The two preferred routes of administration are by continuous IV infusion or subcutaneous injection. When the subcutaneous route is selected for delivery of treatment doses of heparin, the dose of heparin should be higher than the usual IV dose because sub- cutaneous administration is associated with reduced bioavailability.33,34 If an immediate anticoagulant effect is required, a higher initial subcutaneous dose of heparin can be administered.35 Alternatively, an IV bolus of heparin can be given in conjunction with the rst subcutaneous dose. Administration by subcutaneous injection in low doses36 (eg, 5,000 units q12h), moderate doses of plasma recovery of heparin.33 However, at high ther- apeutic doses (.35,000 units q24h) plasma recovery is almost complete.34 After entering the bloodstream, heparin binds to a number of plasma proteins other than AT, reducing its anticoagulant activity. This phenomenon contrib- utes to the variability of the anticoagulant response to heparin among patients with thromboembolic disor- ders38 and to the laboratory phenomenon of heparin resistance.39 Heparin also binds to endothelial cells40 and macrophages, a property that further complicates its pharmacokinetics. Binding of heparin to von Willebrand factor also inhibits von Willebrand factor- dependent platelet function.41 Heparin is cleared through a combination of a rapid saturable and a much slower rst-order mecha- nism (Fig 3).42-44 The saturable phase of heparin clearance is believed to be due to binding to endothe- lial cell receptors45 and macrophages.46 Bound hep- arin is internalized and depolymerized (Fig 4).47,48 The slower nonsaturable mechanism of clearance is largely renal. At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism. The complex kinetics of clearance render the anticoagulant response to hep- arin nonlinear at therapeutic doses, with both the intensity and duration of effect rising disproportion- ately with increasing dose. 