Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of coumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon and acenocoumarol) are used. These agents are vitamin K antagonists (VKA). Vitamin K is essential for the hepatic synthesis of Factors II (prothrombin), VII, IX and X.
Despite the application of many parenteral (unfractionated heparin and low molecular weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombosis remain major medical challenges.
Vitamin K oral anticoagulant drugs are 4-hydroxycoumarin derivatives, which exert their anticoagulant effect by inhibiting vitamin K epoxide reductase and, possibly, vitamin KH2 reductase 1).
These compounds act by reducing vitamin KH2 (reduced form of vitamin K) levels, thereby limiting the cofactor effect of vitamin K on the γ-carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X. VKAs also limit the effect of anticoagulant proteins, protein C and protein S, resulting in an inhibition of these proteins 2) 3).
The VKA dose is determined on an individual basis (not fixed), whereas novel non vitamin K oral anticoagulant are administered in fixed doses, except when a patient has a functional disorder of the liver or kidney.
The evolution of vitamin K, from a dietary deficiency in birds to a postribosomal modifier of prothrombin in man, has been a fascinating scientific saga. Its antivitamin, the oral anticoagulant drugs, has been a powerful probe both of vitamin K action and of drug interactions. These agents have emerged from a limbo of clinical therapeutics to become a light of human pharmacology 5).
Treatment with VKAs is indicated in various medical situations, such as for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrence, atrial fibrillation (AF) and stroke in patients with NVAF, acute myocardial infarction, and vasculopathy, as well as in patients with tissue heart valves or mechanical prosthetic cardiac valves. These drugs are also used as prophylaxis for VTE in high-risk patients (eg, post-orthopedic surgery, embolic peripheral, and arterial disease) 6) 7).
This concerns mostly patients with atrial fibrillation or venous thromboembolism, or those carrying mechanical heart valves. The incidence of VKA-associated ICH is 0.7% per year with atrial fibrillation 8) and 0.5% per year in the patients with a mechanical heart valve 9).