warfarin

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mechanism

• Inhibits vitamin K epoxide reductase (VKORC1) → depletes vitamin K–dependent clotting factors (II, VII, IX, X) and proteins C and S
• Onset delayed 3–5 days (depends on factor VII/II half-lives)

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dosing

Indication	INR target
AF, VTE, bioprosthetic valve	2.0–3.0
mechanical mitral valve	2.5–3.5
mechanical aortic valve (newer bileaflet)	2.0–3.0

• Initiate with heparin bridge until INR therapeutic on two consecutive measurements ≥24h apart
• Typical starting dose 5 mg daily; lower (2–3 mg) if elderly, malnourished, liver disease, or known CYP2C9/VKORC1 polymorphisms
• Adjust dose based on INR checked every 1–3 days initially, then weekly, then every 4–6 weeks when stable

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key points

• Mandatory for mechanical heart valves — DOACs contraindicated
• Numerous drug interactions via CYP2C9, CYP3A4, CYP1A2: amiodarone (↑INR), rifampicin (↓INR), azole antifungals (↑INR), many others
• Dietary vitamin K intake (leafy greens) affects INR — counsel on consistent intake, not avoidance
• Protein C/S depletion occurs before anticoagulant effect → transient hypercoagulable state at initiation (risk of skin necrosis, especially in protein C deficiency) — always bridge with heparin

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reversal

Urgency	Approach
Life-threatening bleeding	4-factor PCC + vitamin K 10 mg IV
Serious bleeding (non-life-threatening)	vitamin K 5–10 mg IV; consider PCC
INR >10, no bleeding	hold warfarin + vitamin K 2.5–5 mg PO
INR 4.5–10, no bleeding	hold 1–2 doses; consider vitamin K 1–2 mg PO

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adverse effects

• Bleeding (GI, intracranial, surgical site)
• Skin necrosis (protein C deficiency — typically days 3–8)
• Teratogenic (first trimester: nasal hypoplasia, stippled epiphyses; any trimester: CNS abnormalities) — use LMWH in pregnancy
• Calciphylaxis (rare, typically in CKD/dialysis patients)