Pharmacological modulation

The mechanism of action of anticoagulant drugs is based on modulation of the activity of clotting factors involved in coagulation. Anticoagulants can directly inhibit the action of clotting factors (e.g. dabigatran and rivaroxaban), inhibit their post-translational modification (e.g. warfarin), or increase the activity of endogenous coagulation inhibitors (e.g. heparin) [24].

Vitamin K antagonists

Vitamin K antagonists (VKA) function by inhibiting a specific enzyme—vitamin K epoxide reductase—that uses vitamin K and post-translationally modifies four coagulation factors (FII, FVII, FIX, and FX). Warfarin has a long history as an anticoagulant and until recently was the only oral anticoagulant available [24].

Heparins

Heparins function by indirectly inhibiting anticoagulation by increasing the ability of an endogenous coagulation inhibitor—antithrombin—to inhibit FXa and FIIa. Low-molecular weight heparins (LMWHs) also enhance antithrombin function, but resulting in a predominant inhibition of FXa. Fondaparinux is a synthetic form of heparin that is composed of the antithrombin binding sequence of heparin [24].

Direct FXa and FIIa inhibitors

The so-called ‘new oral anticoagulants’ or sometimes called ‘NOACs’ are direct anticoagulants that target a single clotting enzyme, either FXa or FIIa thereby inhibiting thrombin generation or thrombin activity [25].

Drug class Example(s) Mechanism of action
VKAs warfarin Inhibit the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X
Unfractionated heparin unfractionated heparin The main mechanism of action is the inhibition of FXa and thrombin (FIIa)
LMWHs enoxaparin, tinzaparin Predominant inhibition of FXa but also of thrombin (FIIa)
Direct thrombin inhibitors dabigatran Binding to the active centre of free and fibrin-bound thrombin
Direct FXa inhibitors rivaroxaban, apixaban Inhibit free FXa and FXa bound to thrombocytes (prothrombinase complex) and to fibrin
Indirect FXa inhibitors fondaparinux Indirect factor Xa inhibitor


Figure: VKAs inhibit the synthesis of FII, FVII, FIX, and FX (green arrows). Heparins inhibit FXa and FIIa indirectly through antithrombin, and fondaparinux indirectly inhibits FXa also via antithrombin (indirect inhibition shown by dashed red arrows on the right). Rivaroxaban and apixaban directly inhibit FXa, and several anticoagulants, including dabigatran, directly inhibit FIIa (shown as solid red arrows on the left).