How does low-molecular-weight heparin (LMWH) work?

By William Aird

LMWH is derived from full-length, highly sulfated polysaccharide (unfractionated heparin) harvested from porcine mucosal tissue by chemical or enzymatic depolymerization, resulting in smaller size polysaccharide fragments (6-22 sugar residues). Heparin binds to antithrombin through a pentasaccharide region leading to the inhibition of thrombin and Factor Xa (FXa). . Only one third of heparin polysaccharide chains display anticoagulant properties implying that a specific sequence in the polysaccharide chain is required for this activity. The number of polysaccharide fragments determines which serine proteases are inactivated by antithrombin. Inactivation of thrombin requires that the heparin be long enough (> 18 sugar residues) to bind both antithrombin and thrombin, serving as a bridge between the protease and its inhibitor. By contrast, inactivation of FXa simply requires the pentasaccharide sequence to bind to antithrombin (there is no need for bridging FXa with antithrombin). The majority of LMWH is shorter than this threshold. Thus, most of its activity is exerted through factor Xa inhibition.

Inactivation of factor Xa and thrombin (IIa) by heparin. Heparin binds to antithrombin through a high affinity pentasaccharide sequence (noted by colored shapes). Antithrombin conformational structure is changed by binding to heparin, accelerating its interaction with thrombin or factor Xa. (Top) Unfractionated heparin (UFH) can inactivate both thrombin and factor Xa. High-molecular-weight heparin (> 18 sugar residues) is required to bind to thrombin, and binding to thrombin is required for its inactivation. (Bottom) Low molecular weight heparin (LMWH) catalyzes the inactivation of factor Xa by antithrombin. Because the majority of polysaccharide fragments in LMWH contain < 18 saccharide units, LMWH has less inhibitory activity against thrombin than UFH. Based on Kumano et al.

Related FAQs: