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The Anticoagulant and Antithrombotic Mechanisms of Heparin

  • Elaine Gray
  • John Hogwood
  • Barbara Mulloy
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 207)

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 

Abbreviations

APC

Activated protein C

AT

Antithrombin

DS

Dermatan sulphate

EPCR

Endothelial protein C receptor

fIIa

Factor IIa (thrombin)

fVIIIa

Factor VIIIa

fIXa

Factor IXa

fVa

Factor Va

fXa

Factor Xa

fXIa

Factor XIa

HCII

Heparin cofactor II

HRG

Histidine-rich glycoprotein

HS

Heparan sulphate

MW

Molecular weight

PCI

Protein C Inhibitor

PF4

Platelet factor 4

RCL

Reactive centre loop

TFPI

Tissue Factor Pathway Inhibitor

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.National Institute for Biological Standards and ControlHertfordshireUK

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