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The Anticoagulant and Antithrombotic Mechanisms of Heparin

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Heparin - A Century of Progress

Part of the book series: Handbook of Experimental Pharmacology ((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.

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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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Authors and Affiliations

  1. National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potter’s Bar, Hertfordshire, EN6 3QG, UK

    Elaine Gray, John Hogwood & Barbara Mulloy

Authors
  1. Elaine Gray
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  2. John Hogwood
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  3. Barbara Mulloy
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Corresponding authors

Correspondence to Elaine Gray , John Hogwood or Barbara Mulloy .

Editor information

Editors and Affiliations

  1. School of Pharmacy, University of London, Brunswick Square 29-39, London, WC1N 1AX, United Kingdom

    Rebecca Lever

  2. Standards and Control, National Institute for Biological, Blanche Lane, Potters Bar, Herts., EN6 3QG, United Kingdom

    Barbara Mulloy

  3. King's College London, Sackler Inst. Pulmonary Pharmacology, Waterloo Campus, London, SE1 9NH, United Kingdom

    Clive P. Page

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Gray, E., Hogwood, J., Mulloy, B. (2012). The Anticoagulant and Antithrombotic Mechanisms of Heparin. In: Lever, R., Mulloy, B., Page, C. (eds) Heparin - A Century of Progress. Handbook of Experimental Pharmacology, vol 207. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23056-1_3

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