Anticoagulant
Warfarin (Coumadin)
Also called Coumadin
Watch the explainer
Heparin vs Warfarin: aPTT vs INR, HIT, Bridging, Antidotes and DOAC Reversal
Indications
- Mechanical heart valves, where DOACs are contraindicated
- Atrial fibrillation, including with mitral stenosis or valve replacement
- Treatment and secondary prevention of DVT and PE
- After MI, to reduce death, reinfarction and embolism
- Thrombotic antiphospholipid syndrome, where DOACs do worse
- LVAD support (off-label)
On the quick cards
Mechanism of action
Warfarin inhibits VKORC1, the vitamin K epoxide reductase subunit that regenerates reduced vitamin K after each use. Without it, γ-glutamyl carboxylase cannot add the Gla residues that let factors II, VII, IX and X and proteins C and S bind calcium and phospholipid, so the liver releases inactive proteins. Circulating factors are untouched, so the effect builds as each one clears, and an established clot is not affected.
Pharmacology
- Hematologic: factors fall in order of half-life (VII 4–6 h, IX 24 h, X 48–72 h, II about 60 h); the early INR rise is factor VII, but protection needs prothrombin to fall, about 5 days
- Hematologic: protein C (half-life about 8 h) falls first, a hypercoagulable window that causes skin necrosis, or venous limb gangrene in acute HIT
- Skin, vessels and kidney: calciphylaxis, cholesterol microemboli (purple toes) and AKI with excess anticoagulation
- Fetal: crosses the placenta; first-trimester exposure causes embryopathy (nasal hypoplasia, stippled epiphyses) in about 5%
Pharmacokinetics
| Onset | INR effect within 24 h, clear by 2–3 days |
|---|---|
| Peak | 72–96 h; full antithrombotic effect about 5 days |
| Duration | 2–5 days; stop 5 days before surgery |
| Half-life | 20–60 h (mean about 40 h); S 21–43 h, R 37–89 h |
| Distribution | Oral absorption essentially complete; Vd about 0.14 L/kg; not found in breast milk |
| Protein binding | About 99%, mainly albumin |
| Metabolism | Liver: S-warfarin by CYP2C9, R-warfarin by CYP1A2 and 3A4; metabolites inactive |
| Elimination | Urine, mostly as metabolites; not dialyzable |
| Pharmacogenomics | CYP2C9*2 or *3 and VKORC1 -1639G>A lower the dose needed and raise early bleeding risk |
Chemistry
- 3-(α-acetonylbenzyl)-4-hydroxycoumarin, related to dicoumarol, the anticoagulant of spoiled sweet clover; named for the Wisconsin Alumni Research Foundation and first sold as a rat poison
- Racemic: S is 2–5 times more potent and cleared by CYP2C9, so CYP2C9 inhibitors (amiodarone, fluconazole, metronidazole, TMP-SMX) raise the INR most
- Weak acid (pKa 5.0–5.9 by source), almost fully ionized at pH 7.4, so it binds albumin tightly and keeps a small Vd
- Warfarin sodium tablets (an isopropanol clathrate), very water-soluble and color-coded by strength (10 mg is white and dye-free); protect from light
Adverse effects and cautions
In the one-pagers
- Blood Products and TransfusionProducts at a glance: 4F-PCC: Factors II, VII, IX, X; proteins C and S: Fast warfarin reversal, small volume
- High-Alert Meds and InsulinAnticoagulants: Warfarin: INR: Vitamin K; bleeding: add 4F-PCC
- Pharmacology by Class and SuffixAnti-infectives: -conazole: antifungal (fluconazole): Liver tests, QT, other drugs: Raises INR on warfarin; lows on sulfonylureas
- Therapeutic DietsDrug–food interactions: Warfarin: Vitamin K: kale, spinach, collards, broccoli: Steady intake, not zero
- Lab Values to KnowBlood counts and clotting: PT / INR: 11–13.5 s / 0.8–1.1: Warfarin monitoring
- Obstetric EmergenciesSepsis and venous thromboembolism: Treat with LMWH (enoxaparin 1 mg/kg every 12 h) or UFH; warfarin and DOACs are avoided (PB 196), and UFH is often substituted near term. Neuraxial block waits 12 h after prophylactic and 24 h after therapeutic LMWH, which restarts 12 or 24 h after the puncture and 4 h after catheter removal (SOAP, ASRA). Thrombolysis for massive PE gave 94% survival, but major bl
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Sources
- FDA label: Jantoven (2017)
- PubChem: warfarin
- ASH HIT guideline (2018)
For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow the order, the label and your institution's protocols.