107 - Antithrombin

Summary

Antithrombin (AT) is considered to be the most important natural anticoagulant found in plasma. AT irreversibly neutralizes thrombin, factor Xa, and other activated proteases of the coagulation cascade. This neutralization reaction is dramatically enhanced by a longstanding therapeutic anticoagulant, heparin. Endothelial cells (ECs) produce HS^AT+ – a specific form of heparan sulfate (HS) that is biochemically related to heparin. In vitro, this EC glycosaminoglycan (GAG) also can catalyze AT neutralization of coagulation proteases; consequently, HS^AT+ has been designated as anticoagulant HS. Based on heparin's pharmacological mechanism of action, it has long been proposed that, in vivo, HS^AT+ produced by the endothelium would activate AT and thereby regulate the antithrombotic tone of the blood vessel wall. The objective of this chapter is to evaluate whether the endothelium deploys HS^AT+ as an output component to regulate coagulation. It is readily apparent that this issue has yet to be conclusively resolved. However, HS^AT+ might participate in an alternative or additional function: the anti-inflammatory signaling activity of AT. Consequently, this chapter also evaluates whether the endothelium deploys HS^AT+ as an input component that mediates cell signaling.

HISTORY

AT also has been referred to as AT-II/heparin cofactor and AT-III. Various names were proposed because AT initially was identified as a biochemical activity. At one point, four distinct antithrombin activities of plasma were described. AT-I and AT-IV reflected the thrombin inhibitory activities of fibrin and a cleavage fragment of prothrombin, respectively. AT-II/heparin cofactor and AT-III respectively reflected the heparin-dependent and -independent anticoagulant activities of AT (1). Fortunately this arcane nomenclature has been abandoned (2).