The therapeutic range of heparin for coronary indica- tions is unknown, but is likely to correspond to heparin levels that are about 10% lower than those used for treatment of patients with VTE. The results of a ran- domized trial in patients with VTE that showed that unmonitored weight-adjusted subcutaneous heparin given twice daily in high doses was as safe and effec- tive as unmonitored, weight-adjusted LMWH chal- lenge the requirement for aPTT monitoring of heparin 1.1.5 Heparin Resistance: Heparin resistance is a term used to describe the situation wherein patients require unusually high doses of heparin to achieve a therapeutic aPTT.86-88 Several mechanisms explain heparin resistance, including AT de ciency,73 increased heparin clearance,38,87 elevations in the levels of heparin-binding proteins,39,89 and high levels of factor VIII88,90 and/or brinogen.90 Aprotinin and nitroglycerin may cause drug-induced heparin resis- tance,91,92 although the association with nitroglycerin In patients with VTE who required large doses of heparin (.35,000 units/d), patients randomized to heparin dosing based on anti-Xa levels (target range between 0.35-0.7 units/mL) had similar clinical outcomes and received lower doses of heparin than those randomized to dose adjustment based on aPTT values.88 Given these results, it is reasonable to adjust heparin doses based on anti-Xa levels in patients with VTE who require very high doses of heparin to achieve a therapeutic aPTT. 1.1.6 Limitations of Heparin: In addition to hemor- rhagic complications, heparin has limitations based on its pharmacokinetic properties; its ability to induce immune-mediated platelet activation, which can lead to HIT32; and its effect on bone metabolism, which can lead to osteoporosis. Other nonhemorrhagic side effects are very uncommon and include skin reactions that can progress to necrosis, alopecia, and hypersen- to heparin are uncommon, an unusually high number of adverse events with heparin were reported in North America in 2007. 