hemostasis II – Flashcards
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| what is thrombopoietin (TPO)? |
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| the factor for hematopoietic stem cells to go toward toward megakaryocytes |
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| how do megakaryocytes produce platelets? |
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| endomitosis, the nucleus is replicated but the DNA remains intact and starts sloughing off cells -> platelets |
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| where is TPO produced? |
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| in the bone marrow, liver and kidney. (EPO produced in the kidney) |
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| what is the receptor for TPO? |
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| CMPL |
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| how are platelets activated? |
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| ADP is released by many platelets and received by P2Y1 and P2Y12 which then through signal cascades changes the conformation of GpIIb/IIIa causing it to bind fibrinogen |
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| what does platelet receptor GpIb/V/XI bind? |
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| vWF and endothelium |
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| what is glanzmann thrombasthenia? |
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| a deficiency in GpIIb/IIIa, which keeps the platelets from aggregating b/c they have to bind to fibrinogen to bind to each other. (a similar effect would be seen with afibrinogenemia) |
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| what is bernard soulier syndrome? |
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| a deficiency in GpIb; therefore platelets cannot adhere to the subendothelium. (similar to vWD, where platelets cannot adhere to the endothelium) |
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| what is the specific amino acid sequence both GpIb and GpIIb/IIIa bind to in fibrinogen and vWF? |
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| RGD: arginine, glycine, aspartate |
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| what is an additional function of vWF? |
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| carrying/protecting factor VIII - so a vWF is similar to hemophila A |
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| what is ADAMTS-13? |
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| a metalloprotease that cleaves vWF (a large multimeric protein produced by endothelial cells), which is itself made in the liver. ADAMTS-13 is the major regulator for vWF size and provides protection against uncontrolled platelet adhesion. |
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| how can a deficiency in ADAMTS-13 cause thrombocytopenia? what is this condition called? |
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| an ADAMTS-13 deficiency is called thrombotic thrombocytopenia purpura and in this case, the platelts are all adhering to large vFW fragments on the subendothelium/aggregations and are not present in general circulation |
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| what causes ADAMTS-13 to cut vWF into smaller pieces? |
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| high shear stress |
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| what two granules do platelets have? |
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| alpha (PF4, vWF, etc) and dense granule (ADP etc) |
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| what is grey platelet syndrome? |
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| large platelets that do not have alpha granules |
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| where do prostaglandins come from? |
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| phospholipase A2 cuts arachidonic acid from the #2 position, COX on platelets make the prostaglandin TXA2 while COX on endothelial cells will make PGI2(prostacyclin). (TXA2 is one of the most potent vasoconstrictors known) |
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| if you eat more omega-6 FA's such as arachidonic acid, what eicosanoids will be produced in greater number? |
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| series 2 prostaglandins (TXA2/PGI2), and series 4 leukotrienes |
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| if you eat more omega-3 FA's such as EPA (eicosapentanoic acid), what eicosanoids will be produced in greater number? |
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| series 3 prostaglandins (antiinflammatory), series 5 leukotrienes |
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| what omega # is linoleic acid? is there a correlation with cardiovascular disease? |
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| omega 6; of which there is a INVERSE correlation with cardiovascular disease with (it may decrease the risk of CVD) |
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| what omega # is linolenic acid? what is it said to do? |
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| omega 3; which should decrease the amount of pro-inflammatory cytokines (TNF-alpha, IL-1, and IL-6) and also decrease CVD |
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| what happens to platelet membranes that PLA2 has cleaved all the arachidonic acid from? |
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| the phospholipids missing an arachidonic acids "flip out" causing the surface to be negatively charged - allowing them to ready for coagulation |
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| what is found on the surface of platelets when activated? |
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| once activated, integrins form a "surface raft" which help the platelet by allowing for stronger surface interatction/signalling events |
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| what are platelet microparticles (PMP)? |
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| these are tiny particles released from cells (including platelets) during apoptosis that have a negative charge which is pro-coagulant/thrombogenic. tissue factor is also found on these microparticles in encrypted form. |
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| what is the shape change that occurs when platelets are activated? |
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| round to discoid |
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| what is the platelet cytoskeleton composed of? |
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| actin and myosin which help tighten up the shape of activated platelets |
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| what are 2 diseases causing defects in platelet adhesion? |
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| bernard soulier disease which is a lack of GpIb/IX/V and vWF deficiency |
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| what are 2 diseases causing problems in platelet aggregation? |
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| glanzmann's (missing GpIIb/IIIb) or afibrinogenemia |
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| what is wiskott-aldrich? |
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| X-linked mutation in WASP, causing hereditary thrombocytopenia |
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| what is an example of a storage pool disease? |
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| grey platelet syndrom |
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| what usually causes TTP? what is the platelet cut off where it has to be considered? |
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| ADAMTS-13, but also infection/autoantibodies. 140,000 is the platelet cut-off |
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| what is essential thrombocythemia? |
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| a rare myeloid neoplastic disorder where there are too many platelets (platelets are abnormal in size and aggregate quickly and inappropriately), pts w/this tend to bleed slightly more. it can be treated with warfarin long term |
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| what does the blood coagulation cascade start with? |
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| the extrinsic, then later it shifts to the intrinsic |
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| what part of the coagulation cascade is associated with the phospholipid surface, platelets, and blood vessels? |
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| the intrinsic pathway |
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| what part of the coagulation cascade is associated with phospholipids and tissue factor? |
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| the extrinsic pathway |
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| what part of the coagulation cascade is associated with thrombin and fibrin clot formation? |
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| the common pathway |
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| what is the key to activation of the coagulation system? |
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| thrombin, which provides feedback activations |
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| what are the 3 things that can activate factor XI in the intrinsic pathway? |
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| XII, VII and thrombin |
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| what 2 things activate factor IX? |
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| factor XI and VII |
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| what 2 factors activate factor X? |
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| VII and IX |
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| what complex shifts the coagulation cascade to the intrinsic system? |
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| tissue factor pathway inhibitor which inhibits the complex of factor VII, tissue factor, and factor X. increased thrombin concentration then activates the intrinsic side through feedback loops |
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| where is tissue factor found in it's inactive state? |
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| tissue factor is an (internal/external) integral membrane protein usually expressed by extravascular cells (esp heart, lungs, testes, uterus, placenta) and encoded on microparticles. it is separated by a primary hemostatic barrier on blood vessels, but following injury it rapidly activates blood coagulation |
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| what is the structure of fibrinogen? where does thrombin cleave? |
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| a mustache where alpha/beta/gama are at each end, gamma points down in the middle where the mouth would be and the alpha/beta chains point up into where the nose would be <- where thrombin cleaves, and once i does = fibrin |
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| what is a fibrin soft clot? |
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| when thrombin cleaves the center alpha and beta chains, this spot gets sticky and it binds to the ends of other fibrin molecules non-covalently |
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| how do soft fibrin clots become hard? |
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| factor XIII crosslinks (ligase between a lysine and a glutamine) adjacent fibrin molecules after being activated by thrombin |
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| what are the procoagulant properties of thrombin? |
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| platelet activation (via integrin), activates factors V, VIII as well as XI and VII, it converts fibrinogen to fibrin and activates factor XIII |
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| what is the lupus antiphospholipid antibody? |
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| people with this have no (or very minor) bleeding disorder, however, their blood is slow to clot in a test tube and they will have a prolonged PTT (b/c antibodies block the phospholipids which are part of the test). in severe cases, this can be treated with oral anticoagulants |
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| how do you determine if someone has phospholipid antibodies? |
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| russel's viper venom activates factor X directly (bypasses blood clotting cascade to test factor X) |
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| how do thrombin and endothelial cells inhibit thrombosis? |
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| thrombin is inactivated by antithrombin III, and endothelial cells provide heparin to potentiate this |
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| how do endothelial cells inactivate factors X and VII? |
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| via tissue factor pathway inhibitor |
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| how do endothelial cells inhibit platelet aggregation? |
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| release of PGI2, NO and ADP phosphatase |
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| how do endothelial cells activate the fibrinolytic system? |
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| by releasing tissue plasminogen activator |
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| how is protein C activated? what does it do? |
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| protein C is activated when thrombin binds to thrombomodulin as expressed by endothelial cells at the correct time. this complex activates protein C which then inactivates factor V and VIII |
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| what does tissue factor pathway inhibitor inhibit? |
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| extrinsic factor X activation, which needs the complex to act |
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| what causes factor V leiden? what happens as as result? |
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| arg->gln mutation. the factor V leiden mutation leads to protein C resistance by factor V, leading to more clotting than usual (5-7x increased risk of thromboembolism) |
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| what are 2 inhibitors in the thrombolytic system? |
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| plasmin activator inhibitor and plasmin inhibitor <- both will allow the clot to remain/continue to form |
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| what are some thrombolytic therapy agents? how are they administered? |
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| streptokinase, urokinase, t-PA (tissue plasminogen activator, alteplase) and recombinant t-PA. these are delievered by catheter to the area of the clot except with pulmonary embolisms (b/c it will dilute the drug and break up other possibly necessary clots) |
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| what kind of protein are factors XII, XI, X, II, VII, plasmin, C1, elastase, and trypsin? what inactivates these? |
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| serine proteases which have 3 AAs in their active site; aspartate, histadine and serine. these are inactivated by serpins which are produced in the liver, circulate the blood and suicide inhibit serine proteases and clear them from circulation |
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| what are serpins/hemostatic inhibitors that block clotting? |
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| ATIII, C1inh, alpha1 protease inh |
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| what are serpins/hemostatic inhibitors that block fibrinolysis? |
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| plasminogen activator inhibitors (PAI), and plasmin inhibitors |
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| what are serpins/hemostatic inhibitors that shift reactions? |
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| TFPI shifts from extrinsic to intrinsic |
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| what does heparin do (2 things)? |
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| binds to antithrombin III and enhances its inhibitory activity by changing its conformation and folding out and drawing targets in |
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| what are benefits of LMW heparin? |
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| higher anti Xa/IIa activity ratio (inhibits thrombin generation, not just thrombin activity), it has a longer half life, it is more uniform/predictive, it may not react with protamine as an antidote, and it has a ****lower association with HIT |
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| are there any benefits of unfractionated heparin? |
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| it may be better for obese, elderly, renally insufficient, and pregnant pts |
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| does LMW heparin have less of a chance of causing HIT? |
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| yes |
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| what is HIT? |
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| a highly prothrombotic, hypercoagulable disorder (not hemorrhagic), caused by exposure to heparin in complex with PF4 on the platelet surface, resulting in an immune rxn -> leading to a systemic thrombotic response (venous 4x more common) |
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| what is hirudin? |
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| a direct thrombin inhibitor that is unaffected by platelet factor 4 and inactivates thrombin bound to fibrin -> more predictable anticoagulant response (derived from leeches) |
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| what can snake venoms do in terms of coagulation? |
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| snake venom can initiate consumption of coagulant substances and; produce a protease that directly hydrolyses prothrombin, directly clots fibrinogen, activates platelets (kills small mammals by overclotting) and activates endothelial cells to produce a plasminogen activator (fibrinolysis) |
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| what happens in DIC? |
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| in disseminated intravascular coagulation, there is consumption of all the platelets and coagulation factors resulting in extreme bleeding somewhere else |
