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. Thus, the apparent bio- logic half-life of heparin increases from approximately 30 min after an IV bolus of 25 units/kg, to 60 min with an IV bolus of 100 units/kg, to 150 min with a 1.1.3 Initial Dosing: The ef cacy of heparin in the initial treatment of VTE is critically dependent on patients assigned to lower starting doses of heparin had higher recurrence rates than those treated with higher doses. In the randomized study by Hull and associates,33 patients with venous thrombosis were of HCII requires a higher concentration of heparin than that needed to promote thrombin inhibition by AT. Heparin s capacity to activate HCII is also chain length-dependent, with maximum catalysis requiring heparin chains composed of a minimum of 24 sac- charide units.12 Consequently, LMWHs are less effec- tive at activating HCII than is heparin. In vitro, heparin binds to platelets and, depending on the experimental conditions, can either induce or inhibit platelet aggregation.22,23 High-molecular- weight heparin fractions with low af nity for AT have a greater effect on platelet function than low- molecular-weight fractions with high AT af nity.24 Heparin can prolong the bleeding time in humans,25 and it enhances blood loss from the microvasculature in rabbits.20,26,27 The interaction of heparin with platelets26 and endothelial cells20 may contribute to heparin-induced bleeding by mechanisms indepen- dent of its anticoagulant effect.27 In addition to its anticoagulant effects, heparin attenuates the proliferation of vascular smooth muscle cells,28,29 inhibits osteoblast formation, and activates osteoclasts; these last two effects promote bone loss.30,31 Heparin-induced thrombocytopenia (HIT) is the most important nonhemorrhagic side effect of heparin. 