Blood Coagulation
Mechanism of Action
Side Effects
The Future

Mechanism of Action

To understand the mechanism of action of warfarin, we have to look in more detail at part of the structure of some coagulation factors9. Factors II( Prothrombin), VII, IX and X have, at their amino terminus, a series of glutamate residues (Glu)-typically 9 to 12. These factors are vitamin K dependent. In a post translational modification in the liver, the glutamate residues are carboxylated in presence of O2, CO2 and the enzyme carboxylase, to form γ- carboxyglutamate (Gla) residues. Vitamin K is essential for the process.

Conversion of Glu to Gla

This carboxylation is essential for the proper functioning of the clotting factors. The newly-formed Gla residues chelate strongly and selectively with Ca2+ (factor IV) and the latter forms ion bridges to anionic phosphate head groups of phospholipid membrane surfaces.

membrane binding  

As was mentioned previously, binding at the membrane surface is a critical step in the process of activation of the clotting factors.

The carboxylation process is associated with the vitamin K cycle. In this cycle, vitamin K is reduced by enzyme Vitamin K reductase to its hydroquinone form, vitamin KH2 , which then catalyses the carboxylation process and is converted to its epoxide (vitamin KO). This is then converted back to vitamin K by the enzyme Vitamin KO reductase.

vitamin k

Vitamin K1


 Warfarin is a vitamin K antagonist. It produces its anticoagulant effect by interfering with the vitamin K cycle. Specifically, it interacts with the KO reductase enzyme so that vitamin KO cannot be recycled back to vitamin K. This leads to a depletion of vitamin KH2, thereby limiting the γ- carboxylation of the coagulation factors mentioned above. Factors like prothrombin are not carboxylated, and cannot effectively bind to phospholipid membranes. Its activation by Factor Xa is not effected. Thus blood coagulation is limited.