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78 Cards in this Set
- Front
- Back
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What are the 4 antithrombotic mechanisms?
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1. inhibit thrombin generation
2. inhibit thrombin action 3. enhance clot breakdown 4. platelet inhibition |
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When do use anticoagulation strategies
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to treat or prevent recurrence of arterial or venous thrombosis
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What are 3 approaches to anticoagulation?
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1. inhibit thrombin generation
2. inhibit thrombin action 3. enhance endogenous inhibitor pathways |
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What are the indirect thrombin inhibitors? (2.5)
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1. Heparin
2. LMWH (enoxaparin, dalteparin) |
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What are the direct thrombin inhibitors? (4)
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1. Lepirudin
2. bivalirudin 3. argatroban 3. dabigatran |
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What makes indirect thrombin inhibitors indirect?
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require ATIII as a cofactor
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What makes indirect thrombin inhibitors unpredictable in their anticoag effect?
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Bind to plasma proteins, esp in presence of activated platelets
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What kind of thrombin do indirect thrombin inhibitors work on?
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Free thrombin, ie the thrombin not already in the clot
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What distinguishes the mechanism of LMWH from heparin?
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binds mostly to FXa (what ATIII usually binds)
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When is unfractionated heparin used?
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venous thrombosis and PE
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What are some disadvantages of unfractionated heparin? (4)
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1. IV or subq only
2. need liver and kidney to excrete 3. depend on ATIII, don't affect existing clot 4. need to monitor -- HIT |
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What is the risk of bleeding on heparin? what increases that risk? (4)
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5%, aspirin, age, liver disease, serious illness
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What are 3 adverse affects of heparin?
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1. osteoporosis
2. bleeding 3. HIT |
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How do you reverse bleeding on heparin?
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protamine
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What is the pathogenesis of HIT?
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develop Ab to heparin - PF4 complex, activates platelets, thrombocytopenia, clots and bleeds
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How do you treat HIT?
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discontinue heparin and use direct thrombin inhibitor (lepirudin/argatroban)
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Advantages of LMWHs over heparin? (5)
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1. longer t1/2
2. less risk of HIT 3. no need to monitor 4. enhanced anti Xa activity 5. safe in pregnancy |
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Where is LMWH cleared?
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kidney
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What are the 3 original LMWHs?
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1. enoxaparin
2. dalteparin 3. ardeparin |
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What is a synthetic LMWH?
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Fondaparinux
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When is fondaparinux used?
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after knee or hip surgery
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What are the direct thrombin inhibitors?
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1. Lepirudin
2. Bivalirudin 3. argatroban 4. dabigatran |
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Where does lepirudin act on thrombin?
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in the clots
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How is lepirudin excreted?
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kidneys
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When is lepirudin used?
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to treat HIT
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When is bivalirudin used?
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given IV to patients with unstable angina or PTCA
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How is argatroban excreted?
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liver
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When is argatroban used?
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HIT
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Are direct thrombin inhibitors reversible?
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no
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When is dabigatran used?
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a-fib (non-valvular)
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What is the MoA of warfarin?
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antagonized vit K activity in the liver blocking modification of factors 2, 7, 9, and 10, and Protein C and S
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How is warfarin given?
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PO
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How long after admin to peak warfarin concentration in blood?
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90 mins
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When is warfarin used?
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VTE, PE, cardiac emboli, a-fib, valve replacement, post MI
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How does vitamin K work on factors 2 7 9 10, C?
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carboxylates their glutamic acid, allows Ca++ to bind, interact with charged surfaces
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How long before warfarin takes effect?
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2 days (just affects synthesis)
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In what order does warfarin affect the factors?
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Protein C, 7, the rest
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How is warfarin metabolized?
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cytochromeP450, excreted in feces and urine
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what is warfarins t1/2?
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35 hrs
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How do you dose warfarin?
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start low and titrate up checking the PT/INR
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What is the target INR on warfarin?
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INR 2-3
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Which drugs potentiate anti-coag effect of warfarin by inhibiting metabolization? (4 +1)
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1. cimitidine
2. clofibrate 3. cotrimoxazole 4. metronidazole (grapefruit juice) |
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Which drugs potentiate warfarin without effecting levels (3)?
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heparin
aspirin NSAIDs |
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What drug impairs the absorption of warfarin?
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cholestyramine
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What drugs increase metabolic clearance of warfarin? (4)
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barbituates, rifampin, carbamazepine, alcohol
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Polymorphisms of what gene affects warfarin clearance?
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CYP2C9
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What is the risk of bleeding on warfarin?
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1-5% per year
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Above what INR are you at risk for hemorrhage on warfarin?
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INR 4
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What are some non-bleeding complications of warfarin (rare)?
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skin necrosis (overlap with heparin), N/V, jaundice, alopecia, rash
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How do you reverse warfarin?
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vit K (oral preferred), FFP
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How do you treat a DVT/PE?
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Start with UFH/LWMH for 5 days until INR >2, start warfarin on first day
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How long do you anticoagulate with reversible risk factor?
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3 months
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How long do you anticoagulate first unprovoked DVT?
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at least 3 mos
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How long do you anticoagulate PE, second unprovoked DVT?
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long-term
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How long do you anticoagulate a clot in a cancer patient?
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3-6 months of LMWH, followed by indefinite warfarin
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Describe the 4 steps of fibrinolysis?
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1. plasminogen binds to fibrin as it forms
2.fibrin stimulates endothelial cells to release tPA 3.tpa cleaves plasminogen to plasmin 4. plasmin breaks down fibrin releasing d-dimer |
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What are two endogenous inhibitors of fibrinolysis?
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1. alpha-2 antiplasmin inactivates unbound plasmin
2. plasminogen activator inhibitor (PAI) inactivates tPA |
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What is the purpose of fibrinolytic therapy?
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breakdown preexisting arterial or venous clot
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What are the three approaches to fibrinolytic therapy?
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1. directly enhance plasmin generation
2. indirectly enhance plasmin generation 3. enhance plasmin action |
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What fibrinolytic agents directly enhance plasmin generation? (3)
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tPA, streptokinase, urokinase
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When do you use fibrinolytics?
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MIs, thrombotic stroke w/in 3 hours, acute PAD, massive PE
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What does plasmin digest?
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fibrin, fibrinogen, factors 2, 5, 8
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What does streptokinase do?
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binds to plasminogen, cleaves to plasmin
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Where is streptokinase produced?
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B-hemolyltic Streptococci
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What is a modified streptokinase?
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anistreplase
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What are streptokinase AEs?
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1. bleeding
2. lytic state resistant to alpha-antiplasmin 3. antibodies to strep cause fevers, chills |
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What makes tPA specific to clots? 2
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1. fibrin important cofactor in cleaving plasminogen to plasmin
2. circulation PAI inactivates in plasma |
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What is alteplase?
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A human recombinant tPA
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What is reteplase?
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a recombinant human tPA that deletes the first 176 amino acids
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What are the three tPA drugs?
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ateplase
reteplase tenecteplase |
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What is tenecteplase?
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a modified tPA with longer t1/2 and greater specificity
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What is urokinase?
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a kidney enzyme that directly converts plasminogen to plasmin - manufactured from post-mortem kidneys
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What are some contraindications to thrombolytic therapy?
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active GI bleed, aortic dissection, head trauma, stroke, surgery, diabetic retinopathy
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What are two big pro-hemostatic approaches?
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1. recombinant factor 7a
2. anti-fibrinolytics |
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What are three ways recombinant factor 7a works?
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1. increases TF occupancy on damages cells
2. binds to activated platelets 3. activates factor X independent of tissue factor |
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What is an anti-fibrinolytic drug?
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aminocaproic acid
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When is aminocaproic acid used?
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adjunct therapy in hemolysis, fibrinolytic OD, intracranial aneurysm
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What does aminocaproic acid do?
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competitively inhibits plasminogen activation
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