LMWHs are polysulfated glycosaminoglycans that are about one third the molecular weight of UFH. LMWHs have a mean molecular weight of 4,000 to 5,000 d (about 15 monosaccharide units per molecule), with a range of
2,000 to 9,000 d. The various LMWHs approved for use in Europe, Canada, and the United States are shown in Table 6. Because LMWHs are prepared by different methods of depolymerization, they differ to some extent in pharmacokinetic properties and anticoagulant profiles, and are not clinically interchangeable.
The depolymerization of heparin yields low-molecular-weight fragments with reduced binding to proteins or cells (Table 7). Indeed, all of the anticoagulant, pharmacokinetic, and other biological differences between heparin and LMWH can be explained by the relatively lower binding properties of LMWH. Thus, compared to heparin, LMWHs have a reduced ability to inactivate thrombin because the smaller fragments cannot bind simultaneously to AT and thrombin. On the other hand, since bridging between AT and factor Xa is less critical for anti-factor Xa activity, the smaller fragments inactivate factor Xa almost as well as larger molecules. Reduced binding to plasma proteins is responsible for the more predictable dose-response relationship of LMWHs. A lower incidence of binding to macrophages and endothelial cells increases the plasma half-life of LMWH compared to UFH, whereas reducing binding to platelets and PF4 may explain the lower incidence of HIT. Finally, the reduced binding of LMWH to osteoblasts results in a lower incidence of activation of osteoclasts and lower levels of bone loss.
Like heparin, LMWHs produce their major anticoagulant effect by activating AT. The interaction with AT is mediated by a unique pentasaccharide sequence, which is found on fewer than one third of LMWH molecules. Because a minimum chain length of 18 saccharides (which includes the pentasaccharide sequence) is required for the formation of ternary complexes among heparin chains, AT, and thrombin, only the 25 to 50% of LMWH species that are above this critical chain length are able to inactivate thrombin. In contrast, all LMWH chains containing the high-affinity pentasaccharide catalyze the inactivation of factor Xa. Because virtually all heparin molecules contain at least 18 saccharide units, heparin has an anti-factor Xa/anti-factor IIa ratio of 1:1. In contrast, commercial LMWHs have anti-factor Xa/anti-IIa ratios between 2:1 and 4:1, depending on their molecular size distribution.
LMWHs have been evaluated in a large number of randomized clinical trials and have been shown to be safe and effective for the prevention and treatment of venous thrombosis. More recently, LMWH preparations also have been evaluated in patients with acute pulmonary embolism and in those with unstable angina. The pharmacokinetic differences between UFH and LMWH can be explained largely by the decreased propensity for LMWH to bind proteins, endothelial cells, and macrophages, as discussed above.