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81 Cards in this Set
- Front
- Back
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Growth Factors are necessary for many aspects of hematopoiesis. Where do most of these growth factors come from?
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Most of the growth factors come from fibroblasts, adipocytes, endothelial cells, and macrophages
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What are the four cellular processes affected by growth factors?
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1. Cellular Proliferation
2. Cellular Differentiation 3. Cellular Mutation 4. Suppression of apoptosis |
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Many hematopoietic growth factors bind to receptors that belong to the family of cytokine receptors. Understand the steps of receptor activation for a cytokine receptor signaling through the JAK/STAT pathway.
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1. Growth Factor binding causes a conformation change in the cytokine receptor.
a. Intracellular recruitment of JAKs occurs b. Activated JAKs phosphorylate each other and the cytokine receptor c. STAT proteins bind to the activated receptors and get phosphorylated. d. The phosphorylated STATs then dissociate from the receptor and dimerize then transloacte to the nucleus where they act as transcription factors |
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What type of molecule is JAK?
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JAK is a Janus Kinase
-phosphorylates enzymes, receptors, etc. |
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What type of molecule is STAT?
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STAT is a binding protein
-Acts as a transcription factor |
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Why does an acquired V617F point mutation in the JAK2 protein lead to myeloproliferative disorders?
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JAK2 V617F results in a constitutivlely active receptor
-the receptor is active even when without growth factor stimulation -This mutation causes abnormal proliferation in cell lines -More extensive Marrow Failure |
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What two lineages of blood cells are most frequently affected by this disorder?
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The JAK2 V617F mutation occurs in the:
1. Erythrocyte cell lines 2. Megakaryocyte cell line |
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Understand how the hormone erythropoietin functions.
Where is erythropoeitin formed? |
Erythropoietin is formed in the kidney.
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What is the target tissue of erythropoeitin?
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The target tissue of erythropoeitin is the bone marrow
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What type of receptor does erythropoietin bind to and what signal transduction pathways are activated?
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Erythropoientin binds to the Epo receptor and triggers the JAK/STAT Pathway
---a cytokine receptor |
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What is the ultimate biological effect of the hormone erythropoietin?
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Erythropoietin is made in response to low blood oxygen.
---The hormone acts to trigger: 1. Proliferation of erythroid lineage 2. Survival of erythrocyte precursors 3. Promote erythrocyte differentiation |
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When erythropoietin binds to its receptor on an erythrocytes precursors, what 3 cellular processes are affected?
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Promotion, survival, and differentiation of erythrocytes and precursors in the erythroid series are all stimulated by the binding of erythropoietin to its receptors.
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What genes are up-regulated (directly or indirectly) by erythropoietin binding to its receptor?
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GATA-1 transcription factor is upregulated. This activates:
1. Heme biosynthetic enzyme 2. Hemoglobin 3. Erythrocyte membrane enzyme 4. Spectrin 5. Transferrin receptor |
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Recombinant erythropoietin is administered in which two clinical situations?
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1. End-stage renal failure
2. Anemia |
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Why is the biconcave disc shape of erythrocytes important?
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The biconcave shape is important for increasing surface area in order to facilitate gas exchange
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Why is it important for the red blood cell to be highly deformable?
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The RBC must be highly deformable to:
1. withstand mechanical stress in the capillaries 2. survive osmotic stress in the kidneys and other extremely hypertonic areas |
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What aspects of the red blood cell's biology gives it this flexibility?
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The cytoskeleton is what gives the RBC its flexibility
1. Spectrin: Gives the cortical actin network flexibility 2. Band 3: bicarbonate-chloride antiporter: attached via ankyrin & spectrin to the actin cytoskeleton 3. Glycophorin C: provides external negative charge: repel other cells & attached to the actin cytoskeleton |
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What happens when a red blood cell is no longer adequately deformable?
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When RBCs become rigid, they are sent to the spleen for digestion
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Know the general structure of heme?
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Heme is a porphyrin ring coordinated with one atom of iron
-Is 4 pyrrole rings joined by methylene bridges |
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What two important classes of proteins require heme?
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Hemoglobin, P450 (all cytochromes), and Myoglobin require heme
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If there is a defect in heme synthesis what clinical symptoms result from deficiencies of these proteins?
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Clinical symptoms from deficiencies in proteins with heme:
1. Anemia 2. Lack of energy/due to decreased amount of cytochrome 3. Neurological symptoms/due to build-up of toxic intermediates |
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The first enzyme in the heme synthesis pathway requires a cofactor. What is the cofactor?
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Vitamin B6 (pyridoxal phosphate) is the cofactor necessary for heme synthesis.
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What two effects does heme have on Vitamin B6?
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Heme exerts feedback inhibition on the enzyme/co-factor system
Heme also effects the production of Vitamin B6 |
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What is the effect of lead poisoning on heme synthesis?
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Lead poisoning inhibits two enzymes necessary for heme synthesis
1. Ferrochelatase 2. delta-ALA dehydratase |
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What is a porphyria, and what are its symptoms?
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Porphyria is a group of diseases that occur as a result of mutations in the enzymes of heme synthesis
--> they produce a build up of toxic intermediates that can cause various neurological symptoms |
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Pyruvate kinase deficiency is particularly devastating in rbc's because of what aspect of their cell biology?
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A loss of Pyruvate Kinase is very bad for RBCs because RBC's do not have mitochondria and can therefore only get ATP through PK
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What is the result of pyruvate kinase deficiency and how does this present clinically?
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The transporters cannot function efficiently and water is lost. ---> increased viscosity of the cytoplasm ---> RBC rigidity
This presents clinically as Hemolytic Anemia |
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What is the hexose monophosphate shunt?
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The Hexose Monophosphate Shunt is used to generate NADPH in order to reduce glutathione
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Why is the hexose monophosphate shunt critical to rbc's?
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Reduced glutathione protects the RBC from oxidative damage
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How does glucose-6-phosphate dehydrogenase deficiency present clinically?
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G6PD deficiency present with Hemolytic Anemia
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The NADH generated by glycolysis is used to reduce which critical protein in red blood cells?
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NADH is generated to reduce Cytochrome b5 in RBCs.
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Why is it important to reduce Cytochrome b5 in Red blood cells?
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Cytochrome b5 is crucial to RBCs because it reduces Fe3 hemoglobin to Fe2 hemoglogin
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Can Fe3 bind to oxygen when bound to hemoglobin?
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NO!
Fe3Hemoglobin can NOT bind to O2---> must be reduced to Fe2Hemoglobin! |
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What is 2,3 BPG?
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2,3 BPG is an allosteric modulator of hemoglobin
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What does 2,3 BPG do to hemoglobin, and why is this important for oxygen delivery to the periphery?
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1. It lowers the affinity of hemoglobin for oxygen
2. It allows oxygen to be more fully released in the peripheral tissue 3. The tissue wants the oxygen more than the hemoglobin does |
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Which subunits of adult hemoglobin does 2,3 BPg bind to?
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In adult hemoglobin, 2,3BPG binds to the beta subunits
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Which subunits of fetal hemoglobin does 2,3 BPG bind to?
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it does NOT bind to fetal hemoglobin because fetal hemoglobin does not have a beta subunit.
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How is 2,3 BPG important for oxygenation of fetal blood?
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By preventing the binding of 2,3 BPG to fetal hemoglobin, the mothers oxygen will readily diffuse to the fetal tissue and bind more readily (fetal tissue has a greater affinity for oxygen than the mothers hemoglobin does)
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How does increasing the concentration of hydrogen ions effect hemoglobin?
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Increasing hydrogen ion concentration lowers the affinity of hemoglobin for oxygen
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How does increasing the CO2 concentration effect hemoglobin?
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Increasing the CO2 concentration lowers the affinity of hemoglobin for oxygen even further than hydrogen ions
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Understand how CO2 concentration effects Hydrogen ion concentration.
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Hydrogen ion concentration drives CO2 concentration.
1. in peripheral tissues CO2 diffuses into the RBC 2. Carbonic anhydrase in the RBC hydrates CO2 to form carbonic acid 3. Carbonic acid rapidly dissociates into H+ and HCO3 --> the bicarbonate diffuses out of the RBC and into the plasma ---> the H+ ion binds to hemoglobin 4. Conformational change occurs that decreases the affinity for oxygen ---> oxygen is more completely released in the periphery 5. Carbonic anydrase is used to cleave HCO3 --> H2O + O2 6. CO2 is transported into the lungs as bicarbonate |
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Why does the concentration of plasma proteins affect the amount of fluid in the interstitial space?
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The osmotic pressure of the plasma proteins regulates fluid distribution
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What are the three phases of hemostasis?
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1. Clot formation (procoagulation)
2. Stopping the clot formation (anticoagulation) 3. Breaking up the clot (Fibrinolysis) |
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What triggers the start of anticoagulation mechanisms?
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Anticoagulation begins as a result of a need to stop the clotting system----> feedback regulation
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Platelets arise from what precursor cell?
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Platelets are derived from MEGAKARYOCYTES
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What physical process are platelets derived from?
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Platelets are budding off parts of the cytoplasm of the MEGAKARYOCYTE.
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Why do platelets have invaginations in their plasma membrane?
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The invaginations in the plasma membrane of platelets are important for increasing surface area ---> houses receptors and phospholipids important in the clotting reaction
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Why do platelets have an actin/myosin system?
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Platelets have an actin/myosin system to reconfigure the membrane upon activation
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When a blood vessel is injured its subendothelial matrix is exposed to blood. How do the components of this matrix contribute to platelet adhesion?
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von Willebrand Factor is a cell adhesion molecule expressed by endothelial cells to help them adhere to collagen in the basement membrane of blood vessels
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How do the components of the subendothelial matrix contribute to the initiation of the clotting cascade and anticoagulation?
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When the endothelium is injured in tissue factor and thrombin receptor, as well as, vWF & collagen from the subendothelial matrix are exposed to the bloodstream:
1GPIa (integrin a2b1) binds collagen 2. platelet changes shape from flat disc to sphere and extends pseudopods 3. GPIb binds vWF 4. This exposes membrane to GPIIb/GPIIIa (integrin allbblla) to fibrinogen and vWF ---> Some platelet adhesion and aggregation will cause some platelets to degranulate ---> ADP then reinforces the cycel |
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When a platelet degranulates it releases ADP, Calcium, serotonin, thromboxane A2, and Fibrinogen. What role do each of these play in the clotting process?
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ADP: reinforces the cycle
Calcium: is a co-factor Seratonin: causes vasoconstriction to reduce blood flow to the area Thromboxane A2: facilitates further aggregation Fibrinogen: activates fibrin |
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What happens to phosphatidylserine during platelet activation, and why is this important for proper clotting?
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As part of the activation process phosphatidylserine is flipped from teh cytoplasmic side to the outer leaflet side of the plasma membrane.
---> negatively charged phospholipid is crucial for localizing the clot |
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How does aspirin interfere with clotting?
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Aspiring is a COX inhibitor
----> blocks the synthesis of TXA2 |
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Fibrinogen molecules are mutually repulsive. What causes this, and what does thrombin do to the molecule to convert it to sticky fibrin?
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Glu and Asp residues in the N-terminal regions of the a and b chains cause fibrinogen molecules to repel each other
-Thrombin removes these negatively charged regions which allows fibrin to aggregate |
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Factor I
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Fibrinogen
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Factor II
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Prothrombin
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Factor III
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Tissue Factor
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Factor XIII
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Fibrin-stabalizing Factor
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Which of the pathways initiates clotting?
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The extrinsic pathway initiates clotting
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How does factor III contribute to the initiation of clotting?
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Factor III initiated clotting by being constantly ready
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What type of protein is factor III?
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Factor III is an integral membrane protein that does NOT need to be cleaved to be activated
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What types of proteins are Factors II, VII, IX, X and XI?
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They are serine proteases
-- breakdown serine amino acids |
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Factors V and VIII are referred to as co-factors, in their activated state, what do they do?
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Both V and VIII tether other factors to platelet membrane
--Both are activated by Thrombin |
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What is the enzymatic activity of factor XIII?
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Factor XIII is used in the process of making a soft clot into a hard clot.
---> It is a Calcium dependent transglutaminase. |
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What is a soft clot?
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A soft clot is an aggregation of Fibrin
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How is a soft clot converted to a hard clot?
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Thrombin cleaves factor XIII to XIIIa---> XIIIa crosslinks the fibrin of the soft clot in 3 dimensions to form the hard clot
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Vitamin K is required by the enzyme that gamma-carboxylates certain glutamate residues on clotting factors. Which clotting factors undergo this gamma-carboxylation?
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Factors VII, IX,X, and prothrombin undergo gamma-carboxylation
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Why is vitamin K necessary for gamma-carboxylation?
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Vitamin K acts as an electron donor
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If vitamin K is not available, what is the fate of the clotting factors involved in gamma-carboxylation?
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If there is not enough Vitamin K present, the factors are not carboxylated and not secreted
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What molecular interaction does the gamma-carboxyglutamate participate in? Why is this biologically important/
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gamm-carboxyglutamate binds to calcium, which in turns binds negatively charged phospholipids on the platelet's surface to form a coordination complex
---> Attaches the factor to the membrane |
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What is Tissue Factor Pathway Inhibitor & how does it work?
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1. Tissue Factor Pathway Inhibitor binds to and inhibits the TF-FVIIa-Calcium-FXa complex
-Domain 1 binds to FXa -Domain 2 binds to VIIa -Domain 3 is needed for endocytosis * after internalization the complex is degraded |
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Thrombomodulin, Protein C, and Protein S work together to slow down the clotting cascade. How do they interact and which clotting factors do they have?
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Thrombomodulin abolishes the clotting function through thrombin--> allows thrombin to activate Protein C ---> Activated Protein C binds to Protein S, which anchors it to the platelet surface and inactivates Factors VIII and V
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What type of protein is thrombomodulin?
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Thrombomodulin is an endothelial cell receptor
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What type of protein is Protein C?
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Protein C is a Serine Protease
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What is a serpin, and how does it work?
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Serpin is a Serine Protease Inhibitor
---> It works by mimicking the protease substrates ---> forms protease/inhibition complexes |
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What is fibrinolysis?
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Once a vascular leak is plugged further propagation of the clot needs to be prevented. Coagulation cascade needs to be turned off & Fibrinolysis turned on.
Fibrinolysis is done to prevent further propagation of a specific clot. |
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What roles do plasmin, plasminogen, tissue plasminogen activator play in fibrinolysis?
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1. Plasmin is a serine protease that degrades fibrin
2. Plasminogen, a serum protein that has a high affinity for fibrin, converted to plasmin by Tissue Plasminogen Activator (tPA) 3. tPA synthesized by vascular endothelial cell ---> it release is stimulated by activated Protein C |
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What is the clinical use of tPA?
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tPA is used clinically to dissolve clots during stroke or myocardial infarction
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Understand the mechanism of Warfarin (Coumadin).
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Coumadin is a Vitamin K antagonist. It prevents recycling of oxidized Vitamin K to its reduced form after its participated in carboxylation of VII, XI, X, & prothrombin
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Understand the mechanism of Heparin.
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Heparin makes anti-thrombin III a better looking substrate to thrombin so that thrombin binds to the ANT III forming a protease/inhibitor complex thus ending the clotting cascade
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Understand the mechanism of Bivalirudin.
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Bivalirudin is a direct thrombin inhibitor, that is reversible. It has a high affinity and specificity for thrombin.
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