Warfarin

• Warfarin is a vitamin K antagonist

  Inhibits the synthesis of vitamin K-dependent clotting factors II, VII, IX and X

  Inhibits synthesis of coagulation regulatory factors protein C and S
• Warfarin takes 48 to 72 hours for its anticoagulant effect to manifest fully.
• Baseline prothrombin levels are assessed before initiating treatment. Subsequently, monitoring encompasses:

  • Time in therapeutic range (TTR) over a maintenance period of at least six months and
  • International normalised ratio (INR) measurements. INR, representing the ratio of patient prothrombin times to control samples, guides dosage adjustments.
• Target INR:

  • Standard = 2.5
  • Recurrent VTE whilst on warfarin = 3.5
  • Varies for mechanical heart valves
• Warfarin is metabolised by CYP450 enzymes and so can have many potential interactions:

  • CYP450 inducers such as carbamazepine and primidone reduce the efficacy of warfarin
  • CYP450 inhibitors such as the macrolides (azithromycin, clarithromycin) and metronidazole increase the INR levels
• In cases of major bleeding, immediate cessation of warfarin is advised, accompanied by administering intravenous phytomenadione (vitamin K) and dried prothrombin complex or fresh frozen plasma.
• Management of bleeding risk in the acute setting depends on the INR:

  • If the INR is between five and eight without bleeding, one to two doses of warfarin should be withheld, the maintenance dose reduced, and INR rechecked after two to three days.
  • For INR levels above eight without bleeding, warfarin should be omitted, oral phytomenadione administered, and warfarin restarted when the INR is less than five.
• Blue toe syndrome = rare side effect at the beginning of warfarin therapy

  sudden painful discolouration of the toes due to micro-embolisms.
• Reversal:

  • Vitamin K - Phytomenadione
  • Dried prothrombin complex - quicker acting
• Warfarin has a half life of 20-60 hours

  Duration of effect 2-5 days
• Commencing warfarin therapy:

  • Takes at least 48-72 hours for anticoagulant effect to fully develop
  • To achieve immediate anticoagulant effect (e.g. PE) - commence concomitant LMWH/UFH for at least 5 days and INR at least 2 for at least 24 hours
  • Starting dose of warfarin is 10mg loading dose for 2 days but no evidence that this is superior to 5mg loading dose
  • Daily maintenance dose is usually 3-9mg depending on INR