Pharmacological activities of heparin chains: should our past knowledge be revised?

Unfractionated heparin is a heterogeneous mixture of sulphated polysaccharides. The anticoagulant activity of unfractionated heparin is mainly accounted for by its fractions with a sequence with binding affinity for antithrombin III. The interaction of heparin with antithrombin III markedly enhances the ability of the latter to inhibit factor Xa and thrombin. Only about one third of the unfractionated heparin molecules contain the high-affinity material and its distribution along the heparin molecules appears to be random-hence the development of low-molecular-weight heparins. Most of the saccharide chains of low-molecular-weight heparins are composed of less than 18 saccharides and have reduced ability to inhibit thrombin relative to their ability to inhibit factor Xa. The potential dissociation of anti-factor IIa activity and the anti-Xa activity provided the pharmacological background for the clinical development of low-molecular-weight heparins. During the last few years, evidence has accumulated on the importance of anti-factor IIa for the expression of the antithrombotic activity of low-molecular-weight heparins. This paper reviews the evidence and revises our knowledge about the pharmacological activity of the heparin chains.