Warfarin Mechanism of Actions | How it works

Warfarin works by inhibiting the vitamin K-dependent synthesis of calcium-dependent clotting factors (which are of active forms) include factors II, VII, IX and X (2,7,9,10). Furthermore, the regulatory factors of protein C, cofactor protein S, and protein Z would be inhibited as well. However, proteins that are not clotting factors may be influenced to a certain extent, such as osteocalcin and matrix Gla protein.

Before we go into details for mechanism of action of warfarin, we have to understand normal mechanism of clotting process. From the diagram above, we can see that the precursors of the clotting factors mentioned above (prothrombin precursor) require carboxylation of their glutamic acid residues catalyzed by gamma-glutamyl carboxylase to become active form (prothrombin), before being able to bind to phospholipid membrane on vascular endothelium of blood vessels. (The newly formed Gla residues from Glu chelate strongly and selectively with calcium ion in which the latter would form ion bridges with the anionic phosphate groups of phospholipid membrance surfaces)

However, the carboxylation process will only be able to proceed in the presence of reduced form of vitamin K (or known as vitamin K hydroquinone). The vitamin K cycle involves enzyme Vitamin KO reductase (or vitamin K epoxide reductase) which reduce oxidized vitamin K (or vitamin K epoxide) to vitamin K which would be then converted to vitamin K hydroquinone by enzyme vitamin k reductase.

Diagram for Mechanism of Action of Warfarin

Warfarin is a vitamin K antagonist which inhibits epoxide reductase step. Hence, vitamin K cannot be formed and thus would diminish availalbe vitamin K hydroquinone in the tissues, lead to the inhibition of carboxylation activity of glutamyl carboxylate. Active clotting factors no longer can be formed and the final result would be anticoagulation effect. However, the anticoauglation activity of warfarin can only be seen apparent after 3 to 5 days due to the half life of previously produced active factors which degrade over several days before replaced by new inactive actors. Furthermore, due to the inhibition of protein C and protein S (vitamin K dependent) which play their role in anticlotting as well, warfarin may cause formation of clot temporarily leading to prothrombic state. 
Hence, it is normally practised to co-administer heparin intravenously to the patient which help reduce the risk of thromosis together with warfarin therapy for 4 to 5 days, with the purpose to have heparin anticoagulation effect before the full activitly of warfarin is achieved.