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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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REVIEW ARTICLES
Directing thrombin
David A. Lane,
Helen Philippou, and
James A. Huntington
From the Department of Haematology, Imperial College London, United Kingdom; the Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom; and the Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
Following initiation of coagulation as part of the hemostatic 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 scrutinized 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 draws together much recent work that has helped clarify structure function relationships of thrombin. It then attempts to provide a cogent proposal to explain how thrombin activity is directed during the hemostatic response.
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