Q2i / 21A10: How does warfarin exert its pharmacological effect (40% marks)? Write brief notes on the pharmacology of the agents that can be used to reverse the effects of warfarin (60% marks)

21A10: Exam Report

How does warfarin exert its pharmacological effect (40% marks)? Write brief notes on the pharmacology of the agents that can be used to reverse the effects of warfarin (60% marks).

43% of candidates passed this question.

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.

Q2i / 21A10: How does warfarin exert its pharmacological effect (40% marks)? Write brief notes on the pharmacology of the agents that can be used to reverse the effects of warfarin (60% marks)

Warfarin is a vitamin K epoxide reductase and vitamin K reductase inhibitor (irreversibly binds to Vit K epoxide reductase complex subunit 1), therefore:

  • Prevents conversion of oxidised vit K to reduced vit K (Vit KH2)
  • Reduced vit K required for gamma carboxylation of glutamate residues for Vit K dependent factors
    • II, VII, IX, X
    • Protein C and S
  • Gamma carboxylation converts factors from inactive to active form
  • Initial hypercoagulable state due to inactive protein C and S (half life 8 and 24hrs)
  • Later anticoagulation effect due to inactive factor VII (half life 6hrs), IX, X and II (half lives 24, 36, 50hrs), disrupting the coagulation cascade

Warfarin Reversal

Vitamin K​

Indications

Supratherapeutic INR with bleeding
INR >10 without bleeding

Pharmaceutics

Oral/IV
1mg PO up to 10mg IV once

Pharmacodynamics

Enables synthesis of new coagulation factors
Requires 2 days for full reversal; 6-24hrs for effect

Side Effects

Pregnancy

Considerations

PO administration requires bile salts for absorption (fat soluble vitamin)
Difficult re-warfarinisation later

Prothrombinex

Indications

Supratherapeutic INR with bleeding
Bleeding with multiple factor deficiencies

Pharmaceutics

3 factor (II, IX, X) pooled human plasma derivative, 500IU of each
Prepared via ion exchange chromatography from cryoprecipitate
Stored as powder, reconstituted with water at 2-8 degrees

25-50IU/kg = 15-300ml IV

Side Effects

Allergy, anaphylaxis
Phlebitis
Thrombocytopaenia
Fever, rash

Considerations

Generally immediately available
No requirement for cross-match prior

FFP

Indications

Supratherapeutic INR with bleeding
Bleeding with multiple factor deficiencies
Prothrombinex not available

Pharmaceutics

Human plasma, contains ALL coagulation factors
Apheresis or whole blood collection, frozen within 18hrs
Stored for 12 months at -25 degrees

10-15ml/kg IV

Side Effects

Effects associated with transfusion

  • Acute/delayed immune and non-immune
  • E.g fluid overload, anaphylaxis, allo-immunisation, transfusion reaction, storage lesions

Considerations

Crossmatch required
Takes time to organise
Thawing required (generally frozen)

Author: Audrey Guo