What is warfarin?

What is Warfarin

Warfarin is an oral anticoagulant medication that works by inhibiting vitamin K-dependent clotting factors (II, VII, IX, and X) through blockade of the vitamin K epoxide reductase enzyme complex (VKORC1), thereby preventing blood clot formation. 1

Mechanism of Action

Warfarin interferes with the vitamin K cycle by inhibiting the C1 subunit of VKORC1, which prevents regeneration of vitamin K1 epoxide and blocks the synthesis of functional clotting factors. 1 This results in:

• Sequential depression of clotting factors based on their half-lives: Factor VII (4-6 hours) decreases first, followed by Factor IX (24 hours), Factor X (48-72 hours), and Factor II/prothrombin (60-72 hours). 2, 1
• Reduction in anticoagulant proteins C and S (half-lives of 8 and 30 hours respectively), which can transiently create a prothrombotic state early in therapy. 1
• The antithrombotic effect requires 6 days to fully develop, as it depends primarily on reducing prothrombin levels, not just achieving an elevated INR. 2

Chemical Properties and Pharmacokinetics

Warfarin is a racemic mixture of R- and S-enantiomers with distinct properties: 1

• The S-enantiomer is 2-5 times more potent than the R-enantiomer and is primarily metabolized by CYP2C9. 3, 1
• Essentially 100% oral bioavailability with peak concentrations within 4 hours. 1
• 99% protein-bound (mainly to albumin), creating potential for drug displacement interactions. 1
• Elimination half-life of 36-42 hours for racemic warfarin, with duration of action of 2-5 days after a single dose. 1

Clinical Indications

According to the FDA label, warfarin is indicated for: 1

• Prophylaxis and treatment of venous thrombosis and pulmonary embolism
• Prevention of thromboembolic complications associated with atrial fibrillation and cardiac valve replacement
• Reduction of death, recurrent MI, and thromboembolic events (stroke, systemic embolization) after myocardial infarction

Additional guideline-supported indications include: 2

• Prevention of systemic embolism in high-risk patients with mitral stenosis
• Prevention of venous thromboembolism after major orthopedic or gynecologic surgery (target INR 2.0-3.0)
• Secondary prevention in patients with prosthetic mechanical heart valves

Therapeutic Monitoring

The target INR range for most indications is 2.0-3.0, which represents moderate anticoagulation intensity. 2 Key monitoring principles include:

• The PT/INR reflects mainly Factor VII reduction in the first few days, then Factors X and II contribute subsequently. 2
• Heparin overlap for 4-5 days is mandatory when treating acute thrombosis, as the anticoagulant effect (elevated INR) develops before the antithrombotic effect (reduced prothrombin). 2
• Start with maintenance doses (5 mg daily) rather than loading doses, as loading doses (10 mg) cause excessive anticoagulation without faster prothrombin reduction. 2

Genetic Factors Affecting Dosing

CYP2C9 and VKORC1 polymorphisms account for approximately 40% of warfarin dosing variability. 2, 3

• CYP2C92 and CYP2C93 variant alleles reduce S-warfarin clearance by 37% (one variant allele) or 69% (two variant alleles), requiring 17% and 37% lower doses respectively. 3, 1
• VKORC1 gene polymorphisms affect the pharmacodynamic target and influence dose requirements. 2, 3
• Patients with variant alleles have increased bleeding risk and require more cautious dose titration. 2

Major Drug Interactions

Warfarin has numerous clinically significant interactions: 2, 4

Drugs that reduce warfarin clearance and potentiate effects:

• Second- and third-generation cephalosporins (inhibit vitamin K cycle) 2, 4
• Amiodarone, metronidazole, trimethoprim-sulfamethoxazole, ciprofloxacin (inhibit CYP2C9) 4
• SSRIs, particularly fluvoxamine and fluoxetine 4
• Acetaminophen >2g/day (can significantly increase INR by day 3) 4

Drugs that increase bleeding risk without affecting INR:

• Aspirin and NSAIDs (inhibit platelet function and cause gastric erosions) 2
• High-dose penicillins and moxalactam 2

When initiating CYP2C9 inhibitors in stable patients, consider preemptive warfarin dose reductions of 20-33% and increase INR monitoring frequency. 4

Important Clinical Pitfalls

• Alcohol ingestion inhibits hepatic enzymes and can significantly increase INR levels. 4
• Hepatic dysfunction potentiates warfarin response through both impaired synthesis of clotting factors and decreased drug metabolism. 2, 4
• Fluctuating dietary vitamin K intake (from green vegetables or supplements) can counteract warfarin's effect, while reduced intake (in sick patients on antibiotics and IV fluids) potentiates it. 2
• Warfarin-induced skin necrosis (occurring days 3-8 of therapy) is associated with protein C deficiency and requires restarting at very low doses (2 mg daily) with concurrent heparin if anticoagulation must continue. 2
• High-intensity anticoagulation (INR 3.0-4.5) is dangerous in patients with cerebral ischemia of arterial origin, causing significantly more intracranial bleeding than aspirin. 2