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78 Cards in this Set

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  • Back
% of RBCs lost per day through normal senescence?
describe the classification of the hemolytic lesions and give examples.
extracorpuscular (from environment) includes damaged prosthetic heart valves, disseminated intravascular coagulopathy, thrombotic thrombocytic purpura, and hypersplenism. Membrane defects include immunohemolytic anemia, RBC membrane protein defects like hereditary spherocytosis and elliptocytosis. intracorpuscular lesions include enzymatic deficiencies and hemoglobinopathies.
microangiopathic hemolytic anemia is AKA?
extracorpuscular anemia
H and PE findings that may suggest hemolysis?
jaundice, history of early cholycystectomy in pt or fam members, family hx of anemia, splenomegaly
lab tests to confirm the presence of hemolysis?
reticulocyte count, LDH, unconjugated bilirubin, haptoglobin (will decrease), RBC morph, Coomb's test (look for anti RBc Abs), Hb stability/electrophoresis, G6PD and PK assays.
coombs test measures what?
Ab and complement
difference between direct and indirect coombs test?
indirect finds free Ab in serum that will bind RBC surface Ag while direct measures Ab already bound to RBC surface Ag. Agglutination is a pos result for both tests
mutation in sickle cell?
B globin only, glu for val
what can cause sickling to decrease?
decrease of Hb S which can be caused by other Hb's or from thalassemia (note 20% of US blacks have a Thal trait) as well as other inherited factors or even being female (more Hb F)
what causes the sickle cells to be sticky?
heme dissociates from the unstable Hb and binds to the RBC membrane thus oxidizing it which causes phosphatidyl serine to flip. In addition, reticulocytes are sticky in general
why do those with sickle cell TRAIT only have 45% Hb S and 55% hb A?
for some reason the mutated B globin is less apt to be translated.
describe common findings of sickle cell in kids.
impaired growth and development; failure to thrive; sickle crises including hand foot syndrome (painful hands and feet); autosplenectomy due to increased RBC dwell time in spleen from sickling, increased infections from autosplenectomy
describe common findings in SS patients that can be severly morbid/fatal and give average age of death.
increased bilirubin can lead to acute cholecystitis. Iron overload from increased absorption. Increased cardiac output due to lower Hct which can lead to failure. Aplastic crises. Micro vaso occlusions lead to pain while macro vaso-oclussions can lead to organ damage. pulmonary hypertension incidence increases as well. Death is usually by 45 yo.
diagnosis of sickle cell disease?
ante-natal screening, clinical presentation, peripheral smear and Hb electrophoresis
important prophylactic used in kids with SS anemia.
pneumococcal vaccination and prophylactic penicillin.
treatment during sickle cell crisis?
hydration to dilute Hb concentration and expand plasma volume, analgesia, look for an underlying reason (ie infection) that caused the crisis.
treatment of SS patients that have a stroke, acute chest syndrome, or priapism
exchange transfusions to decreases S concentrations under 30%, which must be given every 2 or 3 weeks subsequent.
describe the chemotherapeutic treatment for sickle cell.
hydroxyurea which causes no carcinogenesis or mutagenesis, causes marrow to make more Hb F (in 1/2 of pts it can double the Hb F). This can reduce number of crises per year and increase mean survival of pt
treatment for a SS pt with iron overload.
desmerol or another iron kelator
describe how SS can be cured and the potential problems with it
bone marrow transplant. High mortality rate; as kids with SS age, damage from the disease makes BM transplant more likely to be fatal
how do thalassemias create anemia?
unbalanced synthesis of either alpha or beta globin causes the non-mutated globin to be made in excess. It then precipitates and the macs attack this, causing hemolysis
describe the alpha thalassemias and their genetics.
there are 4 alpha Hb genes (2 on each chromosome). Deletion of one gene on one chrom is silent a thal or a thal minor in blacks. Another form of a thal minor is missing both genes on one chrom (seen in asians). Hb H disease only has one alpha gene present. Absence of all alpha genes will result in hydrops fetalis
describe the genetics of B thalassemia
heterozygote is one normal B gene and one decreased beta or null beta gene which leads to thalassemia minor. Homozygote has a defect on both genes and causes thalassemia major
average survival with B thal and place of occurrence.
usually do not live past teens, seen in mediterranean populations.
treatment for thalassemias and effectiveness.
transfusions to keep Hb levels up can alleviate some of CHF. Splenectomy gets survival into teenage years. Iron chelation. BM transplant has been big boom for cure.
describe the pathogenesis of G6PD def.
decreased GSH allows oxidative damage to membrane and cytoplasmic lipids and proteins. Leads to "pitting" which leads to increased splenic dwell time, then they run out of ATP, thus decreased ability to pump out Na+ then they swell and burst
describe the GDP isozymes.
GdB is normal in whites, GdA is normal in blacks, GdA- is most common abnormal phenotype in blacks, GdMed is the most common abnormal phenotype in whites
compare the two diseased isozymes of G6PD and their manifestations.
GDA- is seen in blacks, mod hemolysis, affects older RBCs, hemolysis is usually induced by infection, no need for transfusion and no chronic hemolysis. GdMed in whites has severe hemolysis, affects all ages of RBCs drugs and infection can induce the oxidative insult and cause anemia that sometimes needs transfusions, no chronic hemolysis
describe the genetics of hereditary spherocytosis
mutations in ankyrin, band 3, a spectirn, B spectrin, protein 4.2. can be a mutation in a cytoplasmic architectural protein. 1/1000 to 2500 ppl of northern euro descent have it. 1/3 are de novo mutations (private mutations) that can affect many proteins
describe the signs, sxs, and complications of hereditary spherocytosis.
hemolysis with anemia, splenomegaly, jaundice, reticulocytosis, spherocytes, osmotic fragility. Variation in severity from subclinical to transfusion dependence. Can have biliary, hemolytic, aplastic, and megaloblastic complications
Dx of gereditary spherocytosis
fam hx, coombs neg, no evidence of portal hypertension/liver disease. Will see osmotic fragility and can do SDS page to analyze membrane proteins
treatment for hereditary spherocytosis
splenectomy and folic acid
differentials for hereditary elliptocytosis?
iron deficiency and pernicious anemia
differentials for hereditary spherocytosis.
autoimmune hemolytic anemia and hypersplenism
differentials for microcytic, hypochromic anemias?
decreased heme production via iron def, Pb toxicity, anemia of chronic disease, sideroblastic anemias. Or decreased globin synth via thalassemias
differentials for macrocytic anemias?
folic acid or B12 def. Hemolysis, liver disease, myelodysplastic syndromes
role of copper in anemia?
required as a cofactor for hefastine which is a protein needed to oxidize iron 2 to iron 3 so that iron can pass out of the intestinal cell through the transporter FPT 1.
describe what is going on in the marrow of megaloblastic anemics
lots of erythropoiesis. Lots of red cell precursors that do not make it out of the marrow, they have some Hb and make some bilirubin as red cells are destroyed within the bone marrow.
describe pernicious anemia.
anemia associated with aging in which there is an autoimmune rxn to IF factor in the stomach and thus B12 def ensues.
lab test to differentiate bw folate def and B12 def?
serum cobalamin level or serum TC2 cobalamin level
in B12 def, how long will you need to treat?
usually lifelong (parenterally)
additional nutrietnts required for erythropoiesis?
variety of proteins and amino acids, thiamine, riboflavin, niacin, copper, cobalt, vitamins A,C, and E
nutritional anemias?
vitamin deficiencies, mineral deficiencies other than iron (copper and zinc), starvation, kwashiorkor (protein def), alcoholism,
describe the anemia of starvation.
mild to mod normocytic, normochromic anemia (24 wks of starvation), decreased marrow cellularity and E/M ratio. This anemia is a response to decreased O2 consumption.
describe anemia due to alcoholism
multi factorial (nutritional, chronic GI bleeding, hepatic dysfunction, direct toxic effects of ETOH), macrocytosis (liver disease and increased RBC membrane with cholesterol due to lecithan cholesterol acyl transferase's response to portal hypertension), apparently dimorphic (macro and microcytosis) due to iron and folate def.
treatment of iron deficiency anemia.
oral iron replacement (ferrous sulfate and other formulations), parenteral (IV) iron for specefic clinicla situations in which they cannot absorb iron through the gut. MOST IMPORTANT is to determine the cause of the iron def. It is a sign not a disease in and of itself
role of B12 and folate?
needed to make DNA by converting deoxyuridine to thymidine. B12 is a cofactor and folate is the methyl donor for converting homocysteine to methionine, B12 is also needed to convert methylmalonyl CoA to succinyl CoA which may regulate myelination, without B12 you get neuropathy
where can you find folic acid and what are its requirements?
note pregnant women need more to prevent spina bifida, animal products and leafy green veggies
describe the absorption and catabolism of folic acid
polyglutamate cleaved in jejunum where the monoglutamate is absorbed. binds folic acid receptor, enters via receptor mediated endocytosis, mediated by protein megalin. Once in the cell it is polyglutamated again so it cannot escape. As the RBC's sensesc, folic acid is catabolized, therefore folic acid requirements increase with hemolysis
describe where we can get B12 and where and how much we store.
animal products are the only source. Western diets have ab 5 to 7 ug per day. Stores are 2 to 5 mg mainly in liver, thus several years worth of B12 stores.
describe the absorption of B12
gastric acid and pepsin liberate B12 from the food proteins. R factors in saliva and gastric juice binds B12, pancreatic enzymes release B12 from R factors and then B12 binds tightly to intrinsic factor which is made by parietal cells. IF-B12 binds cubilin in terminal illeum. endocytosis requiring megalin. in plasma B12 binds transcobalamins 1,2,3. 2 is the important one for transport of B12 into cells
causes of folate deficiency?
most common is dietary (lack of fresh fruit and veggies, alcoholism). Malabsorption via sprue disease, extensive small bowel resection, inflammatory bowel disease. Increased requirements: jemolysis, psoriasis and pregnancy
causes of B12 deficiency?
most common is malabsorption: pernicious anemia, gastrectomy, inflammatory bowel disease and subsequent resection of terminal ileum, blind loop syndrome (following surgery they hook up the stomach to the jejunum and can increase bacteria that eat the B12), fish tape worm. dietary (very rare) usually in strict vegans. congenital deficiency of transcobamalin (even more rare)
non neurologic signs and sxs of megaloblastic anemias?
signs: pallor "lemon yellow" skin, dry and smooth skin, smooth, red and beefy tongue. Sxs: weakness, fatigue, painful tongue and mouth, weight loss, loss of appetite, nausea, vomiting, loose and semisolid stools.
neurologic signs and sxs of B12 disease (note can be in absence of anemia)?
sxs: parasthesias, weakness, clumsiness, unsteady gait, delusions, hallucinations, megaloblastic madness. Signs: subacute combine degeneration (dorsal lateral columns), decreased position and vibration sensation, muscle weakness, spasticity, hyperreflexia, clonus, positive romberg sign, disordered mental status exam
lab findings in B12 and folate deficiencies?
anemia, increased MCV, macro-ovalocytes/elliptocytes, thrombocytopenia and/or granulocytopenia, hypersegmented granulocytes, increased LDH, increased bilirubin, megaloblastic changes in marrow, decreased serum folic acid or B12.
lab findings specefic for B12?
increased methylmalonic acid and homocysteine, evidence for atrophic gastritis, anti parietal cell and anti intrinsic factor Abs, concominant thyroid dysfunction
treatment of folic acid def?
1 mg/day orally, if malabsorption, treat the malabsorption
treatmennt of B12?
parenteral B12 1000ug everyday
ways to monitor treatment of B12 or folate deficiencies?
reticulocyte count, LDH, bilirubin… make sure there is response to treatment, if no response, something else is the problem, like infection… UTIs are a biggie
situations in which you should give prophylactic folic acid?
all women contemplating pregnancy, pregnant women, lactating women, pts with chronic hemolysis and increased erythropoiesis
macrocytosis not from folate or B12 deficiency?
reticulocytosis, liver disease, post splenectomy, hypothyroidism, aplastic anemia, hydroxyurea, red cell agglutination
describe copper deficiency (in all respects).
seen in gastric and batriac surgery pts. IV hyperalimentation without adequate copper supplementation. Associated with hyperzincemia. Copper is essential to many proteins and enzymes, results in excessive iron in the liver, but insufficient iron in the bone marrow for effective erythropoiesis. run copper and ceruplasmin levels. will see anemia and neutropenia. blood smear will show sideroblastic anemia with hypochromic microcytic anemia. sxs are myelopathy and polyneuropathy. treat with copper chloride.
main cells EPO acts on?
CFU-E, also slightly acts on BFU-E and erythroid precursors
what chemical is EPO production in the kidneys sensitive too?
therapeutic uses of EPO?
anemia for chronic renal failure, AZT, or cancer chemotherapy. Surgery - autologous blood transfussion b4 surgery. Increase RBCs in athletes (blood doping). Neuro and cardioprotective (new field, apparently anti inflammatory and anti oxidative and protective for stroke, drug companies are trying to find neuroprotective effects, not RBC increasing effects)
describe administration of EPO
note need adequate iron in marrow. Give IV or subQ and titrate up to target Hct.
adverse effects of EPO.
aggravation of pre existing hypertension (usually seen in renal disease patients anyway), immunogenicity: neutralizing Abs for one type of EPO drug that developed and attacked innate EPO lead to RBC aplasia and formulation change of the drug
describe the biochemical structure and active form of folic acid.
pteridine ring connected to P-aminobenzoate connected to one or many glutamic acids. Active form is tetrahydrofolate which is a completely reduced pteridine ring
important rxn of folate in terms of anemia.
deoxyuridylate to thymidylate which is used in DNA synthesis (obviously needed for RBC synth), in this rxn, THF is oxidized to dihydrofolate. Must be reduced back THF to be re-used… note this is a chemotherapy target. OTHER rxn is homocysteine to methionine via methyl donation from THF (note B12 is also a cofactor in this rxn). note this homocysteine rxn is needed to make circulating methyl THF (plasma form) into THF which is later used in thymidylate synth
describe the absorption, distribution, metabolism, and excretion of folate.
hydrolase enzymes called conjugases cleave glutamates off and form monoglutamate so it can be absorbed, is absorbed mainly actively but also passively thus it is an effective oral treatment even in GI disease. Then carried in the blood in the methyl THF form and goes to tissues. Liver is site of storage and it can go through entero hepatic circulation via excretion through the bile and then reabsorption. folates are filtered by the kidney and then excreted, this can lead to a quick def (2 to 3 mo) is you lose folate through urine
describe possible link bw folate and CV disease.
might be an association with high homocysteine and CV disease, so possibility of B12 and folate therapy for preventing/treating CV disease
key points of B12 chemistry.
cobalt in the middle of porphin ring. Drug forms include cyanocobalamin (CN on Co) and hydroxocobalamin (OH on Co). Physiological ones are methyl and adenosylcobalamin
rxns important in B12.
homcysteine to methionine AND methylmalonate to succinate. High levels of methyl malonate in plasma is helpful diagnostically. Importance of homocysteine to methionine is reduction of methyl THF to THF which is needed for DNA synth.
describe the absorption, distribution, metabolism, and excretion of B12
primary cause of B12 def is malabsorption in the intestine. Acid in stomach and pepsin cleaves B12 from protein (B12 has high protein affinity). Then binds the R factor and goes to duodenum. Pancreatic enzymes release it from R protein. Then it binds intrinsic factor from the parietal cells. To the ileum where there is a receptor for IF. receptor mediated endocytosis. In mucosal cells B12 seperates from IF and binds transcobalimin 2 which is carries all the B12 in the plasma. Trans cobalamin 2 receptors in the marrow, liver, and other tissues. receptor mediated endocytosis of the complex to get inside the cell. A deficiency in any of these steps leads to B12 deficiency
describe NO and causes of cobalmin def.
it irreversibly binds cobalamin and leads to megaloblastic anemia. Mainly in abusers (not common at all)
what can hydroxocobalamin be used for?
to treat CN poisoning
when treating a pt with either B12 or folate def, treatment of folate will have what effect?
increase reticulocytes in each, but will not treat neuro effects of B12