - because there is no Fe to bind it
How did it get its name?
Defective protoporphyrin synthesis
Heme is made in the mitochondria of erythroid precursors. If there is deficient protoporphyrin, there will be iron-laden mitochondria that form a ring around the nucleus (Ringed sideroblasts)
What is the final reaction attaching protoporphyrin to Fe in the mitochondria catalyzed by?
What is the rate-limiting step in protoporphyrin synthesis?
ALAS converts succinyl CoA to ALA using B6 as cofactor
Congenital sideroblastic anemia usually involves
ALAS enzyme (rate-limiting)
What are some acquired causes of sideroblastic anemia?
Alcoholism - poisons mitochondria
Lead poisoning - denatures enzymes (ALAD and ferretochelase)
B6 deficiency - cofactor for ALAS
What are the lab findings in sideroblastic anemia?
Iron overloaded state:
Inc serum iron and % sat
When the excess iron kills the cell, it will release the iron which will be eaten by macrophages in the bone marrow or leak into blood
What is thalassemia?
decreased synthesis of globin chains of hemoglobin
What is an advantage of having a thalassemia?
Protection from p. falciparum malaria
What are the 3 types of hemoglobin and their chain components?
HbF (fetal) - 2 alpha 2 gamma
HbA - 2 alpha 2 beta
HbA2 - 2 alpha 2 delta
What chromosome is the Hb alpha gene on?
What chromosome is the Hb beta gene on?
3 deletions of the Hb alpha chain will lead to __ and tetramers of __.
4 deletions of the Hb alpha chain will lead to __ and tetramers of __.
Severe anemia; beta chains (HbH)
Hydrops fetalis; gamma chains (Hb Barts)
a-thalassemia cis deletions are seen in __ populations. Trans deletions are seen in __
Which is worse, cis or trans and why?
Cis, bc inc risk of passing severe thal onto offspring
B-thalassemia major vs minor
Minor- (B/B+)usually asymptomatic; microcytic, hypochromic RBCs, target cells
Major - (B0/B0) same as above also with nucleated RBCs, severe anemia a few months after birth (HbF is temporarily protective), massive extramedullary hematopoesis and erythroid hyperplasia (skull bones)
What infection is particularly worrisome for those with diminished RBC reserves?
Parvovirus B19 - infects erythroid precursors (causes them to shut down for a few weeks) -> aplastic crisis
What is the tx for beta thal major? what is the side effect of treatment?
chronic blood transfusions -> hemochromatosis (iron given with blood, which builds up)
In what diseases do you see a "crewcut" appearance of the skull and expansion of facial bones?
B-thalassemia major - hematopoesis has expanded to other bones besides the long bones
How do you get a macrocytic anemia (and what is the definition of macrocytic?)
B12 or folate deficiency - can't make DNA precursors and the cell won't divide
What is megaloblastic anemia?
enlargement of RBC precursors
What happens to granulocytic precursors in a B12 or a folate deficiency? Where is another non hematologic place you will see change in this deficiency?
Hypersegmented (>5 lobes)
Intestinal epithelial cells - macrocytic
What are some other causes of macrocytic anemia (without megaloblastic change?)
Alcoholism, liver disease, drugs like 5-FU
What are the lab findings of folate deficiency?
inc homocysteine -> inc risk for thrombosis
normal methylmalonic acid
Folate is absorbed in the __. B12 is absorbed in the __.
This drug can cause a folate deficiency
Methotrexate; sulfamethoxazole - inhibits dihydrofolate reductase
Describe how B12 is absorbed by the body
Salivary enzymes (amylase) liberate B12 and R binder binds it. Once in the duodenum, pancreatic proteases detach it from R-binder. B12 then binds intrinsic factor (produced by gastric parietal cells) in the small bowel, then is absorbed by ileum.
What stomach cells produce intrinsic factor? What is the autoimmune destruction of these cells called?
Parietal cells; Pernicious anemia
What can damage the terminal ileum and interfere with B12 absorption?
Crohns, Fish tapeworm D. latum,
dietary deficiency (rare except in vegans after years)
What can distinguish B12 from folate deficiency?
In B12 deficiency, buildup of methylmalonic acid causes subacute combined degeneration of the spinal cord (impairs myelination) - posterior column and lateral corticospinal tract
Inc methylmalonic acid will NOT be seen in folate deficiency
In normocytic anemia, how can you tell if the cause is peripheral destruction of RBCs or underproduction from bone marrow?
Normal reticulocyte count is elevated to 3% in anemia. You need to correct the % because it is falsely elevated (there are less RBCs overall)
Multiply RC by Hct/45
Corrected >3% means there is a good marrow response and they are being destroyed peripherally
< 3% means there is underproduction
Why do reticulocytes look blue?
Bc of residual RNA in cytoplasm bc they are young
Macrophages consume RBCs in hemolysis and break down hemoglobin. What is broken down from there?
Heme ->Protoporphyrin + Fe
Protoporphyrin ->Unconjugated Bilirubin (bound to Albumin) delivered to liver for conjugation/excretion
What are the clinical/lab findings in extravascular vs intravascular hemolysis?
Extravascular (via the RES - macrophages in spleen, liver, lymph nodes)
See anemia with splenomegaly, jaundice (UC bilirubin), gallstones, marrow hyperplasia
Intravascular - hemoglobinemia, hemoglobunuria, hemosiderinuria (days later from renal tubular cells storage), dec haptoglobin (used up trying to save all the free Hb)
What is hereditary spherocytosis? What are the 3 commonly involved proteins?
Inherited defect of RBC cytoskeletal proteins - makes them round
Spectrin, ankyrin, band 3.1
If you saw RBCs with loss of central pallor, inc RDW, and MCHC (mean corpuscular hemoglobin conc.) what would you think?
Hereditary spherocytosis - round cells of varying sizes
What is the diagnosis and treatment for hereditary spherocytosis?
Dx: Osmotic fragility test - won't be able to withstand being placed in a hypotonic solution
What is the mutation in sickle cell anemia?
Autosomal recessive mutation in Beta chain, replaces hydrophilic glutamic acid with hydrophobic valine
What is sickle cell disease vs sickle cell trait?
Trait - 1 mutated B - generally asymptomatic except in cases of hypoxia and hypertonicity of renal medulla
Disease - 2 mutated B
What is the Hb called in sickle cell disease?
What precipitates sickle crisis and why?
Hypoxemia, dehydration, and acidosis
These precipitate HbS and it polymerizes into needle-like aggregates (reversible) that gives the cell a sickled appearance
__ is protective against sickle cell for the first few months of life. What drug can also increase these levels?
Irreversible sickling leads to vaso-occlusive complications, including:
Dactylitis - swollen hands and feet - usually in infants (presenting Sx)
Autosplenectomy - shrunken, fibrotic spleen, inc risk for infection with encapsulated organisms (death in kids)
Acute chest syndrome - pulmonary microcirc. (death in adults)
Renal papillary necrosis
What is the significance of the metabisulfite test?
Cells with any amount of HbS will sickle, works in both disease and trait so a good overall screening test
How will sickle cell disease and trait look on Hb electrophoresis?
Disease: 90% HbS, 8% HbF, 2 HbA2, no HbA (no B chain)
Trait: 55% HbA, 43% HbS, 2% HbA2
less than 50% HbS=asymptomatic
What is the mutation resulting in hemoglobin C?
Autosomal recessive B chain mutation, replacement of glutamic acid with lysine
Mild anemia with HbC crystals
Pathophysiology behind paroxysmal nocturnal hemoglobinuria?
Acquired defect in myeloid stem cells - absent GPI which anchors DAF (CD55), and MIRL, to the cell membrane (DAF protects the RBC by inhibiting C3 convertase so complement can't damage the cell)
Only occurs episodically, usually at night when mild respiratory acidosis (bc breathing more shallowly) activates complement
How do you screen for PNH?
Sucrose - screening
Acidified serum - confirms
Flow cytometry - detects lack of DAF (CD55) on cell surface bc GPI attaches DAF to cell
What are some complications of PNH? What is the most common cause of death?
Iron-deficiency anemia (pts losing hemoglobin in urine)
AML (10% of pts - the stem cells are mutated)
Death is usually due to thrombosis - lysed platelets will release mediators
G6PD deficiency genetic mutation (pattern of inheritance)
X linked recessive mutation resulting in dec half-life of G6PD
What does glutathione do? What regenerates it?
Neutralizes H2O2 by becoming oxidized itself, NADPH (a byproduct of G6PD) is needed to reduce glutathione.
What are the 2 variants of G6PD deficiency and which one is worse?
African - mildly shorter halflife, usually just older cells with oxidative stress
Mediterranean - markedly shorter halflife, hemolysis of young cells
What is a Heinz body?
Precipitation of Hb in G6PD deficiency due to oxidative stress
What can cause oxidative stress in pts with G6PD deficiency?
Where do you see bite cells?
G6PD deficiency - splenic macrophages
Ig__ mediated usually results in extravascular hemolysis of RBCs.
Ig__ usually results in intravascular hemolysis
IgM usually fixes complement in __ temperatures and it is associated with these infections
Cold - extremities (cold agglutinin)
Mycoplasma pneumonia and infectious mononucleosis
IgG coats RBCs in __ temperatures, it is associated with these diseases (2) and these drugs (3)
Warm - central body (warm agglutinin). Ab coated RBC membrane is consumed by splenic macrophages, resulting in spherocytosis
Penicillin, cephalosporins, methyldopa
Penicillin, cephalosporins, and methyldopa can all cause IgG mediated immune hem. anemia, but in different ways. Explain.
Penicillin and cephalosporins - bind to membrane, then Ab binds drug-membrane complex
Methyldopa induces production of autoantibodies
Direct vs. indirect Coombs test
Direct - presence of antibody coated RBCs
Indirect - Ab only, must add test RBCs to anti-IgG
What kinds of conditions can damage RBCs as they pass through the microcirculation?
HELLP (hemolysis w/ elevated liver enzymes and low platelets - complication of pre-eclampsia)
Aortic stenosis (calcified valve) and prosthetic heart valves
What is the hallmark of microangiopathic hem. anemia?
Schistiocytes (helmet cells)
What causes malaria?
Infection of RBCs/Liver with Plasmodium
What causes anemias due to underproduction?
1. micro and macrocytic anemias
2. Renal failure -dec production of EPO
3. damage to bone marrow precursor cells
What cells in the kidney produce EPO?
Peritubular interstitial cells
What is aplastic anemia?
What do you see on biopsy?
damage to hematopoetic stem cells -> pancytopenia with low reticulocyte count
empty fatty marrow
What is pancytopenia?
anemia, thrombocytopenia, and leukopenia
What are some marrow-stimulating factors that can help in aplastic anemia?
GM-CSF, G-CSF (drive granulocytic precursors)
What is a myelophthistic process?
Pathology that replaces bone marrow (metastasis)->pancytopenia
-transerrfin and iron ----
-for very 3 transferring, 1 iron molecule
-in macrophage iron is bound to ----
-to measure transferrin in blood
we measure TIBC
to measure iron in blood, we measure -----
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