Vitamin K Antagonists

Vitamin K is essential for the hepatic synthesis of Factors II (prothrombin), VII, IX, and X, as well as protein C and protein S.^{89, 93} Antagonists of vitamin K have been used as anticoagulants for over 50 years. Warfarin, a synthetic derivative of coumarin, is the most commonly used vitamin K antagonist (VKA) in the United States. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used as an alternative to warfarin.^{7, 94}

Because of the variability in the dose response with VKA medications, monitoring the degree of anticoagulation is imperative. The prothrombin time (PT) is sensitive to changes in prothrombin, Factor VII, and Factor X. Because of inconsistencies in the test substrate, thromboplastin, haematology laboratories now use an internationalised ratio (INR) of PT prolongation. The INR provides a standardised measure of the VKA anticoagulant effect. For most conditions for which VKAs are prescribed, the recommended therapeutic INR range is 2.0 to 3.0. One exception is in patients with artificial heart valves, for whom the range should be 2.5 to 3.5.⁹⁶ As the INR increases, the risk of bleeding increases, doubling with each one-point increase in INR.⁷

A patient’s INR should be monitored frequently when starting a VKA, when changing the dose, and when there are dietary changes or other medications known to interact with VKAs. Once a stable dose that produces a therapeutic INR level is reached, the test ideally should be repeated every four weeks. With usual outpatient care, patients have INRs outside the therapeutic range about 50% of the time; in 14%, INRs are increased above 3.0.⁷

Polymorphisms in the genes for cytochrome P450, CYP2C9 (responsible for metabolic clearance of warfarin), and vitamin K epoxide reductase (which recycles vitamin K) affect the pharmacokinetics of warfarin. Research is currently in progress on the clinical utility of genetic polymorphism testing to guide warfarin dosing.^{97, 98}

Bleeding is the most common adverse event with VKAs. The incidence of major bleeding varies from less than 2% a year with care in an anticoagulation clinic to 4% to 5% a year with usual medical care.⁹⁹ Skin necrosis is an uncommon but serious complication that typically develops between the third and eighth day of treatment. This adverse event may result from an initial prothrombotic state, when levels of proteins C and S have decreased while the clotting factors levels are still normal.⁷