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78 Cards in this Set

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What are the 4 antithrombotic mechanisms?
1. inhibit thrombin generation
2. inhibit thrombin action
3. enhance clot breakdown
4. platelet inhibition
When do use anticoagulation strategies
to treat or prevent recurrence of arterial or venous thrombosis
What are 3 approaches to anticoagulation?
1. inhibit thrombin generation
2. inhibit thrombin action
3. enhance endogenous inhibitor pathways
What are the indirect thrombin inhibitors? (2.5)
1. Heparin
2. LMWH (enoxaparin, dalteparin)
What are the direct thrombin inhibitors? (4)
1. Lepirudin
2. bivalirudin
3. argatroban
3. dabigatran
What makes indirect thrombin inhibitors indirect?
require ATIII as a cofactor
What makes indirect thrombin inhibitors unpredictable in their anticoag effect?
Bind to plasma proteins, esp in presence of activated platelets
What kind of thrombin do indirect thrombin inhibitors work on?
Free thrombin, ie the thrombin not already in the clot
What distinguishes the mechanism of LMWH from heparin?
binds mostly to FXa (what ATIII usually binds)
When is unfractionated heparin used?
venous thrombosis and PE
What are some disadvantages of unfractionated heparin? (4)
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
What is the risk of bleeding on heparin? what increases that risk? (4)
5%, aspirin, age, liver disease, serious illness
What are 3 adverse affects of heparin?
1. osteoporosis
2. bleeding
3. HIT
How do you reverse bleeding on heparin?
protamine
What is the pathogenesis of HIT?
develop Ab to heparin - PF4 complex, activates platelets, thrombocytopenia, clots and bleeds
How do you treat HIT?
discontinue heparin and use direct thrombin inhibitor (lepirudin/argatroban)
Advantages of LMWHs over heparin? (5)
1. longer t1/2
2. less risk of HIT
3. no need to monitor
4. enhanced anti Xa activity
5. safe in pregnancy
Where is LMWH cleared?
kidney
What are the 3 original LMWHs?
1. enoxaparin
2. dalteparin
3. ardeparin
What is a synthetic LMWH?
Fondaparinux
When is fondaparinux used?
after knee or hip surgery
What are the direct thrombin inhibitors?
1. Lepirudin
2. Bivalirudin
3. argatroban
4. dabigatran
Where does lepirudin act on thrombin?
in the clots
How is lepirudin excreted?
kidneys
When is lepirudin used?
to treat HIT
When is bivalirudin used?
given IV to patients with unstable angina or PTCA
How is argatroban excreted?
liver
When is argatroban used?
HIT
Are direct thrombin inhibitors reversible?
no
When is dabigatran used?
a-fib (non-valvular)
What is the MoA of warfarin?
antagonized vit K activity in the liver blocking modification of factors 2, 7, 9, and 10, and Protein C and S
How is warfarin given?
PO
How long after admin to peak warfarin concentration in blood?
90 mins
When is warfarin used?
VTE, PE, cardiac emboli, a-fib, valve replacement, post MI
How does vitamin K work on factors 2 7 9 10, C?
carboxylates their glutamic acid, allows Ca++ to bind, interact with charged surfaces
How long before warfarin takes effect?
2 days (just affects synthesis)
In what order does warfarin affect the factors?
Protein C, 7, the rest
How is warfarin metabolized?
cytochromeP450, excreted in feces and urine
what is warfarins t1/2?
35 hrs
How do you dose warfarin?
start low and titrate up checking the PT/INR
What is the target INR on warfarin?
INR 2-3
Which drugs potentiate anti-coag effect of warfarin by inhibiting metabolization? (4 +1)
1. cimitidine
2. clofibrate
3. cotrimoxazole
4. metronidazole

(grapefruit juice)
Which drugs potentiate warfarin without effecting levels (3)?
heparin
aspirin
NSAIDs
What drug impairs the absorption of warfarin?
cholestyramine
What drugs increase metabolic clearance of warfarin? (4)
barbituates, rifampin, carbamazepine, alcohol
Polymorphisms of what gene affects warfarin clearance?
CYP2C9
What is the risk of bleeding on warfarin?
1-5% per year
Above what INR are you at risk for hemorrhage on warfarin?
INR 4
What are some non-bleeding complications of warfarin (rare)?
skin necrosis (overlap with heparin), N/V, jaundice, alopecia, rash
How do you reverse warfarin?
vit K (oral preferred), FFP
How do you treat a DVT/PE?
Start with UFH/LWMH for 5 days until INR >2, start warfarin on first day
How long do you anticoagulate with reversible risk factor?
3 months
How long do you anticoagulate first unprovoked DVT?
at least 3 mos
How long do you anticoagulate PE, second unprovoked DVT?
long-term
How long do you anticoagulate a clot in a cancer patient?
3-6 months of LMWH, followed by indefinite warfarin
Describe the 4 steps of fibrinolysis?
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
What are two endogenous inhibitors of fibrinolysis?
1. alpha-2 antiplasmin inactivates unbound plasmin
2. plasminogen activator inhibitor (PAI) inactivates tPA
What is the purpose of fibrinolytic therapy?
breakdown preexisting arterial or venous clot
What are the three approaches to fibrinolytic therapy?
1. directly enhance plasmin generation
2. indirectly enhance plasmin generation
3. enhance plasmin action
What fibrinolytic agents directly enhance plasmin generation? (3)
tPA, streptokinase, urokinase
When do you use fibrinolytics?
MIs, thrombotic stroke w/in 3 hours, acute PAD, massive PE
What does plasmin digest?
fibrin, fibrinogen, factors 2, 5, 8
What does streptokinase do?
binds to plasminogen, cleaves to plasmin
Where is streptokinase produced?
B-hemolyltic Streptococci
What is a modified streptokinase?
anistreplase
What are streptokinase AEs?
1. bleeding
2. lytic state resistant to alpha-antiplasmin
3. antibodies to strep cause fevers, chills
What makes tPA specific to clots? 2
1. fibrin important cofactor in cleaving plasminogen to plasmin
2. circulation PAI inactivates in plasma
What is alteplase?
A human recombinant tPA
What is reteplase?
a recombinant human tPA that deletes the first 176 amino acids
What are the three tPA drugs?
ateplase
reteplase
tenecteplase
What is tenecteplase?
a modified tPA with longer t1/2 and greater specificity
What is urokinase?
a kidney enzyme that directly converts plasminogen to plasmin - manufactured from post-mortem kidneys
What are some contraindications to thrombolytic therapy?
active GI bleed, aortic dissection, head trauma, stroke, surgery, diabetic retinopathy
What are two big pro-hemostatic approaches?
1. recombinant factor 7a
2. anti-fibrinolytics
What are three ways recombinant factor 7a works?
1. increases TF occupancy on damages cells
2. binds to activated platelets
3. activates factor X independent of tissue factor
What is an anti-fibrinolytic drug?
aminocaproic acid
When is aminocaproic acid used?
adjunct therapy in hemolysis, fibrinolytic OD, intracranial aneurysm
What does aminocaproic acid do?
competitively inhibits plasminogen activation