Question 8

College Answer

Warfarin is a competitive inhibitor of the enzyme vitamin K epoxide reductase which converts oxidised or inactive vitamin K to reduced or active vitamin K Reduced vitamin K is required for the gamma carboxylation of the glutamate residues in the vitamin K dependant factors (II, VII, IX and X) and proteins C and S. This gamma carboxylation converts these clotting factors from their inactive to their active form resulting in coagulation. The presence of warfarin inhibits this conversion process resulting in anticoagulation. The presence of inactive 
protein C and S explains the initial hypercoaguable effect of warfarin. The three main agents used to reverse the effects of warfarin are vitamin K, prothrombinex and fresh frozen plasma (FFP). It was expected answers would provide a brief overview of all three agents. Most candidates did not highlight the fact that parenteral vitamin K requires a few hours to work whereas prothombinex and FFP work immediately. 

Better answers noted additional facts such as oral vitamin K because it is fat soluble requires the presence of bile salts to be absorbed from the gut or the rare but life threatening hypersensitivity reaction caused by intravenous vitamin K possibly related to its preservative benzyl alcohol. A common omission was the amount of coagulation factors in international units (IU) in an ampoule of prothormbinex or the dose required to reverse warfarin anticoagulation. A description of the clinical pros-cons of the various agents was not required to answer the 
question. 

Discussion

Mechanism of warfarin anticoagulation

• 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
• Warfarin inhibits vitamin K epoxide reductase, which converts oxidised Vitamin K back into its reduced form
• Absence of effective factor VII affects the extrinsic pathway and causes PT elevation
• Absence of effective factor IX affects the intrinsic pathway and causes 9mild) APTT elevation
• Absence of factors X and II affects the final common pathway and results in the specific anticoagulant effect, as active Factor IIa (thrombin) is required for fibrinogen conversion to fibrin

Pharmacology of agents used to reverse 

• Time. Literally waiting for some halflives to wear down may be enough. 
• Vitamin K (phytomenadione) is the reversal agent for warfarin,
  • Increases the availability of the reduced substrate for the activation of clotting factors. 
  • INR 4.5 – 10.0 and high risk of bleeding: Vitamin K (1 – 2 mg orally or 0.5 – 1.0 mg iv).
  • If the patient is acutely bleeding, use a high dose of Vitamin K - 5-10mg IV.
  • It is generally viewed as a benign substance. The argument may be, why not give it?However, the oral form requires bile salts to be absorbed. Also:
    • Adverse effects can occur due to the benzyl alcohol excipient 
    • Liver disease patients may not benefit
• Prothrombinex contains factors II, IX, X and low levels of factor VII. The dose is 25 – 50 IU/kg. 
• FFP is generally reserved for situations when the prothrominex is not readily available. The maximum dose is 15ml/kg.
• FFP and prothrombinex have an immediate effect, whereas Vitamin K may take up to 24 hours to take effect

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.