It also is problematic if patients have serious bleeding because there is no antidote for danaparoid. 2.0 Direct Thrombin Inhibitors In contrast to indirect anticoagulants, which require a plasma cofactor to exert their activity, direct throm- bin inhibitors have intrinsic activity because they bind to thrombin and block its enzymatic activity. The cur- rently approved direct thrombin inhibitors are hiru- din, bivalirudin, and argatroban. Hirudin A 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal leech, Hirudo medicinalis,214,215 hirudin is now available in recombinant forms. Expressed in yeast, recombinant hirudins differ from native hirudin in that the Tyr residue at position 63 is not sulfated. Two recombi- nant forms of hirudin, known as lepirudin and desiru- din, are currently approved for clinical use in North America and in Europe, respectively. Lepirudin is licensed for treatment of thrombosis complicating HIT, whereas desirudin is approved in Europe and the United States for postoperative thromboprophy- laxis in patients undergoing elective hip arthroplasty. Although there are minor differences in the amino- terminal composition of the two forms of recombinant hirudin, their mechanism of action and pharmaco- kinetic properties are identical. Both inhibit thrombin in a bivalent fashion. Thus, their globular amino- terminal domains interact with the active site of thrombin, whereas the anionic carboxy-terminal tails bind to exosite 1 on thrombin, the substrate-binding site.215 Both lepirudin and desirudin form high-af nity 1:1 stoichiometric complexes with thrombin that are essentially irreversible. Dosing and Monitoring: The recommended dose of IV lepirudin for HIT is 0.15 mg/kg/h with or with- out an initial bolus of 0.4 mg/kg. 