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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2605-2612.
Prepublished online as a Blood First Edition Paper on June 30, 2005; DOI 10.1182/blood-2005-04-1710.
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Submitted April 27, 2005
Accepted June 5, 2005
Directing thrombin
David A Lane*, Helen Philippou, and James A Huntington
Department of Haematology, Imperial College London, London, United Kingdom
Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
* Corresponding author; email: d.lane{at}imperial.ac.uk.
Following initiation of coagulation as part of the haemostatic response to injury, thrombin is generated from its inactive precursor prothrombin by factor Xa as part of the prothrombinase complex. Thrombin then has multiple roles. The way in which thrombin interacts with its many substrates has been carefully scrutinised in the past decades but until recently there has been little consideration of how its many functions are coordinated or directed. Any understanding of how it is directed requires knowledge of its structure, how it interacts with its substrates and the role of any cofactors for its interaction with substrates. Recently, many of the interactions of thrombin have been clarified by crystal structure and site directed mutagenesis analyses. These analyses have revealed common residues used for recognition of some substrates and overlapping surface exosites used for recognition by cofactors. As many of its downstream reactions are cofactor driven, competition between cofactors for exosites must be a dominant mechanism that determines the fate of thrombin. This review will draw together much recent work that has helped clarify structure function relationships of thrombin. It will then attempt to provide a cogent proposal to explain how thrombin activity is directed during the haemostatic response.
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