title: Regulation of coagulation by protein S.
abstract: OBJECTIVE
  Protein S has been one of the least mechanistically understood amongst the vitamin K-dependent coagulation proteins, and diagnosis of protein S deficiency and quantification of the associated thrombotic risk are not straightforward. In this review, the regulation of thrombin generation by protein S and the pathophysiological implications of protein S deficiency are discussed in the light of recent findings on the anticoagulant function(s) of protein S.
  
  
  RESULTS
  Protein S expresses both activated protein C-dependent and activated protein C-independent anticoagulant activities, but the former is generally believed to be lost upon binding of protein S to C4b-binding protein. Recently it has been shown that protein S acts as a cofactor of tissue factor pathway inhibitor in the down regulation of factor X-activation, which provides a mechanistic basis for the activated protein C-independent anticoagulant activity of protein S in plasma. In addition, reevaluation of the role of the protein S/C4b-binding protein complex has demonstrated that C4b-binding protein-bound protein S does express activated protein C-cofactor activity, especially during the inactivation of factor Va Leiden.
  
  
  CONCLUSIONS
  These findings underscore the central role of protein S in the regulation of coagulation and may have important implications for the evaluation of the thrombotic risk associated with protein S deficiency.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Castoldi
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
mesh_terms: D001777:Blood Coagulation; D006801:Humans; D017293:Protein S / Q000502:physiology*; D018455:Protein S Deficiency / Q000503:physiopathology; D013917:Thrombin / Q000378:metabolism
chemical_list: D017293:Protein S; D013917:Thrombin