Question 10

College Answer

Warfarin is listed as a level 1 drug in the 2017 syllabus and as such a detailed knowledge of its mechanism of action would be expected from candidates sitting the exam. The reversal agents for warfarin are collectively classed as level 2 drugs and hence the knowledge required would be at a write short notes level. The following topics were expected: what drugs may be used, how they work, in what dose, any common side effects, why/when would one be used in preference to others etc. The use of reversal agents for warfarin is a common practice in ICU. Generally, answers demonstrated a lack of a precise and detailed knowledge with respect to warfarin’s mechanism of action and had a very superficial knowledge with incorrect facts regarding the reversal agents.

Discussion

Mechanism of action:

• Vitamin K is an essential cofactor for the activation of factors II, VII, IX, and X.
• These factors are synthesized as precursors, and require post-translational carboxylation by gamma glutamyl carboxylase.
• Reduced vitamin K is required as a cofactor for this reaction.
• In its absence, the secreted factors are inactive, and the extrinisic pathway is affected.
• Warfarin interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide), thereby modulating the γ-carboxylation of glutamate residues (Gla) on the N-terminal regions of vitamin K-dependent proteins.
• Vitamin K-dependent coagulation factors II, VII, IX, and X require γ-carboxylation for their procoagulant activity; thus warfarin therapy results in the hepatic synthesis of ineffective factors.

Reversal agents:

• Vitamin K (phytomenadione) is a slow reversal agent for patients without any life-threatening acute haemorrhage
  • It increases the availability of the reduced substrate for the activation of clotting factors
  • May take some hours to work
  • May cause problems with the recommencement of warfarin therapy (labile INR)
  • May cause anaphylaxis to the benzyl alcohol excipient (Aziz et al, 1996) 
  • Dose is 0.5-1.0mg, or up to 10mg for acute bleeeding
• Prothrombinex contains factors II, IX, X and low levels of factor VII.
  • The dose is 25 – 50 IU/kg.
  • This blood product concentrate rapidly restores the circulating levels of the necessary factors
  • Low volume: well tolerated by patients with weak ventricles
•  FFP also contains factors II, IX, X and low levels of factor VII.
  • maximum dose is 15ml/kg
  • highly hyperoncotic solution, many cause APO 

Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.

Keller, Christina, Axel C. Matzdorff, and Bettina Kemkes-Matthes. "Pharmacology of warfarin and clinical implications." Seminars in thrombosis and hemostasis. Vol. 25. No. 01. Copyright© 1999 by Thieme Medical Publishers, Inc., 1999.

Ufer, Mike. "Comparative pharmacokinetics of vitamin K antagonists." Clinical pharmacokinetics 44.12 (2005): 1227-1246.

Kearon, Clive, et al. "Effect of warfarin on activated partial thromboplastin time in patients receiving heparin." Archives of internal medicine 158.10 (1998): 1140-1143.

Hirsh, Jack. "Reversal of the anticoagulant effects of warfarin by vitamin K1." Chest 114.6 (1998): 1505-1508.

Aziz, Noorizan Abdul, et al. "Vitamin K1-induced anaphylactic shock." Journal of Pharmacy Technology 12.5 (1996): 214-216.