Atherosclerosis Testing the Water

Acritical regulatory pathway of the blood coagulationcascade is provided by antithrombin, a serine proteaseinhibitor (serpin) that specifically shuts down the activ-ity of factor Xa and thrombin.1 Much of what we know about the mechanisms of antithrombin function has come from studies using the cofactor heparin, that allosterically activates antithrom-bin for optimal presentation to the target protease.1,2 In the case of factor Xa, this activation is sufficient for neutralization of enzyme function.2 The heparin-assisted activation of antithrom-bin is of clinical relevance as heparinoids retain center stage in anticoagulant therapy.3 However, the extracellular environment in which antithrombin functions in vivo is populated by a variety of glycosaminoglycans (GAGs) like heparin sulfate, dermatan sulfate and chondroitin sulfate (CS). GAGs have anticoagulant activity, but they often lack the heparin pentasaccharide unit required for antithrombin activation, which has raised important questions about their precise mechanism of action