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Biology of warfarin and modulators of INR control

Authors
Russell D Hull, MBBS, MSc
David A Garcia, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Warfarin and other vitamin K antagonists (VKAs, also called coumarins; eg, acenocoumarol, phenprocoumon, fluindione) are used in a variety of clinical settings. Use of VKAs is challenging because their therapeutic range is narrow and dosing is affected by many factors including drug interactions, diet, and genetic variation in warfarin and vitamin K metabolism. Time spent with a prothrombin time/international normalized ratio (PT/INR) above the therapeutic range increases the risk of bleeding, and time spent below the therapeutic range increases the risk of thromboembolic complications.

This topic review discusses the biology, mechanism of action, and factors that modulate INR control during anticoagulation with a VKA.

Warfarin administration, and management of warfarin-associated bleeding and supratherapeutic INR, are discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Reversal of anticoagulation in warfarin-associated intracerebral hemorrhage".)

BIOLOGY

Mechanism of action — Warfarin and related vitamin K antagonists (VKAs) block the function of the vitamin K epoxide reductase complex in the liver, leading to depletion of the reduced form of vitamin K that serves as a cofactor for gamma carboxylation of vitamin K-dependent coagulation factors [1]. The epoxide reductase is needed to recycle vitamin K between reduced and epoxide forms. Without gamma carboxylation, the vitamin K-dependent factors, including factors II (prothrombin), VII, IX, and X, are immunologically detectable, but they cannot function because they cannot adequately bind calcium and phospholipid membranes needed for their hemostatic function [2]. (See "Vitamin K and the synthesis and function of gamma-carboxyglutamic acid".)

Gamma carboxylation of glutamic acid residues occurs at the time of protein synthesis; it does not affect the structure or function of existing proteins. Thus, the ultimate anticoagulant effect of VKAs is delayed until the previously synthesized, functional clotting factors are cleared from the circulation. Depletion of both factor X and factor II (prothrombin) is important for clinical efficacy, and factor II has the longest half-life of the vitamin K-dependent factors (approximately three days) [3,4]. Thus, the desired anticoagulant effect of a VKA does not occur for at least three days after drug initiation despite prolongation of the prothrombin time (PT) at earlier time points. The initial prolongation of the PT is due primarily to depletion of factor VII, which has a short half-life (four to six hours) (figure 1) [5]. (See 'PT/INR prolongation' below.)

                           

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