Direct thrombin inhibitors

Abstract

Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy.

Figure 1

Schematics of the interaction of thrombin with six different anticoagulants. Unfractionated heparin (UFH) – UFH mediates its affect through binding to antithrombin and enhancing its reactivity with the enzymatic site of thrombin. UFH requires an additional 13 saccharides that bind to the heparin binding site to maximize its interaction with thrombin. UFH is thus an indirect, parenteral inhibitor of thrombin. Low molecular weight heparin (LMWH) – LMWH lacks the longer chains of UFH and has less binding to thrombin thus decreasing its ability to neutralize thrombin. LMWH is thus an indirect, parenteral inhibitor of thrombin. Lepirudin/Desirudin – Lepirudin and desirudin bind directly and strongly to both the active enzymatic site and exosite 1 of thrombin to inhibit its activity. Lepirudin and desirudin are direct, parenteral inhibitors of thrombin. Argatroban – Argatroban is a small molecule that binds reversibly to the active enzymatic site of thrombin. Argatroban is a direct, parenteral inhibitor of thrombin. Bivalirudin – Bivalirudin is a modified form of hirudin with four glycine residues connecting two amino acids sequences important for binding to thrombin. It is a more reversible inhibitor of thrombin than is lepirudin, and is a direct, parenteral inhibitor of thrombin. Dabigatran – Dabigatran is a small molecule that binds reversibly to the active enzymatic site of thrombin. Dabigatran is an oral, direct inhibitor of thrombin

Figure 2

Chemical structures of the double prodrug, dabigatran etexilate and its active form, dabigatran