Normocytic anemias.docx

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Biochem. and Medical Genetics
Course Code
BGEN 3020
Jason Leboe- Mcgowan

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Normocytic anemias When you do the corrections for the anemia and look for polychromasia; if correction is less than 2%, it is a bad response (BM not responding correctly). First two things you see: early IDA and ACDz – remember that you have to have a normocytic anemia first to become microcytic. Doesn’t occur overnight. Therefore, with a decreased ret ct (ie less than 2%), must include microcytic anemia’s in the differential, and you need to get a ferritin level. IDA goes through diff stages: first thing that happens – decreased ferritin, then Fe decreases, TIBC increased, % sat decrease, and still won’t have anemia. In other words, all Fe studies are ABNORMAL before you have anemia. Then you get mild normocytic anemia, and eventually microcytic anemia. Causes: 1. Blood loss less than a week = normocytic anemia; no increase in ret response b/c nothing wrong with the BM, and not enough time (need 5-7 days for BM to get rev’d up) – so, after one week, would get an appropriate response. 2. Aplastic anemia – no marrow; if that is true, the peripheral blood will show pancytopenia (all hematopoetic cells are destroyed in the marrow); have normocytic anemia, thrombocytopenia, and neutropenia. 3. MC known C = drugs: chloramphenical – used in rocky mtn spotted fever, indomethacin, phenyndutazone, and thyroid related drugs 4. 2 MCC = infections – esp. Hep C (wipes out everything); aplasia of RBC = parvovirus 5. Radiation and malignancy 6. Early IDA and ACDz (need to have serum ferritin levels) 7. Mechanism of normocytic anemia with less then 2% ret ct – renal failure, and decreased EPO (can be given exogenously) – decreased in hep B, C, and HIV. Athletes that ‘dope’ are given EPO, to increase RBC’s to allow more O d2livery to body Mechanisms of hemolysis – 2 ways to kill an RBC: Normocytic anemias with corrective ret ct about 3%: 1. Extravascularly (outside of the BV). They are killed by macrophages, usually in cords of bilroth in the spleen, sometimes in liver sinusoids. Every RBC must go to the cords of bilroth a few times per day and get examined by a macrophage – if the cell picked up an IgG or C3b, it is marked for destruction via phagocytosis b/c the macrophage has receptors for IgG and C3b. If you don’t have IgG or C3b, can still die b/c the cell is in bad shape –abnormal shape: ie sphere will not be able to fit through a 2 micron hole to get to the sinusoids – it can’t – therefore, spherocytes are removed extravascularly b/c they cannot get out; sickle cells cannot get out either b/c they have a bad shape. Another reason for their destruction is b/c they have something inside them that they shouldn’t –a piece of nucleus; what is this called? Howell jolly body; macrophage will get rid of it. There are autoimmune hemolytic anemias, and can be due to IgG or C3b on the surface of the RBC, or extravascular hemolytic anemias is where you have abnormal shape (ie sphere, Sickle cell – will not make it out of the spleen b/c removed by macrophages). End product of phagocytosing an RBC: unconjugated bilirubin. When the RBC is broken down, you have hemoglobin, and there is an enzyme that splits heme from globin and the globin is broken into aa’s and therefore goes to the aa pool. Then, takes the heme, splits it open, and saves the Fe. Now you have protoporphyrin, and spit it out; end result is unconjugated bilirubin in the macrophage within the spleen. Then, the macrophage spits out the unconjugated bilirubin into blood stream (which is insoluble b/c it’s unconjugated). The unconjugated bilirubin then binds albumin and goes to the liver and is conjugated. So, what clinical finding will you see in pts with extravascular hemolytic anemia? Jaundice. Does that bilirubin get into the urine? No. Why? 2 reasons: (1) Lipid soluble and (2) Bound to albumin (albumin does not get into the urine) – so you are jaundiced, but doesn’t get into the urine 2. Intravascular (within the BV) Intravascular is less common – meaning that you die within the BV. How does that happen? You die within the vessel if you bump into something. Example: congenital bicuspid aortic valve with calcium there – if you bump into that, you would damage yourself and die. Example: if you have IgM on the surface of the RBC (IgM is the most potent activator of the complement system); this will go from 1-9, meaning that it will sit on the RBC, activate the complement and dies intravascularly; so, anything that is IgM mediated = intravascular hemolysis. So, what will you release into the bloodstream if you are killing the RBC? Hb. Don’t want to lose all of it and need to retreat it – by getting back the aa’s and retrieving the Fe. Specific protein that is made in the liver that is released when there is intravascular hemolysis – haptoglobin (aka suicide protein – b/c forms complex with Hb and is phagocytosed by the macrophage), therefore giving life to retrieve the Hb, therefore in pts with intravascular hemolysis, the haptoglobin levels decrease. Is it possible to get jaundice? Yes, but usually don’t b/c macrophage is phagocytosing. Intravascular hemolysis: hemoglobinuria, and low haptoglobin levels 3. Summary: Extravascular = macrophages remove = unconj bilirubin is the end product = jaundice is the clinical manifestation Intravascular = Hb in urine, decreased haptoglobin Intrinsic vs. Extrinsic Hemolytic anemia: 1. Intrinsic – something wrong with RBC, causing it to hemolyze: such as no spectrin, or not decay accelerating factor to neutralize complement, no G6PD enzyme in pentose phosphate shunt, or abnormal Hb (ie HbS). Therefore, something wrong inside the Hb molecule, causing it to hemolyze. 2. Extrinsic – nothing wrong with the RBC, just at the wrong place at the wrong time; ie it just happened to smash into the calcified valve (nothing was wrong with it, until it hit the valve). Then it will be dreading going to the cords of bilroth with destroy it b/c it has been marked with IgG and C3b for phagocytosis. Something intrinsically wrong with the RBC causing it to hemolyze but there’s nothing wrong with the BM (but something intrinsically wrong with the RBC), and the corrective ret ct is greater than 3%. MAD – MC intrinsic probs Membrane defect (spherocytosis, paroxysmal nocturnal hemoglobinuria), Abnormal Hb (SC trait Dz), Deficiency of enzyme (G6PD def). Membrane Defects: (a) Spherocytosis: do no see a central area of pallor therefore must be a spherocyte and must be removed extravascularly. Clinically manifest with jaundice from unconjugated bilirubin. Spectrin defect and AD dz; splenomegaly always seen over a period of time. Gallbladder (GB) dz is common b/c there is a lot more unconjugated bilirubin presented to the liver and more conjugation is occurring and more bilirubin is in the bile than usual. So, whenever you supersaturate anything that is a liquid, you run the risk of forming a stone; if you supersaturate urine with Ca, you run the risk of getting a Ca stone; if you supersaturate bile with cholesterol, you will get a cholesterol stone; if you supersaturate with bilirubin, you will get a Ca-bilirubinate stone. Therefore, pts have GB dz related to gallstone dz and then do a CBC with normocytic anemia and a corrected ret ct that is elevated, and see congenital spherocytosis. What’s the diagnostic test? Osmotic fragility – they put these RBC’s wall to wall in different tonicities of saline, and the RBC’s will pop (therefore have an increased osmotic fragility). Rx: splenectomy (need to remove organ that is removing them – they will still be spherocytes and will not be able to form a biconcave disk). (b) Paroxysmal Nocturnal Hemoglobinuria = defect in decay accelerating factor. So when we sleep, we have a mild resp acidosis b/c we breathe slowly (if you have obstructive sleep apnea, the acidosis is worse). When you have acidosis that predisposes the complement that’s sitting on ALL cells circulating in peripheral blood. RBCs, WBCs, and platelets all have
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