Warfarin

Question 1

What is the mechanism of action of warfarin?

Answer 1

Warfarin inhibits vitamin K epoxide reductase (which is required for converting vitamin K into its active state), preventing gamma carboxylation of vitamin K, reducing synthesis of vitamin K dependent clotting factors, II, VII, IX, and X, and the natural anticoagulation proteins C & S.

Question 2

What are the main indications for warfarin therapy?

Answer 2

Atrial fibrillation, venous thromboembolism (VTE), DVT prophylaxis, mechanical heart valves, hypercoagulable disorders.

Question 3

How is warfarin administered?

Answer 3

orally

Question 4

What is Warfarin’s onset of action?

Answer 4

8-12 hours

Question 5

Which clotting factors are inhibited by warfarin?

Answer 5

Factors II, VII, IX, X, and anticoagulants protein C and protein S.

Question 6

Which coagulation pathway does warfarin impact most significantly?

Answer 6

Due to factor VII, the extrinsic pathway is most affected.

Question 7

Why does warfarin initially increase thrombosis risk?

Answer 7

Protein C and S have shorter half-lives than clotting factors, leading to a temporary hypercoagulable state.

Question 8

What test is used to monitor warfarin therapy?

Answer 8

Prothrombin Time (PT)/International Normalized Ratio (INR).

Question 9

What is the therapeutic INR range for most indications?

Answer 9

INR 2.0–3.0 for most indications; 2.5–3.5 for mechanical heart valves.

Question 10

What drugs increase warfarin effect (↑ INR)?

Answer 10

• CYP2C9 inhibitors (azoles, amiodarone).
• Microbiome alteration (Metronidazole, quinolones).
• Acetaminophen (reduces vitamin K recycling).

Question 11

What medications can alter warfarin due to disturbances of the gut microbiome?

Answer 11

These medications can INCREASE the effectiveness of warfarin:
- Metronidazole
- Quinolones

Question 12

How does amiodarone affect warfarin metabolism?

Answer 12

• Amiodarone inhibits CYP2C9, reducing warfarin metabolism and increasing INR.
• The warfarin dose should be reduced by 25-50%.

Question 13

What medications can alter warfarin due to Cyp2C9 inhibition?

Answer 13

These medications can INCREASE the effectiveness of warfarin:
- Azoles
- Amiodarone

Question 14

What medication is known to increase the effectiveness of warfarin due to increased vit K recycling?

Answer 14

Acetaminophen

Question 15

What drugs decrease warfarin effect (↓ INR)?

Answer 15

When a patient is taking any of these medications or has these dietary practices, increase the dose of warfarin:
- CYP2C9 inducers (rifampin, phenobarbital, phenytoin, St. John’s Wort).
- Oral contraceptives.
- Green leafy vegetables (↑ vitamin K intake).

Question 16

What dietary factors can reduce warfarin efficacy?

Answer 16

Increased vitamin K intake (e.g., green leafy vegetables) can decrease INR by increasing clotting factor synthesis.

Question 17

How do NSAIDs interact with warfarin?

Answer 17

NSAIDs increase bleeding risk by inhibiting platelet function but do not affect INR.

Question 18

What herbal supplements increase the bleeding risk associated with warfarin therapy?

Answer 18

Ginkgo biloba (unknown mechanism)
- Garlic
- Ginger

Question 19

How does warfarin compare to heparin in onset of action?

Answer 19

Warfarin has a delayed onset (3-5 days) due to the need to deplete existing clotting factors, while heparin acts immediately.

Question 20

What is the antidote for warfarin overdose?

Answer 20

• Limit or eliminate the dosage of warfarin.
• Give vitamin K for mild elevations and when PCC or FFP is given but has a 12-24 hour delay for effect.
• Give prothrombin complex concentrate (PCC) for life-threatening bleeding.
• Second-line reversal is fresh frozen plasma (FFP) and given if PCC is unavailable.

Question 21

What lab measurement dictates the degree of warfarin correction?

Answer 21

INR.

Question 22

For a patient on warfarin, what is the corrective action when INR is less than 4.5 but subtherapeutic (greater than 2-3)

Answer 22

Patients INR <4.5 and no clinical evidence of serious bleeding should have their warfarin held for 1 or 2 days and then restarted when the INR is in the therapeutic range.

Question 23

For a patient on warfarin, what is the corrective action when INR is between 4.5 and 10?

Answer 23

Patients with INR 4.5-10 and no serious bleeding should have their warfarin held and be given a low dose (1-2.5 mg) of oral vitamin K if there is an increased risk of future bleeding (eg, history of prior bleed).

Question 24

For a patient on warfarin, what is the corrective action when INR is greater than 10?

Answer 24

Patients with INR >10 and no serious bleeding should have their warfarin held and be given a higher dose (2.5-5 mg) of oral vitamin K.

Question 25

For a patient on warfarin, what is the corrective action when there is life-threatening bleeding?

Answer 25

Patients with serious bleeding, regardless of the INR, should have their warfarin held and receive intravenous vitamin K as well as prothrombin complex concentrate (PCC)

Question 26

Why must warfarin be bridged with heparin in acute thromboembolism?

Answer 26

Due to initial warfarin-induced hypercoagulability from protein C depletion, heparin prevents early thrombosis. Warfarin induced skin necrosis (WISN), which is also prevented using a heparin bridge.

Question 27

What genetic polymorphisms affect warfarin metabolism?

Answer 27

Polymorphisms in CYP2C9 (slower metabolism) and VKORC1 (altered warfarin sensitivity).

Question 28

What conditions increase warfarin sensitivity?

Answer 28

Liver disease (reduced clotting factor synthesis), congestive heart failure (reduced metabolism), advanced age.

Question 29

What is warfarin's effect on pregnancy?

Answer 29

Warfarin is teratogenic (contraindicated in pregnancy) and can cause fetal warfarin syndrome (nasal hypoplasia, stippled epiphyses).

Question 30

What is a major complication of warfarin therapy?

Answer 30

Warfarin-induced skin necrosis due to rapid depletion of protein C in patients with predisposing conditions (e.g., protein C deficiency).

Question 31

How does alcohol affect warfarin metabolism?

Answer 31

Chronic alcohol use induces CYP2C9 (↓ warfarin effect), while acute alcohol use inhibits CYP2C9 (↑ warfarin effect).

Question 32

What is the preferred anticoagulant in pregnancy?

Answer 32

Low molecular weight heparin (e.g., enoxaparin) is preferred over warfarin due to its safety profile.

Question 33

How does liver disease affect warfarin metabolism?

Answer 33

Liver disease decreases clotting factor synthesis, increasing INR and enhancing warfarin's anticoagulant effect.

Question 34

How should warfarin dosing be adjusted when starting amiodarone?

Answer 34

Warfarin dose should be reduced by 25-50% due to CYP2C9 inhibition by amiodarone.