Phaemacopeia – Anticoagulants

Master answer

Warfarin Pharmacology

Warfarin Reversal

The following reversal strategies may be either used alone or in combination:

1. Stopping warfarin
   • S-warfarin is eliminated via oxidation predominantly by CYP2C9 (and to a lesser extent by CYP3A4 and 1A2) → inactive metabolites
   • Elimination half-life of S-warfarin is 29 hours
     • ∴ in patients with normal hepatic metabolic and synthetic functions  take 4 ~ 5
   • days for INR to normalise
2. Vitamin K
   • Can be given either enterally or parenterally (IV, IM) (bioavailability ≈ 100%)
     • Requires few hours to work
     • Enteral administration Requires presence of bile salts to be absorbed by gut
     • Parenteral administration has rare but life threatening complication of hypersensitivity probably related to its preservative, benzyl alcohol
   • Low dose vitamin K (1 ~ 2.5 mg) will slowly reduce INR over 24 hours
     • but often will not result in complete reversal and would not significantly affect re-establishment of anticoagulation with warfarin
   • High dose vitamin K (10 mg) will slowly reduce INR over 12 hours
     • ∴ often given together with clotting factors (e.g. FFP)
3. Fresh frozen plasma
   • Plasma from donated blood, which contains all clotting factors
   • ∴ immediately reverses coagulopathy
   • However, short duration of action (24 ~ 48 hours) ∴ reserved for active bleeding
   • Used when PCC not available
   • Dose 2 ~ 4 units (10-15ml/kg) depending on INR and bleeding risk
   • Disadvantages = relatively large fluid volume, possible transfusion reactions (e.g. immune reaction, TRALI, infection, etc)
4. PCC – Prothrombin complex concentrates (Prothrombinex)
   • Human plasma derivative containing concentrates of factors II, IX and X
   • 500IU PCC has 500IU of II, IX, X each in a vial
   • ∴ immediately reverses coagulopathy
   • Dose 25 ~ 50 IU/kg
   • Advantages = reliable reversal, smaller fluid volume, avoids transfusion
   • complications associated with FFP
   • Disadvantages = expensive
5. Recombinant activated factor VII (NovoSeven)
   • Controversial treatment, present in some guidelines
   • Indication = life threatening bleed with significantly elevated INR
   • Given together with vitamin K and FFP
   • Disadvantage = thromboembolic complications