Blood Coagulation
Mechanism of Action
Side Effects
The Future


The laboratory test to determine the coagulation ability of blood is the Prothrombin Time (PT). This reflects the depression of vitamin k dependent factors. However, the results of this test depends on a variety of factors, including the actual reagents used. A system of standardising the PT in oral anticoagulant control was introduced by the World Health Organisation (WHO) in 1983 10. It is based on the determination of an International Normalised Ratio (INR) which provides a common basis for communication of PT results and interpretation of therapeutic ranges.

The INR is calculated as

INR = (patient PT / control PT) ISI

where ISI = International Sensitivity Index  and is the correction factor which includes effects of the reagent used, etc.

The anticoagulant efficacy of warfarin is influenced by pharmacokinetic factors. Warfarin is a racemic mixture and is well absorbed orally. It is transported in the blood by albumin, a plasma protein. It is metabolised in the liver by the cytochrome P450 family of enzymes. The principal enzyme of the P450 family which modulates the in vivo anticoagulant activity of warfarin is 2C9.

Human serum albumin complexed with myristic acid and S-warfarin (red)

The 2 enantiomers are metabolised by different pathways and have different half-lives and potencies. The S-(-)-isomer is 5 times more potent than the R-(+)- isomer, but is also metabolised more quickly, thus having a smaller half-life. Metabolism is by hydroxylation and reduction and metabolites are principally excreted in urine.

The effects of warfarin are also heavily influenced by interactions with other drugs. Drugs which potentiate the anticoagulant effect include anabolic steroids, cimetidine, fluconazole, miconazole, metronidazole, propanolol, tetracycline, flu vaccine and aspirin. Other drugs inhibit the action of warfarin and include barbiturates, rifampin, carbamazepine, cholestyramine and even high-vitamin K-content foodstuff.

The anticoagulant ability is also affected by endogenous factors including diarrhoea, hepatic disorders, elevated temperature, infections, hepatitis and vitamin K deficiency.