lec 8.docx

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

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Lecture 8 Myeloproliferative dz – neoplastic stem cell dz that has lost all regulation and nothing can inhibit it anymore. 4 dz’s that fit under this definition: 1. Polycythemia rubivera 2. CML (only leukemia in this category) 3. Agnogenic myeloid metaplasia – BM is replaced by fibrous tissue 4. Essential thrombocythemia – where a stem cell that makes platelets goes crazy and make 1 million, 600 platelets for microliter, 5. Myelodysplastic syndrome Polycythemia rubivera: 4 H’s: 1. Hyperviscosity (remember Pouseau’s law = TPR = viscosity/radius ). With polycythemia, it will have an increased resistance and TPR will go up; it will predispose to thrombosis, which kills you – thrombosis of anything – ie dural sinuses; MCC Budd chiari = hepatic vein thrombosis; coronary artery, SMV, anything can be thrombosed b/c blood slugging around and this is why phlebotomy is done. Phlebotomy is performed to make you Fe def – they want to make you Fe def – why? If you make them Fe def, b/c then it will take longer to make RBC’s, so you purposefully slow down the process. 2. Hypovolemia – only polycythemia that has an increase in plasma volume that matches the increase in RBC mass; none of the other causes have an increase in plasma vol (these are measured with radioactive techniques). So, it is very rare to see an increase in plasma vol with polycythemia, except for this case. Why? Myeloproliferative dz’s take years and years to develop therefore plasma vol is able to keep up; therefore both increase together over time. 3. Histaminemia – all cells are increased: RBC’s, WBC’s, platelets, including mast cells and basophils. Example: Classic hx: pt takes a shower and gets itchy all over body – this is a tip off for polycythemia rubivera – why? Mast cells and basophils are located in the skin and temperature changes can degranulate mast cells, causing a release of histamine, leading to generalized itching (very few things cause generalized itching – bile salt deposition in the skin in pts with obstructive jaundice, and pts with mast cell degranulation), face is red looking, too b/c of histamine b/c vasodilatation, leading to migraine-like headaches. 4. Hyperuricema – b/c nucleated hematopoetic cells are elevated, they then die, and the nuclei have purines in them. The purines will go into purine metabolism and become uric acid. Example: pt on chemotherapy must also be put on allupurinol to prevent urate nephropathy and prevent renal failure from uric acid. (allupurinol blocks xanthane oxidase). When killing cells you’re releasing millions of purines when the nucleated cells are killed and the tubules are filled with uric acid, leading to renal failure. Must put them on allupurinol. This called tumor lysis syndrome. The same thing occurs in polycythemia rubivera b/c there is an increase in number of cells that eventually die and you run the risk of hyperuricemia. RBC mass/plasma vol/O2 sat/EPO Polycythemia rubivera – h,h,N (inappropriate), low (have too much O2 b/c you have piles of RBCs and therefore suppress EPO (it’s a hormone). The hint was O2 content=1.34 * Hb * O2 sat +pO2 COPD, tetralogy of fallot, high alt – H, N, L, H (appropriate polycythemia b/c it’s responding to hypoxia) Renal adenocarcinoma, hepatocellar carcinoma, any cyst (renal, esp. ie hydronephrosis, wilm’s tumor) – H, N, N, H (even with normal gas studies b/c ectopically produced) Relative Polycythemia – N, L, N, N ILeukemias They are a malignancy of the BM and mets anywhere it wants. General characteristics of Leukemia; therefore, will always have: 1. Generalized lymphadenopathy, hepatosplenomegaly, etc… 2. Abnormal cells in the peripheral blood – BLASTS (myeloblasts, lymphoblasts, monoblasts, megakaryoblasts) – so some abnormal blasts are in the peripheral blood 3. B/c it is arising in the BM, will always crowd out the normal hematopoetic cells, and will ALWAYS have an anemia, usually normocytic 4. Thrombocytopenia b/c crowding out the normal megakaryocytes from making platelets 5. Usually an increase in WBCs ct with abnormal cells present 6. Acute vs. chronic – Do a bone marrow test and look at blasts – if blasts are <30%, this is chronic; if the % blasts is >30%, it is acute. Therefore the blast ct tells if its acute vs chronic Age brackets: Know age brackets 0-14 = ALL 15-39 = AML – myeloblast with Auer rods in peripheral blood 40-59 AML, CML (separate with BM – AML with >30% and CML with <30%, 9, 22, Philly c’some) 60+ = CLL MC overall leukemia regardless of age = CLL MCC generalized nontender lymphadenopathy in pt 60+ = CLL; not b/c it’s a lymphoma, but b/c it mets to lymph nodes). Different Types of Leukemia: Example: peripheral smear of 49 y/o, 150,000 WBC ct, 1% myeloblast in peripheral blood and BM, generalized nontender lymphadenopathy, hepatosplenomegaly, thrombocytopenia, and normal anemia – dx? CML (look at age bracket and % blasts). To prove, get 9, 22 study (abl protooncogene with nonreactor tyrosine kinase activity and goes from 9 to 22 and fuses with the cluster fusion gene). LAP – leukocyte alkaline phosphatase stain can also be used. Look at which neutrophils take it up – mature neutrophils all have LAP in them; neoplastic neutrophils do not – why? B/c they are neoplastic. So, if no stain, know its neoplastic (normal cells take up stain). Called a LAP score – always low in CML. So, the two tests: Philly c’some and LAP score, which is always low. Example: tear drop cell b/c there was a dictator in BM, and cells have to move to the spleen, so there is a migration of hematopoetic cells from the BM to the spleen. When you take up hematopoesis anywhere other than the bone marrow, this is called extramedullary hematopoesis. So, the spleen in huge – esp. in atherogenic myeloid metaplasia. Some of the megakaryocytes go back to the marrow to lay down collagen; and megakaryocytes go back. Fibrosis of the BM occurs (used to be called myelofibrosis metaplasia). So, not everyone left the BM, and stay in the fibrotic marrow. For them to get to the spleen, they have to work their way through strands of fibrotic tissue, often times damaging their membrane, leading to tear drop cells (so, it gets passed the ‘barbed wire’ – fibrous tissue – and getting into the sinusoids, they are tear drop cells in the peripheral blood). So, pt with huge spleen, with tear drop cells – atherogenic myeloid metaplasia. Example: too many platelets – essential thrombocythemia (makes too many platelets) Example: 4 y/o pt that presents with sternal tenderness, fever, generalized nontender lymphadenopathy, hepatosplenomegaly, normocytic anemia, 50,000 WBC count many of which had an abnormal appearance cells. What is the dx? ALL (acute lymphoblastic leukemia. MC cancer in kids; the most common type is: common ALL Ag B cell leukemia. CD10+; calla+ Ag B- cell ALL, associated with down’s syndrome Example: 65 y/o, normal criteria, smudge cells and normocytic anemia. They also have hypogammaglobinemia b/c they are neoplastic B cells and cannot change to plasma cells to make Igs. Therefore, MCC death in CLL = infection related to hypogammaglobinemia. What is the Dx? CLL Example: 62 y/o, normal criteria, special stain of TRAP (tartrate resistant acid phosphatase stain) – hairy cell leukemia (know the TRAP stain) Example: 35 y/o pt, with normal criteria, with 50,000 abnormal WBCs and Auer rods (abnormal lysosomes), 70% blast cells in the BM. What is the Dx? AML. Know what Auer rods look like, know the leukemia that infiltrates gums (acute monocytic anemia – M5), and acute progranulocytic anemia (M3) – they always have DIC, has a translocation 15,17. Rx = retinoic acid (vit A – causes blasts to mature into b9 cells). 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 co
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