Chapter

Heparin - A Century of Progress

Volume 207 of the series Handbook of Experimental Pharmacology pp 43-61

Date:

The Anticoagulant and Antithrombotic Mechanisms of Heparin

  • Elaine GrayAffiliated withNational Institute for Biological Standards and Control Email author 
  • , John HogwoodAffiliated withNational Institute for Biological Standards and Control Email author 
  • , Barbara MulloyAffiliated withNational Institute for Biological Standards and Control Email author 

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Abstract

The molecular basis for the anticoagulant action of heparin lies in its ability to bind to and enhance the inhibitory activity of the plasma protein antithrombin against several serine proteases of the coagulation system, most importantly factors IIa (thrombin), Xa and IXa. Two major mechanisms underlie heparin’s potentiation of antithrombin. The conformational changes induced by heparin binding cause both expulsion of the reactive loop and exposure of exosites of the surface of antithrombin, which bind directly to the enzyme target; and a template mechanism exists in which both inhibitor and enzyme bind to the same heparin molecule. The relative importance of these two modes of action varies between enzymes. In addition, heparin can act through other serine protease inhibitors such as heparin co-factor II, protein C inhibitor and tissue factor plasminogen inhibitor. The antithrombotic action of heparin in vivo, though dominated by anticoagulant mechanisms, is more complex, and interactions with other plasma proteins and cells play significant roles in the living vasculature.

Keywords

Antithrombin Factor Xa Heparin cofactor II Protein C inhibitor Thrombin Tissue factor plasminogen activator