Pharmacology
Warfarin: mechanism and vitamin K dependent factors
Warfarin is an oral anticoagulant that blocks the liver enzyme recycling vitamin K, so clotting proteins called factors II, VII, IX and X are made in an inactive form.
Remember
Warfarin works indirectly: by blocking vitamin K recycling in the liver, it leaves factors II, VII, IX and X inactive, and it does not act on platelets or clots directly.
Clotting factors II, VII, IX and X (clotting proteins that the liver makes) are vitamin K dependent. Before they work, each needs a chemical modification called gamma-carboxylation. The modified regions let the proteins use calcium to attach to cell membranes, which is where clotting takes place.
The helper molecule (cofactor) for that step is reduced vitamin K, the active form of the vitamin. Once used, the liver enzyme vitamin K epoxide reductase recycles it back into the reduced form. Warfarin blocks this enzyme, so reduced vitamin K is not recycled. The factors are still made, but they stay inactive, and clots form less readily.
Protein C and protein S are natural anticoagulants (proteins that damp down clotting) that rely on vitamin K in the same way, so warfarin lowers these too.
This makes warfarin an indirect anticoagulant: it changes how clotting factors are made. It does not bind thrombin (the enzyme that finally forms fibrin) or factor Xa (a clotting enzyme) itself, unlike dabigatran, which blocks thrombin directly.
Active factors already in the blood have to be cleared first, so full effect takes about 3 to 5 days. Heparin (an anticoagulant given by injection) can be used as a bridge (a short overlap with a faster-acting anticoagulant) until the INR (international normalised ratio, a blood test that compares the clotting time of the patient's plasma with a standard control) reaches its target range.
Remember factors II, VII, IX and X as the 1972 factors: 10, 9, 7 and 2.
Key facts
- Target
- vitamin K epoxide reductase in the liver; blocking it stops vitamin K being recycled.
- Made inactive
- factors II, VII, IX and X, plus protein C and protein S.
- Not acted on directly
- factors V, VIII, XI and XII, which are not vitamin K dependent.
- Onset
- slow, full effect takes about 3 to 5 days, so heparin can bridge the gap.
- Monitoring
- the INR.
- Main adverse effect
- bleeding.
Exam traps
- Warfarin does not block thrombin directly; it reduces the liver's production of working prothrombin (factor II, which thrombin comes from) and the other vitamin K dependent factors, whereas direct thrombin inhibition is how dabigatran works.
- Warfarin does not act through antithrombin III (the body's natural brake on clotting); that is how heparin works, whereas warfarin acts on vitamin K recycling.
- Warfarin does not block cyclooxygenase-1 (COX-1, an enzyme in platelets); aspirin, an antiplatelet drug that stops platelets clumping, irreversibly blocks it, whereas warfarin acts on clotting factors made in the liver.
- Factor XI is not vitamin K dependent, so warfarin does not act on it directly, and it is easy to mix up with the four vitamin K dependent factors because its number is close to IX and X.
- Replacing IX with V gives II, V, VII and X, a classic slip when recalling the 1972 factors: factor V is not vitamin K dependent, and factor IX is then missing from the set.
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