Vitamin K and Warfarin Interaction
Vitamin K directly antagonizes warfarin's anticoagulant effect by promoting the synthesis of vitamin K-dependent clotting factors, requiring careful management to prevent both bleeding and thrombotic complications.
Mechanism of Interaction
- Warfarin works by inhibiting vitamin K epoxide reductase (VKORC1), which reduces the regeneration of vitamin K1 epoxide, thereby decreasing the synthesis of vitamin K-dependent clotting factors (II, VII, IX, X) and anticoagulant proteins C and S 1
- Vitamin K administration counteracts warfarin's effect by providing substrate for the synthesis of these clotting factors, effectively reversing anticoagulation 1, 2
- The half-lives of these clotting factors vary significantly: Factor VII (4-6 hours), Factor IX (24 hours), Factor X (48-72 hours), and Factor II (60 hours), explaining the time course of INR changes after vitamin K administration 1
Clinical Management of Elevated INR
For INR 4.5-10 Without Bleeding:
- For patients with INR between 4.5 and 10 without bleeding, guidelines suggest against routine use of vitamin K, as simply holding warfarin doses is often sufficient 2
- If the patient has increased bleeding risk factors (elderly, history of stroke, GI bleeding, renal insufficiency), omit the next warfarin dose and consider administering 1-2.5 mg oral vitamin K 2
- Randomized trials show that vitamin K administration lowers INR more rapidly than simply holding warfarin, but has not demonstrated reduction in major bleeding events 2
For INR >10 Without Bleeding:
- For INR >10 without bleeding, administer 3-5 mg oral vitamin K, which will typically lower INR within 24-48 hours 2
- Monitor INR closely and repeat vitamin K as necessary 2
- The absolute risk of bleeding increases significantly when INR exceeds 4.5-6.0, though remains relatively low at <5.5 per 1000 patient-days 3
For Patients with Active Bleeding:
- For serious bleeding with elevated INR, administer 5-10 mg vitamin K by slow intravenous infusion (over 30 minutes) 2, 4
- For life-threatening bleeding, use 4-factor prothrombin complex concentrate (PCC) as first-line therapy plus 10 mg intravenous vitamin K 4
- Fresh frozen plasma should only be used if PCC is unavailable 4
- PCC has advantages over plasma including faster onset (5-15 minutes vs. hours), no need for blood typing, minimal volume overload risk, and lower infection transmission risk 4
Dietary Vitamin K Considerations
- Patients on warfarin should maintain consistent dietary vitamin K intake rather than avoiding vitamin K-rich foods 5
- A practical approach is to maintain a constant weekly dietary vitamin K intake of approximately 65-80 micrograms/day 5
- Dark green vegetables contain high amounts of vitamin K1 (100-570 micrograms/serving), but occasional typical servings (<100g) likely have minimal lasting impact on INR 6
- Less recognized sources of vitamin K include plant oils, baked goods, margarines, and salad dressings, which may contribute to warfarin resistance 5
- Very large amounts of vitamin K from a single meal (400g of vegetables with 700-1500 micrograms of vitamin K1) can measurably change INR 6
Important Considerations and Pitfalls
- High doses of vitamin K1 (e.g., 10 mg) may lower INR more than necessary and lead to warfarin resistance for up to a week 2
- If warfarin is to be resumed after administration of high doses of vitamin K, bridging with heparin may be necessary until the patient becomes responsive to warfarin again 2, 4
- Oral vitamin K administration is preferred over intravenous due to risk of anaphylactoid reactions with IV administration 3
- Patient-specific factors increasing bleeding risk include age >65 years, history of stroke or GI bleeding, renal insufficiency, anemia, and concomitant use of drugs affecting platelet function 2
- Individualized vitamin K dosing based on index INR and body surface area has been shown to be more effective than fixed-dose regimens in returning patients to target INR range (68.9% vs. 52.8%) 7