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Anticoagulants, Plt Inhibitors, Fibrinolytics

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Answer
Anticoagulants   inhibit blood clotting cascade, prevent clot formation, toxicity = bleeding  
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Heparin, Warfarin (Coumadin), Factor 10a Inhibitors, Direct thrombin inhibitors   anticoagulants  
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clotting factors   circulating inactive protein produced by liver  
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factor 10   inactive in clotting cascade  
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factor 10a   active in clotting cascade, where intrinsic and extrinsic pathways meet, prothrombin (circulating PRO) to thrombin to fibrinogen to fibrin (final product)  
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Fibrin   insoluble, binds to plt plug wraps around it to form blood clot  
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blood vessel and tissue injury activates what?   clotting cascade  
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Can you have blood vessel injury w/o tissue injury?   Yes, HTN, DM, smoking, atherosclerosis  
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clotting cascade   need previous factor to activate next factor (if not cascade stops)  
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Why is calcium important for clotting?   play a role in clotting cascade, co-factor for prothrombin to thrombin  
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EDTA in tube for labs   binds to calcium in that tube to prevent clotting (traps calcium), keeps blood from clotting  
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Heparin anticoagulant   given IV, sulfated mucopolysaccharide, natural made, negatively charged, acidic, found in mast cells, heterogeneous, comes in different sizes and risks with same MOA, potent, used prophylaxis of thrombus, used in combo w/anti-plt for ACS & unstable angina  
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Unfractionated heparin (HMW-large polymer) anticoagulant   made by bovine lung and porcine gut, high affinity for antithrombin 3 1000x; speeds up (cofactor) inactivation of factor 10a and thrombin = greater risk of bleeding  
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LMW Heparin (enoxaparin-Lovenox)and Rivaroxban-Xarelto anticoagulant   made by gel filtration, selectively inhibit factor 10a, poorly inactivate thrombin = less risk and bleeding; wt. based; thrombin still active; greater therapeutic index  
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Fondaparinux (Arixtra) anticoagulant   made by synthetic pentasaccharide (5 sugar), no effect on thrombin, selectively inactivate factor 10 only; wt. based; thrombin still active  
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Heparin anticoagulant   act as a co-factor which enhance the actions of protease anti-thrombin 3, well-tolerated, immediate effects b/c its a co-factor of AT3 stimulating inactivation of clotting factors  
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Anti-thrombin 3 (AT3) function?   inactivate thrombin and factor 10a; inhibit clotting factors 2a, 9a, 10a (thrombin); inactivate factor 10a to factor 10 = shutting clotting cascade pathway down  
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Treatment for heparin toxicity - bleeding?   protamine sulfate - heparin antagonist, basic, + charged protamine binds with - charged heparin  
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HIT (heparin-induced thrombocytopenia)   pts on HMW for 7 days, autoimmune activation & destruction of plts = thrombotic disorder; hypercoagulable state  
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Whose at risk for HIT?   surgical, elderly pts, venous thrombosis increase w/ indwelling catheter, renal failure  
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Treatment of HIT?   d/c heparin, protamine sulfate, direct thrombin inhibitor, anticoagulant  
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Etiology of HIT   heparin binds to plt (hapten) which attracts IgG then IgG binds to plts activating the complement system to destroy (splenic macrophages) plts (thrombocytopenia); plt activation, plt release, plt aggregation = thrombosis  
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Which form of heparin is NOT reversed by protamine?   Warfarin (Coumadin) and Fondaparinux (Arixtra): LMW  
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Warfarin (PO) anticoagulant   oral anticoagulant, inhibits the regeneration of vit.K, inhibits liver vit.k reductase: cannot bring oxidized vit.k to reduced vit.k, prevents synthesis of 4 clotting factors: 2, 7, 9, 10  
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Vitamin K   essential co-factor for synthesis of clotting factors in the liver  
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Vitamin K reductase   takes oxidized form of vit.K and reduce it to make vit.k active  
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vitamins made by the body serve as what?   co-factors which are recycled  
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Oxidized vitamin K   cannot be used as a co-factor for clotting synthesis/factors  
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Warfarin (PO) anticoagulant   delays-cons: not seen for 18-24 hrs b/c there is clotting factors still in circulation; clotting factors already made need to be used up first which takes about 24 hrs; long half-life and given orally (PO); pros: 100% absorbed, 99% plasma PRO bound  
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warfarin Bound to plasma protein   inactive  
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warfarin displaced from plasma protein   active  
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y-glutamylcarboxylase   requires the presence of reduced vit.k  
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Warfarin anticoagulant   metabolized by liver CYP450, activated by liver CYP2C9, half-life 36 hrs, interact through plasma PRO displacement or CYP450 effects; do not during pregnancy (cross placenta bleeding in fetus)  
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Drugs that decrease warfarin effects   cholestyramine, barbs, rifampin, reduced vit.k, phenytoin, carbamazepine  
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Drugs that enhance warfarin effects   chloral hydrate, amiodarone, Plavix, ethanol, fluconazole, fluoxetine, metronidazole, sulfamethoxazole (TMP-SMX), broad-spectrum ABX (cephalosporins), anabolic steroids  
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what would reverse the effects of warfarin most quickly?   activated vitamin K (replaced the vit.k being blocked) and whole plasma b/c active clotting factors  
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Factor 10a inhibitors anticoagulants   Rivaroxban (Xarelto) LMW  
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Rivaroxban (Xarelto) anticoagulant, LMW   factor 10a inhibitor, PO, used for prevention of venous thrombosis following hip/knee replacement, a.fib, stroke, given as a fixed dose-no monitoring, more rapid onset, shorter half-life (10h) than warfarin  
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Direct thrombin Inhibitors anticoagulants   given IV; bind and block the active site of thrombin; hirudin (lepirudin), bivalirudin, argatroban, melagatran, ximelagatran, dabigatran  
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Hirudin (lepirudin) Direct thrombin Inhibitors anticoagulants   from leech saliva (recombinant lepirudin) bind to both catalytic and active site of thrombin  
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Bivalirudin Direct thrombin Inhibitors anticoagulants   approved for coronary angioplasty, bind to both catalytic and active site of thrombin  
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Argatroban, Melagatran Direct thrombin Inhibitors anticoagulants   used for HIT and angioplasty; bind only to thrombin active site  
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Ximelagatran Direct thrombin Inhibitors anticoagulants   first oral agent, removed from market r/t liver toxicity; pros: reversible, no effect on 10a  
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Dabigatran (PO) Direct thrombin Inhibitors anticoagulants   no antidote, pros: reversible, no effect on 10a  
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True/False Warfarin is the preferred anticoagulant in pregnant women   false-cross placenta leading to bleeding in the fetus  
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