Anticoagulant

Warfarin (Coumadin)

Also called Coumadin

Reviewed by Alex G, BSN, RN, CEN, CCRN, CMC, NREMT-P · From the Reference tab of the app

9:40

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Heparin vs Warfarin: aPTT vs INR, HIT, Bridging, Antidotes and DOAC Reversal

9:40 video · Chapters and full transcript

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)

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

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

• Bleeding, Reversal, HIT and DICReversing anticoagulants in major bleeding: Warfarin: 4F-PCC plus vitamin K 10 mg IV (slow): PCC 25–50 units/kg by INR; FFP only if no PCC
• LVAD BasicsAnticoagulation: Warfarin, INR usually 2.0 to 3.0 (the implant center sets it).
• Blood Products and TransfusionProducts at a glance: 4F-PCC: Factors II, VII, IX, X; proteins C and S: Fast warfarin reversal, small volume
• Endocarditis and Valve EmergenciesComplications and antithrombotics: Surgery likely (e.g. S. aureus), no stroke: warfarin or DOAC to UFH (ESC IIa)
• 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
• After Cardiac SurgeryCABG vs valve, and the sternum: Mechanical valve: Lifelong warfarin: INR 2.5 AVR (3.0 if risk factors), 3.0 MVR; no DOACs

In the algorithms

• Massive Hemoptysis

Other anticoagulant drugs

• Heparin
• Enoxaparin
• Argatroban
• Bivalirudin
• Apixaban

Sources

1. FDA label: Jantoven (2017)
2. PubChem: warfarin
3. 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.