DTIs were developed to overcome the limitations of the heparin/AT complex to inactivate tissue-bound thrombin (Weitz and Buller, 2002). The prototype DTI is hirudin, a naturally occurring 65-amino acid polypeptide first isolated from the salivary gland of medicinal leeches but now manufactured using recombinant DNA technology. Hirudin and argatroban are approved for the treatment of HIT (see Chapters 14 and 15), argatroban is also approved for use in patients with or at risk of HIT undergoing PCI (see Chapter 15), and bivalirudin is licensed as an alternative to heparin in patients with or without HIT undergoing PCI (see Chapter 16). Hirudin, argatroban, and bivalirudin are all parenteral agents and do not address the unmet need for an oral anticoagulant to replace warfarin. Several oral DTIs have been developed; ximelagatran was the first orally available DTI and dabigatran etexilate is currently being evaluated in phase III clinical trials.

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