"The DTls can be distinguished within their class by monovalent and bivalent compounds. Bivalent DTJs include intravenous hirudin and bivalirudin. In contrast, univalent DTls include argatroban, ximelagatran, dabigatran, and AZD0837, with the last three being developed for oral use.Ximelagatran was the first oral DTI within this class to show potential for treatment of AF, and the first in the United States for which FD,A approval was applied. However, applications for FDA marketing approval were later withdrawn based on data from the Stroke Prevention with the Oral Direct Thrombin Inhibitor Ximelagatran Compared with Warfarin in Patients with Non-valvular Atrial Fibrillation (SPORT1F III] trial showing an increased risk of elevated liver enzyme levelsThe newest oral DTls under investigation include dabigatran and AZD0837. Dabigatran received FDA approval in October 2010 for the indication of thrombosis prevention in nonvalvular AF. It was approved in Japan in January 2011 for the same indication. Dabigatran is currently marketed for prevention of stroke and systemic embolism in patients with non-valvular AF"Table 1: Summary of characteristics of DTI http:/fen. wikipedia. org/wiki/ Bivalent/ UnivalentRoute of administrationBinding to active site and/or exositeIndicationsNativeHirudinB[Parenteral) Has no indicationsLepirudinBParenteral [iv/sc)IrreversiblePrevention of further thrombosis in patients with HITDesirudinBParenteral (iv/sc)IrreversibleEurope: treatment of VTE USA: Prevetion of DVT in patients undergoing hip replacement surgeryBivalirudinBParenteral (iv)ReversiblePrevention of acute ischemic complications in patients with unstable angina and with or at risk of HIT undergoing PTCA or PCIArgatrobanUParenteral (iv)ReversiblePrevention and treatment of thrombosis in patients with HITXimelagatranUOralReversibleEurope: Prevention of VTE USA: FDA never gave approvalDabigatran EtexilateUOralReversiblePrevention of stroke and embolism in patients with AFPARENTERAL DIRECT THROMBIN INHIBITORS# Heparin and LMWH are indirect inhibitors of thrombin because their activity is mediated by antithrombin. In contrast, direct thrombin inhibitors do not require a plasma cofactor; instead, these agents bind directly to thrombin and block its interaction with its substrates. Approved parenteral direct thrombin inhibitors include !epirudinr argatroban, and bivalirudin# Lepirudin and argatroban are licensed for treatment of patients with HIT, whereas bivalirudin is approved as an alternative to heparin in patients undergoing percutaneous coronary interventions, including those with HIT.Table (Harrison):Comparison of the Properties of Lepirudin, Bivalirudin, and Argatroban LepirudinBivralitrudinArgatrobanMolecular mass70001980527Site (s) of interaction with thrombinActive site and exosite 1Active site and exosite 1Active siteRenal clearanceYesNoNoHepatic metabolismNoNoYesPlasma half-life (min)602545">