Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res. 1976;9(6):575-583. 9. Harenberg J. Pharmacology of low molecular weight hepa- rins. Semin Thromb Hemost. 1990;16(suppl):12-18. 10. Johnson EA, Kirkwood TB, Stirling Y, et al. Four heparin preparations: anti-Xa potentiating effect of heparin after sub- cutaneous injection. Thromb Haemost. 1976;35(3):586-591. binds noncovalently to the active site of thrombin to form a reversible complex.224-226 The plasma half-life of argatroban is 45 min. It is metabolized in the liver226 via the cytochrome P450 3A4/5 enzyme system. Con- sequently, argatroban must be used with caution in patients with hepatic dysfunction. Because it is not renally excreted, however, argatroban is particu- larly useful in patients with HIT with severe renal impairment. Argatroban is licensed for treatment and preven- tion of HIT-associated thrombosis and for antico- agulation during percutaneous coronary interventions when heparin is contraindicated because of a recent history of HIT. Argatroban is given as a continuous IV infusion with an initial dose of 1 to 2 mg/kg/min and the dose is adjusted to maintain the aPTT ratio in the 1.5 to 2.5 range (Linkins et al).32 2.1 Monitoring of Direct Thrombin Inhibitors Although the aPTT is used to monitor therapy with direct thrombin inhibitors, this test is not ideal. The dose-response is not linear and the aPTT reaches a plateau with higher doses of the various drugs. In addition, aPTT reagents vary in their sensitivities to direct thrombin inhibitors. The ecarin clotting time yields a more linear dose-response, but this test is not widely available and has not been standardized. All of the direct thrombin inhibitors increase the INR, albeit to a variable extent. 