Warfarin

Introduction

Warfarin is an anticoagulant that acts by inhibiting the enzyme that recycles vitamin K from its oxidized form resulting in active vitamin K depletion. Warfarin is sometimes considered a vitamin K antagonist, however does so indirectly as above. Since vitamin K is required for the synthesis of the clotting factors II, VII, IX, X, protein C and protein S, warfarin inhibits their production producing the anticoagulant effect. Warfarin was initially used as a pesticide against rodents (rat poison).

The onset of action of warfarin relates to the half-life of the above mentioned clotting factors. Factor VII has a short half-life and thus is depleted quickly (within 1-2 days) resulting in the International Normalized Ratio (INR) level increasing despite the lack of true anticoagulation since factors II, IX and X have longer half-lives (3-5 days). Also, protein C and protein S decline quickly with warfarin administration which results in a paradoxically increased thrombogenic potential until all the clotting factors are fully inhibited. Therefore, administration of unfractionated heparin or low molecular weight heparin to achieve immediate anticoagulation and prevent thrombosis is recommended until the INR is therapeutic for 2 consecutive days.

Due to variability in absorption and dietary vitamin K intake, dosing for warfarin is variable. A low therapeutic index exists and thus the INR level needs to be monitored regularly. For most conditions the INR is maintained between 2-3, however in certain instances (i.e. mechanical mitral valve prosthesis) a goal of 2.5-3.5 is recommended.

Indications

Thromboembolic prophylaxis in atrial fibrillation and atrial flutter, deep venous thrombosis, pulmonary embolism, left ventricular thrombus, coronary aneurysms, pulmonary hypertension, stroke.

Adverse Effects

Bleeding, warfarin necrosis, cold sensation

Miscellaneous

Warfarin overdose is quite common and can cause life-threatening bleeding. Since multiple factors alter vitamin K such as dietary intake and normal gut flora, the INR level can increase if vitamin K intake declines (due to acute illness) or antibiotics eliminate normal vitamin K producing flora. Reversal of warfarin includes the administration of vitamin K, however this takes a few hours to have its effect since the vitamin K clotting factors require synthesis. Infusion of fresh frozen plasma (FFP) has an immediate reversal effect.

Warfarin necrosis occurs in the setting of protein C or protein S deficiency within the first 1-2 days of warfarin administration. Since protein C and S have short half-lives, their activity is decreased rapidly with warfarin therapy and a prothrombotic effect occurs which can cause cutaneous thrombosis resulting in skin necrosis. There is a potential for secondary infection and limb loss. Using unfractionated heparin or low molecular weight heparin to achieve immediate anticoagulation and prevent thrombosis until the INR is therapeutic for 2 consecutive days can prevent warfarin necrosis.

Purple toe syndrome can occur within the first few weeks of warfarin initiation and is thought to be from cholesterol embolism. This can be painful, but does not usually cause necrosis or digit loss. Warfarin therapy must be discontinued in this setting.