Direct thrombin inhibitors (DTIs) are a class ofmedication that act asanticoagulants (delayingblood clotting) by directly inhibiting theenzymethrombin (factor IIa). Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replaceheparin (and derivatives) andwarfarin in various clinical scenarios.
There are three types of DTIs, dependent on their interaction with the thrombin molecule.Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.[1] The third class of inhibitors, which are gaining importance recently, is the allosteric inhibitors.
Hirudin and derivatives were originally discovered inHirudo medicinalis:
Univalent DTIs include:
Thrombin demonstrates a high level ofallosteric regulation.[2] Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant.[3] Some of the allosteric inhibitors discovered include DNA aptamers,[3] benzofuran dimers,[4]benzofuran trimers,[5] as well as polymeric lignins.[6] A new sulfated β-O4 lignin (SbO4L) has been discovered which has shown a dual mechanism of action for anti-thrombosis. This SbO4L shows allosteric inhibition of thrombin for fibrinogen, while providing a competitive inhibition of thrombin interaction with platelet glycoprotein Ibα (GPIbα), thereby preventing thrombin mediated platelet aggregation.[7] However, despite the growing interest and the advances in allosterism, no allosteric thrombin inhibitor has yet reached the stage of clinical trials.
Bivalent DTIs enjoy limited use in circumstances whereheparin would be indicated such as theacute coronary syndrome ("unstable angina"), but cannot be used. As they are administered by injection (intravenous,intramuscular orsubcutaneous), they are less suitable for long-term treatment.[1]
Argatroban (as well as the hirudins) is used forheparin-induced thrombocytopenia (HIT), a relatively infrequent yet serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venousthrombosis risk) but not with the causative agent, heparin.[1]
Ximelagatran showed good efficacy compared with warfarin in several trials in prevention and treatment ofdeep vein thrombosis and as thromboprophylaxis inatrial fibrillation.[1] Development was stopped by manufacturerAstraZeneca, however, because of reports ofliver enzyme derangements andliver failure.[8]
Dabigatran is an oral direct thrombin inhibitor. Dabigatran (Pradaxa) was found to be noninferior to Warfarin in prevention of ischemic stroke, as well as intracranial hemorrhage risk and overall mortality for non-valvular atrial fibrillation according to the RE-LY trial.[9]
There is notherapeutic drug monitoring widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). Theecarin clotting time, although not in general clinical use, would be the most appropriate monitoring test.[1]