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. This is discussed by Linkins et al32 in this supplement. Figure 2. Molecular weight distribution of LMWHs and hep- arin. LMWH 5 low-molecular-weight heparin. (Reprinted with permission from CHEST.7) Table 2 Anticoagulant Effects of Heparin Effect Comment Binds to AT and catalyzes the inactivation of thrombin and factors IIa, Xa, IXa, XIa and XIIa Major mechanism for anticoagulant effect, produced by only one-third of heparin molecules (those containing the unique AT-binding pentasaccharide) Binds to HCII and catalyzes inactivation of factor IIa Requires high concentrations of heparin and is independent of the pentasaccharide Binds to factor IXa and inhibits factor X Activation Requires very high concentration of heparin and is AT- and HCII-independent AT5antithrombin; HCII5heparin cofactor II. 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e27S weight-based nomogram (starting dose, 80 units/kg bolus followed by 18 units/kg/h by infusion). 