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Key events that facilitated the subsequent development of small molecule active site inhibitors, such as argatroban, were the observation that fibrinopeptide A had antithrombotic properties and determination of the crystal structure of thrombin. Hirudin and argatroban have found their niche for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as an alternative to heparin for patients undergoing percutaneous coronary intervention. The development of orally active direct thrombin inhibitors was challenging because of the need to convert water-soluble, poorly absorbable, active site inhibitors into fat-soluble prodrugs that were then transformed back to the active drug after intestinal absorption. Dabigatran etexilate was the first new oral anticoagulant to be approved for long-term anticoagulant treatment in 6 decades. This Review highlights the development of DTIs as a translational success story; an example in which the combination of scientific ingenuity, structure-based design, and rigorous clinical trials has created a new class of anticoagulants that has improved patient care.<\/jats:p>","DOI":"10.1161\/circresaha.112.264903","type":"journal-article","created":{"date-parts":[[2012,9,14]],"date-time":"2012-09-14T15:14:10Z","timestamp":1347635650000},"page":"920-929","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":75,"title":["Translational Success Stories"],"prefix":"10.1161","volume":"111","author":[{"given":"Michiel","family":"Coppens","sequence":"first","affiliation":[{"name":"From the Population Health Research Institute, Hamilton, Ontario, Canada (M.C., J.W.E., J.H.); the Department of Medicine, McMaster University, Hamilton, Ontario, Canada (M.C., J.W.E., J.I.W., J.H.); Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.W.E., J.I.W.); AstraZeneca R&amp;D M\u00f6lndal, M\u00f6lndal, Sweden (D.G.); and the Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Eikelboom","sequence":"additional","affiliation":[{"name":"From the Population Health Research Institute, Hamilton, Ontario, Canada (M.C., J.W.E., J.H.); the Department of Medicine, McMaster University, Hamilton, Ontario, Canada (M.C., J.W.E., J.I.W., J.H.); Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.W.E., J.I.W.); AstraZeneca R&amp;D M\u00f6lndal, M\u00f6lndal, Sweden (D.G.); and the Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gustafsson","sequence":"additional","affiliation":[{"name":"From the Population Health Research Institute, Hamilton, Ontario, Canada (M.C., J.W.E., J.H.); the Department of Medicine, McMaster University, Hamilton, Ontario, Canada (M.C., J.W.E., J.I.W., J.H.); Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.W.E., J.I.W.); AstraZeneca R&amp;D M\u00f6lndal, M\u00f6lndal, Sweden (D.G.); and the Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey I.","family":"Weitz","sequence":"additional","affiliation":[{"name":"From the Population Health Research Institute, Hamilton, Ontario, Canada (M.C., J.W.E., J.H.); the Department of Medicine, McMaster University, Hamilton, Ontario, Canada (M.C., J.W.E., J.I.W., J.H.); Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.W.E., J.I.W.); AstraZeneca R&amp;D M\u00f6lndal, M\u00f6lndal, Sweden (D.G.); and the Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Hirsh","sequence":"additional","affiliation":[{"name":"From the Population Health Research Institute, Hamilton, Ontario, Canada (M.C., J.W.E., J.H.); 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