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144 Cards in this Set
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How are the two types of anemias that we will talk about in this lecture?
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1) Hemolytic Anemia
2) Aplastic anemia |
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What is hyperproliferative anemia?
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Anemia in which there is an increase in RBC destruction.
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What is the life time of a RBC?
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About 120 days.
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How does the body know to get rid of the RBC cells once they get old and reach senescence?
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The membrane of the RBC has charges on it that signals the reticuloendothelial (RE) system, mainly macrophages, to take them out of circulation once they reach that stage.
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How many ways are there to take a red blood cell out of circulation?
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Two ways: an intravascular and an extravascular way.
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When the RBC is taken out by the RE system, is that intravascular or extravascular?
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It is extravascular. It is not in the blood vessels themselves. It is called extravascular phagocytosis.It is done by the macrophages in the spleen or the liver.
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When is it intravascular?
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In intravascular hemolysis RBCs lyse in the circulation releasing hemoglobin into the plasma. Causes include mechanical trauma, complement fixation, and other toxic damage to the RBC. The fragmented RBCs are called schistocytes.
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What is hemolytic anemia?
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Anemia resulting from increased RBC destruction.
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In hemolytic anemias where does the problem lie?
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Outside the bone marrow.
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What should the bone marrow do in response to hemolysis in the circulation or periphery?
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It should react to it with compensatory erythroid hyperplasia. RBC production may increase 10 times.
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If the anemia is so severe that even with the hyperplasia the patient is still anemic, what is that called?
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It is called frank anemia.
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What happens to the RBC life in hemolytic anemia?
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The lifespan is shorter...45-60 days instead of the normal 120.
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How do we know this?
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Cr51 assay! Because RBC's were taken out, mixed with chromium 51 and reinfused, and then blood was checked serially and was seen that the life time is 45-60 days.
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What are productive anemias due to?
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Problem with iron, B12, or folate. Also if there is hematopoietic cell damage we again encounter a disorder of RBC production -->this is due to myelopoietic syndrome that we will talk about later.
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How does a normal bone marrow respond to anemia?
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Via erythroid hyperplasia.
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Do we routinely perform Cr51 assays?
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No. It is used for research purposes mostly.
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What does a mature RBC look like?
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No nucleus, few enzymes, maybe some ribosomes that are later lost.
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What happens to the Hb as RBC decays?
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It seperates into heme moiety and globin chains, then the globin chain is broken down into AA's which are reutilized to build more proteins.
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What else is the heme moiety made up of?
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There is also protoporphyrin (PP) ring and iron inside the ring.
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What is protoporphyrin broken down into?
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It is broken down into non-conjugated bilirubin, which has to go through the liver where it conjugates.
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What happens to this conjugated bilirubin?
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It goes into bile, or secreted through feces or through urine as stercobilin (stercobilinogen, or urobilin)
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What is an important finding in HA patients?
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Dark urine.
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What happens in iron overload?
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Iron released into circulation.
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How is this iron immobilized?
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Via transferrin, a protein, and it is taken to sites where it is needed for buildup of either new RBC's which is done in the bone marrow or used as co-enzymes in many reactions.
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What happens in intravascular lysis?
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You have lysis of RBC's in circulation. This is uncommon and quite dangerous. Hb released into plasma.
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What happens to this heme?
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It is either oxidized to Met-Hb, or it is filtered by the kidney and you get hemoglobinuria or hemosiderinuria.
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What evidence do you need to conclude that there is intravascular hemolysis?
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Either hemoglobinuria or hemosiderinuria.
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Why?
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This is not normal; normally Hb is broken down into bilirubin and it is conjugated. The iron gets bound to transferrin.
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What effect does this intravascular hemolysis have on the kidneys?
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It is very harmful. They are big molecules that can damage the kidneys. So the main problem with intravascular hemolysis is kidney damage which we look out for.
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What is hemosiderin?
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High molecular weight iron. It is ferritin molecules that are nonsoluble, and they can appear in the urine.
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What are the two questions you need to ask yourself in order to be able to classify the hemolytic anemia?
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1) Where does the damage occur?
2) Is it congenital or acquired? |
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What is another possibility?
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They can be both congetinal and acquired...so combined.
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What are the possibilities for sites of injury?
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Intracorpuscualr disorders, RBC membrane disorders, Extracorpuscular disorders.
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What are intracorpuscular disorders?
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Something IN the RBC is not normal:
Enzyme defect, abnormal Hb, |
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What is it called when the Hb is not normal?
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It is called Thalassemia/Sickle cell.
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What is meant by RBC membrane disorder?
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Spherocytosis...this is associated with increased hemolytic tendency.
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What is meant by extra-corpuscular disorder?
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RBC is normal but there is something outside the RBC that attacks RBC which causes hemolysis.
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What is a common cause of this?
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Immune hemolytic anemia. Cause premature destruction of RBC's.
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So based on this what can be categorized as congenital and what as acquired?
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Intracorpuscular disorders and RBC membrane disorders can be classified as congenital while extra-corpuscular diseases can be classified as acquired.
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What are the pertinent information that you need to get from the patient in HA?
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Detailed family history, drug exposure, recent infections. You need to ask about their symptoms related to anemia.
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What should you look for in physical examination?
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pallor, jaundice (sclera), dark urine, splenomegaly.
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What are the general symptoms of anemia?
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Fatigue, weakness, cold, palpitations, reduced ability to perform tasks.
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At what level of bilirubin will you start seeing jaundice?
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At 2mg% you may have jandice in the sclera.
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Why is there spleenomegaly?
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Because spleen is the site of RBC destruction.
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What are the lab findings associated with hemolytic anemia?
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1) Increased indirect bilirubin.
2) Increased urobilinogen. 3) Decreased haptoglobin 4) Increased LDH 5) Hemoglobinemia 6) Hemosiderinuria |
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Why do you get increased LDH?
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Because RBC's have LDH in them and as they lyse, they release this enzyme.
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When do you get hemoglobinemia? When do you get hemosiderinuria?
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Hemoglobinemia-->vascular hemolysis
Hemosiderinuria-->Intravascular hemolysis |
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What are the finding associated with increased RBC production?
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Reticulocytosis, Erythroid hyperplasia in BM...E:M ratio of 1:1.
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What are reticulocytes?
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Cells that are larger than normal RBC's w/o nucleus, but still have ribosomes. They are easily identified using the proper stain.
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What does it mean if you have anemia with no reticulocytes?
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It means that it is not because of an increase in RBC production...It means that there is some sort of damage in BM which makes the RBC compartment non-effective and you don't have a normal response to anemia.
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Whats is the first response in excessive bleeding?
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To increase reticulocyte count to compensate for the bleeding.
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What is the reticulocyte count in excessive bleeding?
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About 20%.
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What do you see in bone marrow biopsy?
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You see that there is an increase in erythroid cell precursors.
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Why is reticulocyte assessment important?
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Because it actually mirrors what goes on in the bone marrow...
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What would you see in the bone marrow if you were to do a biopsy in a patient with HA?
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You would see that the erythroid compartment is enlarged with hyperplasia of RBC's and the normal erythroid to myeloid ratio goes down in BM...becomes 1:1 in HA.
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What is the normal ratio of E:M in bone marrow?
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~1:3...RBC:WBC
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What is the conclusion if you don't see increased reticulocyte count in hemolytic anemia?
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It means you have damage in the bone marrow.
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What are the finding associated with RBC damage that you may see in HA?
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Peripheral blood smea: anisocytosis, poikilocytosis, fragmented RBC.
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What is anisocytosis?
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Different sizes and shapes of RBC
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What are some specific tests that you can do to diagnose this?
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You can do a coombs test or an osmotic fragility test.
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What is the most common membrane disorder?
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Spherocytosis...associated with only mild anemia, mild jaundice, present with slight splenomegaly, and pigmented bile stones at early age.
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What is the incidence rate? How is it inherited?
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1:1000-1:4500; The inheritance in autosomal dominant.
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What is the pathogenesis of hemolytic anemia?
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There is defect in the membrane proteins: ankyrin, spectrin, Band3.
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What is the clinical presentation?
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mild anemia, jaundice, splenomegaly, pigmented bile stones.
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What is a bile stone made up of?
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Cholesterol, Ca2+, and bile...When you have increased production of these three components you have a tendency to form early bile stone production.
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What happens if one of the proteins, ankyrin, spectrin, or band 3, are missing or are defective?
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The membrane isn't tightly connected to the cytoplasm or cytoskeleton of the cell...It is more easily torn away...it is loose.
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What do you see when you do the workup of these patients?
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You see macrocytic, hyperchromic anemia.
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Why should we have microcytes?
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It can't be iron deficiency, you have it because this shape gives you the maximum surface area for volume .
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Why is the membrane easily torn here?
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volume is the same as a normal cell but the membrane is less so it is tight and easily tears.
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Why is it hyperchromic?
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Because the same amount of Hb is concentrated in a smaller area.
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What is the specific osmotic fragility test?
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We have decreased surface to volume...what happens in a normal RBC as it is exposed to NaCl? it will eventually lyse...these cells lyse easier/sooner.
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What is important about treatment of hemolytic anemia the intracorpuscular hereditary type?
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It doesn't have to be treated unless it is more severe in which case you can perform splenectomy.
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Would this ameliorate the anemia?
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No but it will make the anemia more mild because the main site of destruction is taken away.
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What do you have to give patients with HA? Why?
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Folic acid...it is an essential precursor in DNA synthesis via thymidine...and since the DNA synthesis in these patients is in over drive and BM is working very hard you need to supplement with enough folic acid.
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What happens if there isn't enough folic acid?
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The patients can enter what is called aplalstic crisis.
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What is this aplastic crisis?
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There is no ability for them to make cells, not because of the hemolytic anemia but because of the partial deficiency of the folic acid.
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What is the underlying defect in hemolytic anemia of intracorpuscular hereditary type?
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There is a defect in the glycolytic pathway: There is a pyruvate kinase deficiency.
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How is this transmitted?
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It is autosomal dominant.
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So what is the pathogenesis? Why does it lead to anemia?
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Since you need PK def, there is a ATP def, and this leads to premature destruction of RBC's.
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What is the clinical presentation of hemolytic anemia?
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severe anemia from birth,severe jaundice , splenomegaly
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The enzyme that is missing is responsible for production of ONE freakin ATP! Why does this cause RBC lysis?
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Because RBC is incapable of carrying out aerobic respiration. Only does glycolysis. So this 1 ATP is quite substantial.
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What is the test that you do to diagnose this?
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The auto-hemolysis test and you ask for PK levels.
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How do you treat it?
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Spleenectomy and folic acid supplement.
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What is the auto-hemolysis test?
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If you put in RBC's of patient with this defect and RBC of normal patient...they will lyse eventually...If you add glucose the lysing happens later...but in patients with this disorder it doesn't help that much...it is only slightly corrected.
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Is the PK deficiency absolute?
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No it is only partial. If it was absolute it would be incompatible with life.
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What is an important defect in the hexose monophosphate shunt?
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Common defect: G6PD, deficiency.
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What is the incidence? What is the inheritance?
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200 million people worldwide are affected. It is X linked.
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Why is it more prevalent in malaria infested regions?
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Because the parasite can't live in the oxidative milieu when there is deficiency of this enzyme.
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What happens in G6PD deficiency?
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There is a lack of G6PD enzyme which leads to inability to reduce NADPH to NADP.
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Why is this important?
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Because NADP is involved in gluthation pathway and the gluthathione is needed whenever we have oxidative stress...NADP will reduce the gluthathione and become oxidized.
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What type of structural abnormality will this cause in respect to Hb?
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It causes Hb to stick to the RBC membrane and causes the formation of Heinz bodies.
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How many enzyme variants of G6PD do we have generally?
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2 Type A and type B.
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Which one is the normal variant?
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Type B.
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How many subtypes of A are there?
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2; A+ and A-
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Where can you find type A+?
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in 20% of the African American population.
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Which population is affected by the type A- variant?
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10% of the Central African population.
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What is another type of G6PD?
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The Mediterranean type.
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In which population is this type prevalent?
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Sepharadic Jews, and the other Mediterranean population like Sicillians.
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What is the pathogenesis?
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Inability to survive oxidative stress.
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What is the clinical expression of this disease?
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hemolysis upon oxidative stress (fever, oxidating drugs.
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When is the type A symptomatic?
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Only when the pt is stressed.
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What do you see with the Mediterranean type?
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chronic mild hemolysis with exacerbation upon stress, Favism, Intravascular hemolysis.
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What is favism?
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An acute condition seen chiefly in Italy, following the ingestion of certain species of beans,characterized by fever, headache, abdominal pain, severe anemia, prostration, and coma
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Which one of these is more severe?
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The Mediterranean type.
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How do you evaluate patients with G6PD deficiency?
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Via staining of Heinz bodies, and looking at RBC fragments.
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What is important about testing these patients?
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You need to make sure that you are not testing them during a hemolytic crisis.
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Why?
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Because you are looking at cells that have near zero levels of G6PD enzyme. When you have old cells and they lyse, they are replaced by new cells and you might have activity that is abnormally low.
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How do you treat?
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The treatment is also preventative. You learn what to avoid eating.
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What do these patients have to avoid?
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Anti-malaria drugs, sulfa drugs.
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What do you have to give them when they have a crisis?
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You have to give them supporotive treatment...give lots of fluids to wash out the kidneys.
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What type of hemolytic anemia is caused as a result of extracorposcular probelm?
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Immune hemolytic anemias.
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How many types are there?
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There are two types: Warm antibody and cold antibody.
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What is the range of actitivity of cold antibodies?
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4-25 degrees...lower than the body's temperature.
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What is the pathogenesis of warm auto immune hemolytic anemia (AIHA)?
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Extravascular destruction of RBC coated with IgG or C3.
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What is the etiology of warm AIHA?
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1) Idiopathic
2) Secondary to systemic immune disorder (SLE) 3) Secondary to lymphoproliferative disorders (NHL, CLL) |
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What is the clinical presentation of warm AIHA?
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Usually adults, mild to severe hemolysis, splenomegaly, possible remissions and exacerbations.
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What are the lab findinngs in warm AIHA?
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1) Microspherocytes,
2) Positive coombs test |
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How do you treat?
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Treat the cause
Prednison 1mg/kg Splenectomy Immunsupression Folic acid Blood transfusion |
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Where do you see microspherocytes?
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In the peripheral blood.
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Why do you see these?
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Because the RBC's are coated with Ab's and they are being removed from the circulation via macrophages in spleen.
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What is a positive Coombs test?
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You have these RBC's that have antibody on them, and if you put them in a tube and react them with anti-human IgG or C3, you get agglutination of RBC's.
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Why do you treat with prednisone?
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Because it is a steroid and has immunosuppressive effects.
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How does a steroid produce immunosuppressive effects?
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It kills plasma cells and lymphocytes,
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What if they relapse after prednisone therapy?
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You have to do spleenectomy.
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What is important about blood transfusion in these patients?
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Because you may have cross reaction with Ab can occur...so you have to be careful. If you have an episode you need to stop the transfusion.
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Why do you do an indirect coombs test?
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You have ab's in lower amounts, usually in the patients sera and not on the RBC's...so you might still get some hemolysis.
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How do you do an indirect coombs test?
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You take the patients serum and react it with normal RBC's.
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How is it that this works? It is not the patients blood!
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Because the antibodies are RBC specific and not patient specific.
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When do you do an indirect coombs test?
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When you suspect some autoimmune hemolysis and the direct coombs test is already negative because the amount of antibody is not enough to give you a positive coombs test. You are basically trying to make sure that the antibodies are not there.
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What is the pathogenesis of cold AIHA?
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Monoclonal IgM attached to I/i
Antigen on RBC membrane |
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What is the etiology of cold AIHA?
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1) Idiopathic
2) Infectious (Mycoplasma, IMN) 3) Secondary to lymphoproliferative disorders |
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Why is this a problem in Israel where the temperature doesn't decrease that much?
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Because it is in the extremities, the core temperature is still 37 degrees.
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What is the clinical presentation of these patients?
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Acrocyanosis and Hemolysis
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What is acrocyanosis?
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Bluish extremities (tip of ears, nose)
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What causes this blueish extremity?
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Because these are the more these ab’s attached to extremities of body where cold temp is present, then move to the central circulation and they might cause there the activation of complement and lysis (usually more intravascular lysis) – usually not severe (in israel), responds well to warming of patient;
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What does this reaction depend on?
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The hemolysis depends on a few things:
1) Antibody titer 2) Antibody thermal amplitude 3) Environment temperature |
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Do these patients respond well to steroid treatment? Why?
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They respond less well, because the problem here is not Ab production but here the complement system is involved.
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What can you do?
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you can warm them up.
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What is a lab test for cold AIHA?
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Coombs positive test but only for C3.
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How do you treat these patients?
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Treat the initial cause and patient warming.
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In what other case could you have antibodies against the RBC forming?
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Iatrogenic: due to drug treatment via different mechanisms.
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What is an example of this?
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Penicilin in high doses (pen-V or VK), it can attach to RBC membrane; there’s production of Ab against this change in the membrane of RBC; now it is no longer the normal RBC of the body...there is a penicillin attached and there will be production of Ab’s against this product;
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What is the haptin mechanism?
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when you have the medication attached to plasma protein – can attach to RBC surface; now there’s production of Ab’s against this;
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What are two other drugs that cause this?
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Quinidine and methyl dopa...
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