CHEST-2012 Oral Anticoagulants Flashcards
MOA of anticoagulant effect of Vitamin K Antagonists
Interfere with the cyclic interconversion of Vitamin K via enzyme Vit K epoxide reductase (VKOR) –> decreases formation of coagulation factors II, VII, IX, X
VKAs produce their anticoagulant effect by interfering
with the cyclic interconversion of vitamin K
and its 2,3 epoxide (vitamin K epoxide), thereby
modulating the g -carboxylation of glutamate residues
(Gla) on the N-terminal regions of vitamin K-dependent
proteins ( Fig 1 ). 1-8 The vitamin K-dependent coagulation
factors II, VII, IX, and X require g -carboxylation
for their procoagulant activity, and treatment with
VKAs results in the hepatic production of partially
carboxylated and decarboxylated proteins with reduced
coagulant activity. 9,10 Carboxylation is required for a
calcium-dependent conformational change in coagulation
proteins 11-13 that promotes binding to cofactors
on phospholipid surfaces.
MOA of procoagulant effect of VKA
VKAs inhibit carboxylation of the regulatory anticoagulant proteins C, S
Transient procoagulant effect caused when baseline anticoag protein C and protein S levels are reduced before the other procoag factors are decreased
Peak warfarin drug level after oral administration
90 minutes after administration
Half-life of racemic warfarin
36-42hr half-life
Which warfarin enantiomer is more potent?
S-enantiomer (about 3-4 times more potent than R)
Genetic mutations of which CYP enzyme has most interactions with warfarin metabolism
CYP2C9 (most mutations result is reduced S-warfarin clearance –> prolongs half-life of S enantiomer)
Genetic mutations of — can lead to increased warfarin resistance
VKORC1. Mutations on this gene lead to decreased warfarin effects on the Vitamin K cycle, so higher doses will be required to achieve goal INR
Why is the PT test used to monitor VKA therapy?
PT responds to changes in 3 of the 4 factors reduced by warfarin (II, VII, and X)
PT measured in the first few days of therapy represents a reduction of which clotting factor?
Factor VII (half-life is only 6 hours)
Half-life of factor II is 60 hours
Half-life of factor X is 48-72 hours
Formula for INR calculation
INR = (patient’s PT/mean normal PT)^ISI of thromboplastin
Effect of gender on warfarin dosing
Generally women need less warfarin to maintain INR than men at equivalent age
Effect of physical activity on warfarin dosing
Increased physical activity can decrease warfarin’s anticoag effect –> require more warfarin to maintain INR
How does POC INR testing work
POC monitor measures thromboplastin-mediated clotting time, and microprocess converts the time into a PT/INR result
Uses capillary blood or venous blood
Time of effect of Vitamin K
Begins at 2 hours after administration, INR correction within 24 hours
Dose equivalent of IV vs oral Vitamin K at 24 hours
Effect on INR of 5mg oral = 1mg IV vitamin K at 24 hours
How to minimize anaphylatoid reaction to IV vitamin K
Mix in 50mL bag of IV fluid, administer over 20 mins at least
Benefits of prothrombin complex concentrates (PCC) over fresh frozen plasma (FFP) when reversing warfarin
FFP can carry infective agents, cause volume overload, requires cross-match, requires time to thaw and administer. Must also be given Vitamin K.
PCC do not need cross-match, no risk of volume overload, infusion time of 15-30 minutes
Forms of PCC
3-factor product (contains good amount of II, IX, X and little VII)
4-factor product (contains good amount of II, VII, IX, X, and Proteins C and S)
Brand name of 4-factor PCC
Kcentra
When to use recombinant activated factor VII
For life-threatening bleeding if other effective agents are not available
Factor VIIa generates thrombin burst via intrinsic and extrinsic pathways –> does not need platelets so good for patients with low platelet function
Serious adverse effects of warfarin
Hemorrhage, skin necrosis, limb gangrene, purple toe syndrome
Cause of warfarin skin necrosis and limb gangrene
Skin necrosis: thrombosis of venules/capillaries with subcutaneous fat
Limb gangrene: outflow obstruction of venous circulation
Usually seen with protein C deficiency
How to manage skin necrosis or limb gangrene with warfarin
Restart warfarin at a low dose while bridging with parenteral agent, then gradually increase warfarin dose over 1 week or more.
Goal is to avoid abrupt fall in Protein C levels before the other clotting factors are reduced
What is purple toe syndrome
Occurs during initiation of VKA therapy, about 3-8 weeks after starting
Sudden appearance of bilateral, painful purple lesions on the toes and sides of feet that blanch with pressure
Nonhemorrhagic cutaneous complication due to cholesterol emboli
How to manage purple toe syndrome
Stop warfarin, initiate LMWH.
Possibly consider using a NOAC
Effect of warfarin on fetal bone formation
Warfarin interferes with carboxylation of Gla proteins synthesized in bone –> results in fetal bone abnormalities
Oral direct thrombin inhibitor
Dabigatran
Why dabigatran must be given orally as a prodrug
Active molecule is strongly polar and can’t be absorbed by the gut. Must be in prodrug form (dabigatran etexilate) to be absorbed. After absorption, serine esterases convert it to dabigatran via ester cleavage)
Does dabigatran cause reversible or irreversible inhibition of thrombin?
Reversible inhibition
Half-life of dabigatran
12-17 hours
Time for dabigatran to reach steady-state levels
2-3 days (and why it needs to be bridged)
Elimination mechanism of dabigatran
Renal elimination
Factors that affect absorption of dabigatran etexilate
Gastric pH (so PPIs, postoperative state, and P-glycoprotein inhibitors/inducers will interact)
Increasing gastric pH decreases absorption of dabi
P-glyco inhibitors will increase dabi exposure
P-glyco inducers will decrease dabi exposure
Role of CYP450 enzymes on dabigatran
No effect on dabi’s metabolism
Incidence of GI bleed of dabi vs warfarin
More GI bleed with dabi than with therapeutic warfarin
Reverse bleeding with dabigatran
Idarucizumab (Praxbind)
