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| | *started here on 01/13/10. | | *started here on 01/13/10. |
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| - | =Blood=
| + | GkXRCK Appreciate you sharing, great article post.Much thanks again. Keep writing. |
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| - | ==Extracellular fluids==
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| - | *Includes blood plasma, lymph, and interstitial fluid.
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| - | *Lungs are a good model of interstitial fluid because the whole organ is bathed in a fluid that is critical for function but is outside of all the cells.
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| - | ===Extra versus intra cellular fluids===
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| - | *Protein levels are different.
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| - | *Difference is maintained by plasma membrane.
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| - | *Sodium is high outside the cells, potassium is high inside.
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| - | *Na+ and K+ are the molecules and gradients used to move things quickly across the membrane to equilibriate.
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| - | ===Extracellular fluid===
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| - | *Blood, lymph, and interstitial fluid are all similar in electrolytes.
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| - | *They are not similar in the amount of blood cells, proteins, and lipids.
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| - | *But the difference is less than between extra and intra- cellular.
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| - | ===Functions of blood===
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| - | *Transport, regulation of heat, ph, and fluid balance, and defense.
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| - | | + | |
| - | ====Transport====
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| - | *Moves nutrients (sugars, aas, fatty acids, electrolytes, and water), gasses (O2 and CO2), wastes (urea, uric acid, water, CO2), and hormones.
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| - | *Blood can move things that are not very soluble in water.
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| - | | + | |
| - | ====Regulation====
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| - | *Heat: talked about it last semester.
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| - | *pH:
| + | |
| - | **metabolism produces pH changes but the blood has buffers to deal with this.
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| - | **blood carries acids and bases to organs of excretion.
| + | |
| - | **blood pH is slightly alkaline: 7.35-7.45.
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| - | *Fluid balance:
| + | |
| - | **Osmotic balance is normal even though osmolytes are different.
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| - | | + | |
| - | ====Defense====
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| - | *Phagocytic cells:
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| - | **Part of the innate immune system.
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| - | **Ingest microorganisms.
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| - | *Antibody producing cells (B cells), T cells,
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| - | **Part of the specific immune system.
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| - | *Chemicals to regulate blood flow and clotting.
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| - | | + | |
| - | ===Blood as a tissue===
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| - | *Blood is more viscous than water.
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| - | **This is because of proteins, cells, etc.
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| - | **Changing levels or proteins or cells can change viscocity which can mean it takes more work to pump it around.
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| - | **If the blood volume is elevated, the resulting elevated blood pressure can damage vessels and strain the heart.
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| - | | + | |
| - | ==Blood - detail of components==
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| - | *After centrifugation, you get the plasma (55%), the buffy coat (the leukocytes, platelets), and the erythrocytes (RBCs, 45%).
| + | |
| - | *The erythrocyte fraction is called the hematocrit.
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| - | *Anemia is not making enough RBCs and therefore presents with too low hematocrit.
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| - | *Polycythemia is making too many RBCs and therefore presents with too high hematocrit.
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| - | *Hydration can also change hematocrit, too.
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| - | *Plasma and serum are different. Serum results from allowing RBCs to clot and then spinning out. If you put in anticoagulant in, then spin, you generate plasma. So the difference is that plasma has clotting factors and serum doesn't.
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| - | **Edta chelates Ca++ such that blood cannot clot.
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| - | *95% of plasma proteins are albumins and globulins.
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| - | *Fibrinogen makes up 4% of the plasma protein levels.
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| - | ===Plasma proteins===
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| - | *Albumin:
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| - | **Made by the liver.
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| - | **Most abundant protein in plasma.
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| - | **Transports lipid-soluble components.
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| - | **Add an osmotic force to the plasma.
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| - | ***Inside and outside of cells must be osmotically balanced and proteins can help with this. So the albumins are blancing all the protein (like Hb) in blood cells.
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| - | *Globulins:
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| - | **alpha (HDL and others), beta (transferring, LDLs, VLDLs), and gamma (antibodies) globulins are called that because that's the way they came off the chromatography. So alphas are heaviest (carrying the heaviest stuff), then beta, then gammas are the lightest.
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| - | **One globulin of interest is transferrin. It carries Fe around in the body. It keeps Fe from wandering around and messing stuff up. Transferrin allows the liver to store Fe. Transferrin is a beta globulin.
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| - | **The gamma globulin fraction of blood serum will have the antibodies needed after a snake bite.
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| - | **Inside and outside of cells must be osmotically balanced and proteins can help with this. So the globulins are blancing all the protein (like Hb) in blood cells.
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| - | | + | |
| - | ===Plasma protein function===
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| - | *Carriers as we've mentioned.
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| - | *Act as buffers because they have lots of positive and negative side chains (amphoteric).
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| - | *They are part of the clotting cascade.
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| - | *They contribute from the osmotic pressure. We call the choloital osmotic pressure to speak specifically of the effect of proteins on osmotic balance.
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| - | *Proteins can be broken down into amino acids for energy (starvation).
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| - | ==Osmotic pressure - tonicity==
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| - | *Isotonic means it has the same osmotic pressure of the plasma. Isotonic saline (0.85% NaCl) can be used to increase blood volume.
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| - | *Hypertonic means that the tonicity of the plasma is higher than normal. This can be because you have too much protein or because you have too little water. This means water will move out of the cells.
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| - | *Hypotonic means the tonicity of the plasma is lower than normal. This could occur because of liver disease (albumin can't be made). This decreases the choloital osmotic pressure. This causes adema because the cells will take up water to balance osmotic pressure.
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| - | ==Formed elements==
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| - | *We call them formed elements because most of them are not cells.
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| - | *Platelets nor RBCs are cells; RBCs have no nuclei and platelets are just chunks of cells.
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| - | *We don't have to memorize the intermediate states of the cells (myelocytes, band cells, etc.).
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| - | *''Blast'' means not fully differentiated.
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| - | *HSCs are committed to the hematopoietic line.
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| - | *Factors that stimulate HSC development:
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| - | **EPO -> RBCs
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| - | **Thromopoietin -> platelets
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| - | **Colony stimulating factor -> WBCs
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| - | **Cytokines -> WBCs
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| - | ***Released by WBCs themselves and macrophages.
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| - | *You can stimulate how long it takes to generate a cell but only by a day or two.
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| - | *RBCs live for only a couple of weeks.
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| - | *WBCs (particularly those for memory of immune pathogens) can live for years.
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| - | ===Erythrocytes===
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| - | *Fully mature has no nucleus or organelles.
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| - | *It is a biconcaved disc for increased surface area to volume ratio and flexibility.
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| - | **Shape is held together by spectrin.
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| - | *We can make about 2 million RBCs / second! That's 230 billion / day.
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| - | *You can make RBCs in the spleen and liver, but this is only under extreme conditions.
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| - | *RBCs die after 4 months because they have no nucleus so they cannot repair themselves.
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| - | *They are broken down by macrophages in the spleen, liver, and marrow.
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| - | *Hemocytoblasts -> myeloid stem cells -> proerythroblast -> bone marrow -> erythroblasts (basophilic, polychromatophilic, normoblast) -> start generating lots of Hb and turning red -> loss of nucleus -> reticulocyte (still has some small organelle) -> enter circulation -> finish up making Hb -> mature red blood cell.
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| - | | + | |
| - | ====Stuff required for erythropoiesis====
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| - | *2/3 of the body's iron is in RBCs.
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| - | *We don't want to waste Fe, so we use ferritin and transferrin to store (in the liver) and transfer iron.
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| - | Why is iron required?
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| - | *It is required for the heme group because it is in the center.
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| - | *B12 is required so you can make erythrocyte maturation factor and thus mature your RBCs.
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| - | *Pyridoxine and folic acid are required for DNA synthesis since we're making lots of protein.
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| - | ====Hormonal control of RBC production====
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| - | *EPO
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| - | **Causes HSCs to go down RBC lineage.
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| - | **Increases speed of differentiation.
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| - | **Comes from kidney in response to hypoxia.
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| - | *The stimulus is low blood oxygen, not necessarily low numbers of RBCs. So it could be:
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| - | **reduced numbers of RBCs which means there is less oxygen getting carried around,
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| - | **reduced O2 in the RBCs because of high altitude,
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| - | ***This is altitude sickness: can't catch breath, heart is going a mile a minute, etc. Gets better because you make more RBCs.
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| - | **increased tissue demand for O2 because of aerobic exercise.
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| - | *EPO extends the life of patients on dialysis. It used to be that they handed out EPO to the most needy dialysis patients. Now that we have a recombinant form, it is abused by athletes.
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| - | **EPO increases RBCs which increases O2 carrying ability which leads to increased stamina. However, more RBCs also means increased viscocity and makes the heart work harder.
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| - | | + | |
| - | ===Article about EPO abuse===
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| - | *There have been 18 deaths among top cyclists because of EPO.
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| - | *Hard to measure abuse of EPO because it is natural.
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| - | *So we try to measure the hematocrit (RBCs) but this can be counter-acted with saline injection. Well, this leads to increased volume and harder work on the heart and death.
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| - | *Doping is when you take some blood out before the event and inject them back in before the event.
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| - | *So, this is hard to catch, too, because hematocrit levels are quite variable based on temperature, work load, etc.
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| - | *So this article suggests that we measure via transferrin receptor : ferritin ratio.
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| - | *Transferring receptors are released by the RBC precursor cells so Transferrin receptor will go up whenever RBC production is up.
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| - | *Ferritin gets broken down if it doesn't have Fe bound.
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| - | *If you're making lots of RBCs, then Ferritin isn't storing any Fe, so it is going down.
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| - | *So the ratio will be very sensitive because one factor (transferrin receptor) is going up and the other (ferritin) is going down.
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| - | ===More regulation of RBC production===
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| - | *Intrinsic factor is required for absorbing B12 from diet.
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| - | *B12 + IF bind to form erythrocyte maturation factor which is required for the last steps of RBC maturation.
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| - | *If you don't have this, your RBCs will not be carrying as much oxygen and a form of anemia will occur.
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| - | *stopped here on 01/13/10.
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| - | *started here on 01/20/10.
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| - | ====Hemoglobin====
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| - | *Carries both oxygen and CO2.
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| - | *Hb is made up of four peptide chains and four heme groups.
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| - | *Heme is iron surrounded by a porferin ring.
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| - | *It takes many enzymes to make the porferin ring.
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| - | *Oxygen binds to heme group, CO2 binds to peptide chains.
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| - | *Color of heme complex changes upon binding: bright red when oxygenated.
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| - | *CO2 is more readily bound by Hb after it has lost it's oxygens.
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| - | *The four chains are two sets of pairs: alpha and beta chains.
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| - | *There are other versions of Hb, however, which are made of different chains.
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| - | **96% is 2 alpha, 2 beta.
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| - | **2% is the '''A2 form''': 2 alphas, 2 deltas.
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| - | **2% is fetal Hb: 2 alpha, 2 gammas.
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| - | ***Fetal hemoglobin has a higher affinity for O2 such that the fetus can steal oxygen from the maternal blood supply.
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| - | ***Change over from fetal form to adult form 6 months after birth.
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| - | Are the different chains different genes or splice variants.
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| - | *Different genes.
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| - | ====Sickle Cell Disease====
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| - | *Named for the shape of the RBC.
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| - | *Especially common in the malaria belt of Africa.
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| - | *Phenotype is different shape, less flexibility, increased lysing of cells.
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| - | *Note that only the homozygous case shows the diseased phenotype because most of the beta chains will be good.
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| - | *The shape blocks easy flow of blood causing hypoxia and tissue death and swelling.
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| - | *A sickle cell crisis has pain, swelling, tissue death.
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| - | *Most populous form is a 2 aa change in the beta chain.
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| - | **Wikipedia says glutamate to valine via one nucleotide change.
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| - | *Sickle cell death was one of the first where protein mutation was characterized. Done with individual aa sequencing.
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| - | *Even though we know all this, we have no cure.
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| - | *So why does this (potentially pre-maturation lethal mutation) survive in population?
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| - | **The hypothesis is that it must convey some advantage to the individual.
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| - | **And it does: patients who are carriers and diseased for the beta chain gene are resistant to malaria.
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| - | ***This occurs because the cells leak potassium which is lethal to the malaria parasite.
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| - | ***It could also be because malaria spends some of its time inside the cells and the ion concentration difference is harmful to the parasite.
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| - | ====Biophysics of sickle cell hydroxyurea therapy====
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| - | *When beta chain polymerizes, you get less oxygen carrying ability and cell shape change.
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| - | *The beta chains will polymerize when they are deoxygenated.
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| - | *The delay time for polymerization (after deoxygenation) should be longer than the transit time from capillaries (where oxygen is removed) to the lungs (where oxygen is added again).
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| - | *The math shows us that if we can increase the delay time even just a little, we can make a big difference.
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| - | *Hydroxyurea increases fetal Hb which increases the delay time.
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| - | *Hydroxyurea can only be used in adults, because it can affect bone marrow and stem cells and might mess up growth in children.
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| - | *Old paper, but there doesn't seem to be new therapies.
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| - | *Arginine butyrate also increases Fb.
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| - | ===RBC turnover===
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| - | *RBCs have a 100-120 day lifespan.
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| - | *Macrophages in spleen and liver recycle the RBCs.
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| - | *When broken down:
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| - | **Aas are put into blood stream.
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| - | **Iron from heme group is bound to transferrin in the blood stream.
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| - | ***Note that transferrin is pretty abundant.
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| - | ***Extra iron (that is, transferrin-bound iron) is stored in the liver.
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| - | **Porferin ring is a pigment that gets broken down into biliveriden, then bilirubin, then leaves the macrophage and enters the liver via albumin, then excreted in the bile, then gets secreted (mostly in the feces, some in the urine).
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| - | ***Bilirubin is toxic if free in the blood.
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| - | ***Don't need to know all the forms, good enough to know that it gets convereted and to know the track it follows.
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| - | ===Jaundice===
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| - | *This is a build up of bilirubin that the liver can't handle and thus it ends up in the blood stream and other tissues of the body (eyes, skin, mucus membranes).
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| - | *Recall that bilirubin is toxic, mainly to the nervous system.
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| - | Is it a neutortransmitter that overloads the system.
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| - | *Can be caused by liver disease (one cannot process or cannot transport bilirubin) or by excessive tissue damage (because bunches of RBCs are getting turned over).
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| - | *Jaundice can also be seen in newborns with a not-quite-mature liver.
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| - | **Happens even in full-term babies.
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| - | **It is easy to treat when the liver will mature, you just treat the bilirubin: put them under UV light because bilirubin is broken down by UV light.
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| - | ===Anemia===
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| - | *There are lots of causes.
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| - | *Can be a decrease in RBCs or a decrease in amount of oxygen carrying capacity.
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| - | *Regardless of cause, symptoms include weakness, shortness of breath, chills, chronic mental and physical fatigue.
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| - | **All of this due to lack of making ATP because of lack of oxygen.
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| - | ====Causes of anemia====
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| - | =====Insufficient RBCs=====
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| - | *Hemorrhagic anemia
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| - | **Perhaps because of loss of blood.
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| - | **Remember that this can be a slow, consistent loss, like an ulcer.
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| - | *Hemolytic anemia
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| - | **Body makes RBCs but they are lysing.
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| - | ***There may be a defect in the membrane causing them to not last as long (say 40 days) such that your body has to be making more RBCs all the time.
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| - | **Incorrect infusion
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| - | ***This can cause lysis of lots of RBCs.
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| - | **Parasitic infections.
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| - | *Aplastic anemia:
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| - | **Most likely in cancer patients.
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| - | **Something about work environment.
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| - | ***I think has to do with the fact that exposure to toxins can cause aplastic anemia and the workplace is often a place of toxin exposure.
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| - | =====Decreases in hemoglobin production=====
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| - | *Iron-deficiency anemia
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| - | **Could be from poor diet with too little iron.
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| - | **Inadequate absorption of iron
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| - | ***There are diseases that can cause this. Some are hereditary.
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| - | **Loss of irons stores
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| - | ***Liver disease can cause this problem.
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| - | **Deficiencies in iron metabolism
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| - | ***This is very rare, might occur in iron transport proteins.
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| - | *Pernicious anemia
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| - | **This is a deficiency of vitamin B12.
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| - | **If you don't have enough B12, then even if you have ''intrinsic factor'' you can't develop Erythrocyte Maturation Factor which is crucial for RBC maturation.
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| - | **This would lead to immature RBC formation.
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| - | =====Abnormal hemoglobin=====
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| - | *Thalassemia
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| - | **Common in the Greek population.
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| - | **This is a broken synthesis of the globin chains.
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| - | **Alpha and beta versions are deficient in synthesis of their respective chains.
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| - | *Sickle cell
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| - | **Talked about it.
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| - | ===Polycythemia===
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| - | *Too many RBCs.
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| - | *Not as rare as you'd think.
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| - | *Polycythemia vera (true) comes from a tumor that generates lots of RBCs.
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| - | **This is rare.
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| - | **Usually due to tumors.
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| - | *Secondary polycythemia occurs when a consequence of a disorder is the increased production of RBCs.
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| - | **High altitudes:
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| - | ***Don't have adverse effects like use of EPO.
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| - | **Emphysema:
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| - | ***This and pulmonary fibrosis change the structure of the lung such that there is inefficient gas exchange causing low oxygen at the kidney and a continuous signal to make more RBCs.
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| - | **Pulmonary fibrosis:
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| - | ===Porphyrins===
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| - | *A mutation in one of the many enzymes that make this complex ring molecule can cause disease.
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| - | *This class of diseases are called porphuria.
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| - | *Vincent van Gogh had this disease as did the royal family of Transylvania.
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| - | *There are many different forms of the disease depending on the different parts of the pathway affected.
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| - | *Some of these forms of disease seem to get worse at puberty.
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| - | Why does that make sense?
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| - | *Symptoms:
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| - | **Skin lesions caused by sunlight.
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| - | **Gum degeneration.
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| - | **Rampant hair growth (hands and face, especially).
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| - | **Aggravated by alcohol and certain chemicals in garlic.
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| - | **Crankiness.
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| - | **Inability to clear toxins (or something like that?).
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| - | *Treatment:
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| - | **Infusion of red blood cells from healthy donors.
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| - | ===Restoration of blood volume===
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| - | *Isotonic fluids can restore blood volume.
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| - | *For whole blood cells and packed RBCs, you have to do blood typing.
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| - | *Anemia needs packed RBCs.
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| - | | + | |
| - | ===Blood typing===
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| - | *Measures antigens on RBCs.
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| - | *If you mismatch, the host cells will kill the infused cells and agglutination will occur (a clumping of the cells that are being attacked).
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| - | **This will hit the kidney first, causing kidney failure, and resulting in sepsis.
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| - | ====ABO Antigens====
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| - | *Two types: A and B.
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| - | *Can have one, both, or neither.
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| - | *Type AB has no antibodies so they can receive any type of blood.
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| - | *Type O has A and B antibodies so they can only get O blood.
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| - | *The antibodies from the donor will react onto the host blood cells, but there are not enough to be a problem.
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| - | ====Rh factor====
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| - | *Rh because it was first described in a rhesus monkey.
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| - | *Most people are Rh positive.
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| - | *If you are Rh negative, you don't have the antibodies inherently, you must be sensitized to them.
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| - | *So you can tolerate the first interaction, but then the person will develop antibodies.
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| - | Why wouldn't you develop an immune response to the B antigen?
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| - | *If you're type A and you get AB blood, you don't develop the B antibodies because you already have them. So in this ABO case, the reaction would look like the Rh reaction upon second exposure.
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| - | =====Rh in pregnancy=====
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| - | *This also manifests itself as a problem when the mother is Rh- and the fetus is Rh+.
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| - | **This isn't a problem in the first pregnancy because Rh factors don't cross the placental membrane.
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| - | **During delivery, however, the membranes rupture and the two circulation systems can mix such that the Rh+ fetal cells enter the mother's system and she develops antibodies.
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| - | **Still not a problem.
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| - | **However, once she has a second child that is Rh+, the antibodies can cross the membrane such that '''hemolytic disease of newborns''' occurs.
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| - | **This can only be treated with an in-utero blood transfusion.
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| - | **So why don't ABO cause this problem? Because they are too large and cannot cross the membrane.
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| - | *Rh factor and pregnancy:
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| - | **You can treat a first-time mother with RhoGam which binds the antigen (Rh factor) and blocks the mother's immune reaction.
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| - | Does RhoGam prevent issues with Rh+ baby once the mother has been sensitized?
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| - | **If you don't do this, and the mother develops antibodies, the fetus of a second pregnancy will require transfusions before birth and after birth (because the mom's antibodies are still floating around).
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| - | ===White blood cells===
| + | |
| - | *They combat foreign substances in the body.
| + | |
| - | *They engulf stuff, chemically detoxify stuff, produce antibodies, and release chemical messengers.
| + | |
| - | *This provides an '''integrated defense system'''.
| + | |
| - | *WBCs must be able to leave the bloodsteam, called diapedesis.
| + | |
| - | *Lymphocytes can leave circulation and come back in; the other 5 types only cross out of the blood, then die.
| + | |
| - | *Leukocytes are attracted (to cross the vessel wall) by inflammatory responses, chemical attractants, tissue damage, or chemicals released by infected tissue.
| + | |
| - | *Lymphoid line leads to basophils, eosinophils, and neutrophils.
| + | |
| - | *One can characterize leukocytes by nucleus shape and whether or not they have granules (spottiness in the microscope).
| + | |
| - | *We want to be able to identify these cells because a differential count can give us clinically relevant clues to what is going on.
| + | |
| - | | + | |
| - | ====Granulocytes====
| + | |
| - | *Neutrophils: stain lilac with acidic and basic dyes.
| + | |
| - | *Eosinophils: stain with acidic dyes.
| + | |
| - | *Basophils: stain with basic dyes.
| + | |
| - | | + | |
| - | ====Agranulocytes====
| + | |
| - | *Monocytes:
| + | |
| - | **Turn into macrophages.
| + | |
| - | **Are not terminally differentiated.
| + | |
| - | *Lymphocytes:
| + | |
| - | | + | |
| - | *White blood cells are only a small part of the blood volume.
| + | |
| - | *Neutrophils are most abundant among WBCs in the blood, then lymphocytes, monocytes, and eosinophils.
| + | |
| - | | + | |
| - | *we'll finish Blood next time and all the readings.
| + | |
| - | | + | |
| - | *stopped here on 01/20/10.
| + | |
| - | *started here on 01/25/10.
| + | |
| - | | + | |
| - | *we probably won't finish blood today.
| + | |
| - | | + | |
| - | *Neuts are most abundant, then lymphocytes.
| + | |
| - | *The others are important, too, though.
| + | |
| - | | + | |
| - | =====Neutrophils=====
| + | |
| - | *AKA polymorphonuclear leukocytes.
| + | |
| - | *They usually last about 10 hours in the circulation unless activated to fight an infection.
| + | |
| - | *They are the most active early-on in an infection because they can be recruited very quickly.
| + | |
| - | *They are phagocytes so they can get rid of bad guys pretty quickly via hydrolytic-proteolytic enzymes.
| + | |
| - | *They can also ingest particlate matter.
| + | |
| - | *They release prostaglandins and leukotrienes which are inflammatory and chemoattractants for other leukocytes.
| + | |
| - | *Neuts have multiple types of granulocytes:
| + | |
| - | **Those containing hydrolytic-proteolytic enzymes (to fuse to phagocytized pathogen, or to release into the tissue).
| + | |
| - | ***Note that if you release these granules, there will be tissue damage and you will have inflammation.
| + | |
| - | **Those containing defensisns, small molecular compounds that are good at poking holes in microorganisms, thus causing it to die.
| + | |
| - | **Granules with prostanoids (contains prostaglandins and leukotrienes) which do some tissue damage to cause inflammation and attract other white blood cells. This processes generally kills neutrophils such that pus is formed by the broken bodies of neutrophils.
| + | |
| - | *Neuts are the most motile of all granulocytes.
| + | |
| - | | + | |
| - | ======The tangled webs that neutrophils weave======
| + | |
| - | *Explores how neutrophils can contain some of their noxious chemicals.
| + | |
| - | *The paper observed that when stimulated, the neutrophils were secreting DNA (which is very sticky) and histones and proteins beyond just the prostaglandins that we knew about.
| + | |
| - | **Some of these things degrade bacterial virulence factors.
| + | |
| - | **The authors also suggest that the DNA and proteins may serve to contain the tissue damage and the microbes.
| + | |
| - | *They determined that the neutrophils died when secreting all these things, but not through lysis.
| + | |
| - | *Questions that remain:
| + | |
| - | **What are the signals that make neuts do this?
| + | |
| - | **Why don't all neuts do this?
| + | |
| - | **How do we control this process?
| + | |
| - | | + | |
| - | =====Eosinophils=====
| + | |
| - | *Make up only 2-4% WBCs. That is, in a normal, healthy person with no infections, etc.
| + | |
| - | *Eosinophils are less motile than neuts, but they definitely migrate.
| + | |
| - | *The cells phagocytize proteins thus detoxifying them.
| + | |
| - | *Eosinophils have oxydases, peroxidases, and phosphatases in their granules so they can release it and destroy pathogens (find out which ones).
| + | |
| - | *These cells follow chemotactants generated by an antigen-antibody interaction.
| + | |
| - | *Eosinophils can also be signaled to move by mast cells / basophils (same thing for our concerns).
| + | |
| - | *Eosinophils are increased upon allergic reactions and autoimmune diseases because of signals from basophils and antigen-antibody interactions.
| + | |
| - | *Eosinophils inactivate inflammtory chemicals like histamine (because histamine is a protein).
| + | |
| - | *Kill things too large for phagocytosis.
| + | |
| - | | + | |
| - | =====Basophils=====
| + | |
| - | *Basophils are localized whereas mast cells are systemic.
| + | |
| - | *Only 1% of the WBCs.
| + | |
| - | *Found more outside the bloodstream than inside (especially connective tissue).
| + | |
| - | *Their granules contain heparin and histamine (an anticoagulant and a vasodilator, respectively).
| + | |
| - | **These two factors increase blood flow to an infected area, increase eosinophil and neutrophil recruitment, and increase capillary permeability.
| + | |
| - | **This is all good when there is an infection.
| + | |
| - | | + | |
| - | ====Lymphocytes====
| + | |
| - | *Second most abundant after neuts, 20-30%.
| + | |
| - | *Found mostly in the lymphoid peripheral tissue, not in blood.
| + | |
| - | *There are three types:
| + | |
| - | **T cells: responsible for cell mediated immunity (directly killing other cells that are infected).
| + | |
| - | **B cells: antibody mediated immunity (target cells for degradation).
| + | |
| - | **Natural Killer cells: recognize global types of antigens.
| + | |
| - | *B and T cells are very specific; NK cells are not that specific.
| + | |
| - | | + | |
| - | ====Monocytes====
| + | |
| - | *Only live for a few days in blood stream, then move into tissue.
| + | |
| - | *Originate in bone marrow.
| + | |
| - | *Only fully differentiate upon moving into tissue, into macrophages.
| + | |
| - | *Macrophages are phagocytic.
| + | |
| - | *Macrophages release chemical signals to recruit more phagocytic cells.
| + | |
| - | *There are several types of macrophages:
| + | |
| - | **Fixed: reside in a particular tissue. Then we name them like "alveolar macrophage" or "liver macrophage".
| + | |
| - | **Wandering: move throughout tissues.
| + | |
| - | *Macrophages are also antigen presenting cells, so they ride the fence between the innate and the adaptive immune systems.
| + | |
| - | *Microglia are the macrophages of the brain.
| + | |
| - | | + | |
| - | ====Differential WBC count====
| + | |
| - | *This is about determining the relative amount of each type of WBC.
| + | |
| - | *You take the buffy coat and count them.
| + | |
| - | *These can support an hypothesis like those below but cannot prove any of them.
| + | |
| - | *High neuts: bacterial infection or severe tissue destruction.
| + | |
| - | **Upon tissue damage, platelets will recruit neutrophils.
| + | |
| - | *High eosinophils: allergic reactions, parasitic infector or autoimmune disease.
| + | |
| - | **Because mast cells and basophils recruit eosinophils.
| + | |
| - | *High basophils: allergic reaction.
| + | |
| - | *High lymphocytes: viral infection (because viruses are ''inside'' the cell, so a T cell must detect the presented antigen).
| + | |
| - | *High monocytes: viral or fungal infection.
| + | |
| - | | + | |
| - | ===Thrombocytes===
| + | |
| - | *Platelets!
| + | |
| - | *Come from the myeloid lineage.
| + | |
| - | *The progenitor cell grows and turns into the huge megakaryocyte.
| + | |
| - | *Platelets come from parts of the megakaryocyte breaking off.
| + | |
| - | *Platelets have no nucleus but are surrounded by membranes.
| + | |
| - | *Platelet granules contain serotonin, Ca++, enyzmes, ADP, PDGF.
| + | |
| - | *Platelets aggregate and adhere to sites of vascular damage.
| + | |
| - | *Platelets are key for sealing a broken vessel by aggregation.
| + | |
| - | *This is the first line of defense for a broken vessel.
| + | |
| - | *Megakaryocytes are generated through lots of mitosis but no cell division.
| + | |
| - | *A single megakaryocyte will give off thousands of platelets.
| + | |
| - | *Thrombopoietin enhances formation of mkcyte and increases formation of platelets.
| + | |
| - | | + | |
| - | ====The root of platelet formation====
| + | |
| - | *It is not just a random breaking apart of the mgcyte.
| + | |
| - | *There were two theories going into this research:
| + | |
| - | **Cytoplasmic fragmentation: mgcytes have cell membranes running through them that divide the cytoplasm into the platelets and then it enters the blood stream and fragments.
| + | |
| - | **Proplatelet elaboration: Mgcytes sit outside the blood vessels and extend processes into the blood vessels and the sheer force of the blood stream pulls off chunks of platelets.
| + | |
| - | *To distinguish between these theories, the authors:
| + | |
| - | **engineered the mice to have fluorescent mgcytes,
| + | |
| - | **opened marrow cavity of the brain,
| + | |
| - | **use microscopy to watch the mgcyte, (this is hard to do in live animals)
| + | |
| - | *Visualization of the process shows that the megakaryocyte has a membrane bound inner sac and that the mgcyte's membrane runs through the endothelial wall of the vessel such that the sheer force of the blood stream pulls off chunks of the process.
| + | |
| - | *The speed of blood flow may determine how fast platelets are being broken off.
| + | |
| - | | + | |
| - | ===Leukopoiesis===
| + | |
| - | *Generation of WBCs.
| + | |
| - | *We don't need to know all the factors for each line of WBCs.
| + | |
| - | *Colony-stimulating factors is the name giving to all the leukopoiesis factors.
| + | |
| - | *All WBCs differentiate to some degree in bone marrow.
| + | |
| - | *Lymphocytes fully differentiate in lymphoid tissue.
| + | |
| - | *Some of the CSFs are generated by macrophages and T-lyphocytes.
| + | |
| - | *Phagocytic cells have a shorter lifespan than others.
| + | |
| - | *Lymphocytes can live for years.
| + | |
| - | *Leukocytes are broken down by the liver, spleen, and lymph nodes.
| + | |
| - | *Increased WBCs generally means there is an infection.
| + | |
| - | *Leukemia is a proliferation of immature WBCs.
| + | |
| - | **Leukemias are named for their type of precursor from which they came.
| + | |
| - | | + | |
| - | ===WBC physiology===
| + | |
| - | *In order to fight stuff, WBCs have to get out of the circulation.
| + | |
| - | *There are different chemotactants for each type of WBC.
| + | |
| - | *Many of these signals come from other WBCs, infected tissue, or from an infectious agent itself.
| + | |
| - | *Most cells move out through the capillaries, not the main blood vessels and thus there are few cells that must be crossed by the WBCs.
| + | |
| - | *Blood and cells in it are moving rapidly, however, so we must first slow down the exiting cells.
| + | |
| - | *So first, it starts getting a little sticky such that it rolls.
| + | |
| - | *On the endothelial cells there are selectins which interact with integrins on the exiting WBCs. These interact to slow cells down and make them sticky. There must be something controlling this, however, otherwise all WBCs would leave all the time!
| + | |
| - | *Only lymphocytes can leave and reenter the blood stream; all others can only leave and die.
| + | |
| - | | + | |
| - | ====Adhesion Molecules: the path to a new understanding of acute inflammation====
| + | |
| - | *This article says that chemical crosstalk is bidirectional between the exiting WBCs and the endothelial cells being crossed.
| + | |
| - | *Here's the process:
| + | |
| - | **A macrophage in tissue recognizes a foreign body and is giving off soluble mediators (like histamines, interleukins, etc.).
| + | |
| - | **The endothelial cells and WBCs are affected by the soluble mediators.
| + | |
| - | **Selectins on the PMN move out onto the tips of the cell membrane because of the signal and then the selectins start interacting with glycoproteins on the endothelial cells. After some protein synthesis, even more selectins will be expressed.
| + | |
| - | **Finally, the WBC binds and doesn't move.
| + | |
| - | **Now the endothelial cell will present more immunoglobulins (fueled by inflammatory signals) such that there is tight binding. Here, integrins bind tightly to the endothelial cells after being activated by the signals from macrophages.
| + | |
| - | **Diapedesis is mediated by e-cadherin interactions.
| + | |
| - | **Then the WBC flattens and spreads out.
| + | |
| - | **Then WBC migrates through the tight junction.
| + | |
| - | **Then WBC resumes rounder shape and performs its function.
| + | |
| - | She said both have selectins. Which cell has integrins?
| + | |
| - | *Only leukocytes.
| + | |
| - | | + | |
| - | ===Clinical considerations===
| + | |
| - | | + | |
| - | ====Bone marrow transplantation====
| + | |
| - | *Useful because it is enriched in stem cells.
| + | |
| - | *Useful for treatment for radiation poisoning or chemotherapeutic drug poisoning.
| + | |
| - | *It can also be useful for gene therapy because we can fix a problem and put it in the person and know that the change will be propagated.
| + | |
| - | *We need to be careful to avoid immune reaction.
| + | |
| - | **This is about HLA typing, not ABO or Rh typing.
| + | |
| - | **The only identical HLA types are identical twins.
| + | |
| - | **This is a typing for the antigens on host cells that might cause an immune response. So we type as closely as possible so an immune response won't be too strong.
| + | |
| - | *There is a possibility of graft versus host disease.
| + | |
| - | **This is the opposite of normal transplant rejection considerations.
| + | |
| - | **With bone marrow, it is possible for the donor marrow to mount an attack against the host, and that is not good.
| + | |
| - | **And therefore we need to remove T-cells (lymphocytes).
| + | |
| - | | + | |
| - | ====Alternatives to bone marrow transplantation====
| + | |
| - | *As the ability to do transplants becomes more possible, it is more needed so we don't have enough bone marrow.
| + | |
| - | *But really all we need is the stem cells from bone marrow.
| + | |
| - | | + | |
| - | =====Clinical promise - ethical quandry=====
| + | |
| - | *Normally UCB (umbilical cord blood) is discarded after birth.
| + | |
| - | *UCB SCs must be typed but not as strictly because it hasn't developed all of its HLA types.
| + | |
| - | **So it isn't as likely to cause an immune rejection.
| + | |
| - | *It has been estimated that if we just collected all the blood from every delivery, we would have all the stem cells we could need.
| + | |
| - | *Questions:
| + | |
| - | **What's the best way to collect it and store it?
| + | |
| - | **How long can it be stored?
| + | |
| - | **What testing is necessary to protect the recipient?
| + | |
| - | ***Which tests do you do and how many do you do?
| + | |
| - | **Which patient should receive the treatment until sufficient stores can be built up?
| + | |
| - | ***It is especially useful for treating childhood diseases and adults take more.
| + | |
| - | *Issues keeping us from collecting all UCB:
| + | |
| - | **Do you need to get consent from donor parents?
| + | |
| - | **Should testing for genetic disease be performed?
| + | |
| - | **Should the parents be informed of the results of the genetic disease?
| + | |
| - | ***What if the disease is terminal?
| + | |
| - | ***What if the disease was chronic (diabetes) and could be affect insurance coverage?
| + | |
| - | *Other ethical issues:
| + | |
| - | **Who should regulate the use of the material?
| + | |
| - | **Should companies be allowed to approach parents before delivery to store cord blood when it is not known how long the blood can be stored?
| + | |
| - | ***Remember that we don't know how long it will last so maybe by 30 it's no good anymore.
| + | |
| - | *$125 annual storage fee, $1700 for kit and processing, $150 shipping service, and probably multiple thousands of dollars for a Dr. to use the kit to collect the blood.
| + | |
| - | | + | |
| - | =====Ubilical cord blood transplantation and banking=====
| + | |
| - | *An update on the previous paper.
| + | |
| - | *Stem cells are not totally free of immune response; it is still required that you do some typing.
| + | |
| - | *Partial response is acceptable and reduces the risk of GVHD.
| + | |
| - | *Banking can occur for at least 5 years. But beyond that we don't know.
| + | |
| - | *The issue of testing:
| + | |
| - | **What is done now: HLA tissue typing, a few infectious agents.
| + | |
| - | **No rules, no consensus, only a best practice guide by the FDA.
| + | |
| - | *UCB stem cells seem to proliferate more slowly than native HSCs.
| + | |
| - | *It is hard to use UCB in adults because it takes so many for a good transplantation. This often requires multiple sources (donors) and the two fight and one overcomes the other. However, this isn't a big problem, really.
| + | |
| - | **During the first month, there is double chimerism: three different genetic materials--the host and the two recipients.
| + | |
| - | *HLA matching isn't as important because
| + | |
| - | *Many times these cells don't proliferate as well.
| + | |
| - | | + | |
| - | ==Hemostasis==
| + | |
| - | | + | |
| - | *stopped here on 01/25/10.
| + | |
| - | *started here on 01/27/10.
| + | |
| - | | + | |
| - | *Hemostasis is how the blood contributes to homeostasis.
| + | |
| - | *What happens when a blood vessel is broken>?
| + | |
| - | *Four steps:
| + | |
| - | | + | |
| - | ===Local vasoconstriction===
| + | |
| - | *This is called the vascular phase.
| + | |
| - | *Vasculature is constricted immediately.
| + | |
| - | *This slows blood loss.
| + | |
| - | *Collagen is exposed and cells release ADP, tissue factor, and prostacyclin.
| + | |
| - | *Collagen, ADP, and tissue factor and prostacyclin are important for the next two steps.
| + | |
| - | | + | |
| - | ===Formation of a platelet plug===
| + | |
| - | *Prostaglandins, thromboxanes, and prostacyclins form the prostanoids.
| + | |
| - | **Prostacyclins inhibit clot formation.
| + | |
| - | **Prostaglandins encourage clot formation.
| + | |
| - | *Platelets, upon being exposed to collagen, degranulate.
| + | |
| - | *Platelets release:
| + | |
| - | **ADP: stimulates platelet aggregation and secretion,
| + | |
| - | **Thromboxin A2 and serotonin: stimulate vascular spasms,
| + | |
| - | **clotting factors: proteins that play a role in clotting,
| + | |
| - | **PDGF: helps epithelial repair,
| + | |
| - | **Ca++: helps with the next couple of steps.
| + | |
| - | *This forms a plug by the stickifying of the membranes such that they stick to each other and to the broken cells of the endothelium and the collagen.
| + | |
| - | *So how do we limit it to the site of injury?
| + | |
| - | **Through the release of prostacyclin (PGI2) by endothelial cells which reduces platelet coaggulation.
| + | |
| - | **Through the breakdown of ADP by emzymes in the blood.
| + | |
| - | **Through high levels of serotonin which block the action of ADP to further clot formation.
| + | |
| - | **Through the fact that prostaglandins (which are encouraging clot formation) have very short half-lives in the blood so they don't react throughout the body because they are degraded before they can travel very far.
| + | |
| - | *So how does aspirin affect the clotting cascade?
| + | |
| - | **A low dose of aspirin inhibits prostaglandins and thus decreases the platelet degranulation reaction and thus decreases plug formation.
| + | |
| - | **A high dose of aspirin can affect the formation of PGI2 and thus decrease PGI2's ability to reduce platelet coaggulation.
| + | |
| - | | + | |
| - | ===Clotting cascade===
| + | |
| - | *This cascade involves tens to a hundred of proteins.
| + | |
| - | *We'll only study a simple model.
| + | |
| - | *An enzyme called thrombin converts fibrinogen (soluble in the blood) to fibrin (which is an insoluble fibrous plasma protein).
| + | |
| - | *Fibrin then forms a mesh that traps RBCs and some plasma to form a clot.
| + | |
| - | *The roman numerals describe the order in which they were discovered.
| + | |
| - | *Other names have poorer logic like "christmas factor".
| + | |
| - | *There are three stages:
| + | |
| - | **Formation of prothrombinase,
| + | |
| - | ***prothrombinase cuts thrombinogen to thrombin.
| + | |
| - | **Conversion of prothrombin to thrombin
| + | |
| - | **Conversion of fibrinogen to fibrin
| + | |
| - | *Intrinsic means all the factors are in the blood, extrinsic means some come from outside the blood.
| + | |
| - | *There are two ways to activate factor X: intrinsic (slower) and extrinsic (faster).
| + | |
| - | *We don't need to memorize the pathways.
| + | |
| - | *Note, however, that Ca++ and vitamin K are absolutely necessary for both intrinsic and extrinsic cascading.
| + | |
| - | *What activates intrinsic versus extrinsic.
| + | |
| - | **Extrinsic would be factor III from a damaged endothelial cell whereas intrinsic would be factor XII from the blood.
| + | |
| - | *Common pathway:
| + | |
| - | **Requires Ca++ (can use Ca++ chelators to stop clotting).
| + | |
| - | **Requires vitamin K because it is required for production of many of the proteins in this cascade, like prothrombin, and factors 7, 9 and 10.
| + | |
| - | ***Vitamin K comes from bacteria in the large intestine and is absorbed as a fat soluble vitamin.
| + | |
| - | **Factor X generates prothrombinase which then cuts prothrombin into thrombin which then cuts fibrinogen to fibrin.
| + | |
| - | | + | |
| - | ===Clot retraction and dissolution===
| + | |
| - | *As time goes on, the clot draws together to close wound and open a vessel.
| + | |
| - | *Clot retraction is initiated by thrombosthenin, a platelet factor.
| + | |
| - | *Now we need to get rid of the clot.
| + | |
| - | *Fibrin is broken down by plasmin, a proteolytic enzyme.
| + | |
| - | *Plasminogen must be activated into plasmin.
| + | |
| - | *TPA = tissue plasminogen activator is formed by the endothelial cells and cleaves plasminogen into plasmin such that fibrin is degraded.
| + | |
| - | *Staphlokinase and streptokinase are from bacteria and used clinically to activate TPA.
| + | |
| - | *We use SK and SP to break apart clots in stroke and MI patients.
| + | |
| - | | + | |
| - | ====Clot busters====
| + | |
| - | *SK and SP break up clots, that's their clinical use.
| + | |
| - | *However, since, SK and SP are exogenous, they can produce an immune response.
| + | |
| - | **They are cheaper (than tPA), however, because we can get them from growing up bacteria.
| + | |
| - | *Note that SK will break down free fibrin which increases your chance of bleeding.
| + | |
| - | *Read article on our own.
| + | |
| - | | + | |
| - | ===Anticoagulants===
| + | |
| - | *There are two types: physiological (endogenous) and therapeutic (clinically administered).
| + | |
| - | *Physiological:
| + | |
| - | **PGI2 is a prostenoid that inhibits platelet adhesion (a prostacyclin).
| + | |
| - | **Antithromboplastin inactivates TF3 which is part of the clotting cascade. Antitrhomboplastin normally serves to balance.
| + | |
| - | **Factor C is similar to antithromboplastin in that it blocks TFV and TFVIII.
| + | |
| - | **Heparin which is released by basophils / mast cells, inactivates thrombin, thromboplastin, and prothrombin.
| + | |
| - | *Therapeutics:
| + | |
| - | **Heparin is great because it is natural and it can be reversed.
| + | |
| - | **Calcium chelators cannot be used ''in vivo'' because it will kill them because no calcium means no neurotransmission or muscular function.
| + | |
| - | **Warfarin or dicumarol inhibit synthesis of prothrombin by limiting use of vitamin K in the liver.
| + | |
| - | ***Warfarin won't completely inhibit clotting, so it can be titrated.
| + | |
| - | | + | |
| - | ===Disorders of hemostasis===
| + | |
| - | | + | |
| - | ====Thrombocytopenia====
| + | |
| - | *Low numbers of platelets.
| + | |
| - | *Can come from
| + | |
| - | **decreased production in bone marrow from radiation or cytotoxic chemicals.
| + | |
| - | **sequestration of platelets by the spleen
| + | |
| - | ***congestive splenomegaly: what is this?
| + | |
| - | **destruction of platelets by autoimmune disease
| + | |
| - | ***idiopathic thrombocytopenic purpura: when the immune system breaks down the body's immune system.
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| - | *Symptoms: easy bruising because capillaries break all the time and usually platelets are the simple fix. There may also be bleeding in the joints because vessels there take a large beating.
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| - | ====Disseminated intravascular coagulation====
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| - | *This is blood clot formation in the capillaries.
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| - | *Usually happens in respnose to bacterial infection that damages endothelial cells. This exposes collagen and starts the platelet clotting process.
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| - | *When amniotic fluid leaks into the blood stream, it can cause init of platelet and clotting cascade.
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| - | *Rarely, cancers can start this cascade.
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| - | ====Hemophilia====
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| - | *Hemophilia A: deficiency in factor 8
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| - | **85%
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| - | *B: deficiency in factor IX
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| - | *C: deficiency in factor XI.
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| - | *A and B are x-linked so males are infected and women are carriers.
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| - | *C is not x linked and is not as severe.
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| - | *Symptoms include uncontrolled bleeding, subcutaneous bleeding, vessel damage in the joints, and actual damage in the joints.
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| - | ====Deficiencies in clotting factors====
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| - | *Afibrogenemia:
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| - | **there is a hereditary form but is usually from liver disease.
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| - | **if the liver isn't working, then not all the clotting proteins can be made, like fibrinogen.
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| - | *Hypoprothrombinemia
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| - | **liver disease can cause this, as can vitamin K deficiency because K is required for generation of prothrombin.
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| - | **Hemorrahgic disease of newborns:
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| - | ***Because newborns don't have the normal bacteria in the gut that generates vitamin k or if their liver isn't fully formed, they may not be able to generate the proteins well enough.
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| - | **Therefore it makes sense that if you are taking lots of antibiotics you may become vit k deficiency.
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| - | =====Thromboembolytic disorders====
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| - | *Thrombus:
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| - | **A clot in an unbroken blood vessel which may occlude the whole vessel.
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| - | **If the vessel is a coronary vessel, it generates a heart attack.
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| - | **We're most worried about clots in heart, lungs and brain.
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| - | | + | |
| - | *Embolus:
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| - | **When a clot moves to a bad location.
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| - | *Aspirin use:
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| - | **Low doses inhibits thromboxane A2 formation and therefore platelet and aggregation.
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| - | **In high doses, will affect PGI2 and will have the opposite affect because it inhibits the inhibitor.
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| - | | + | |
| - | *moved on to the [[Lymphatic / Immune notes]] on 01/27/10.
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GkXRCK Appreciate you sharing, great article post.Much thanks again. Keep writing.
