title: Protein S is a cofactor for tissue factor pathway inhibitor.
abstract: Protein S is a vitamin K-dependent protein that acts as a cofactor of the anticoagulant protein APC. However, protein S also exhibits anticoagulant activity in the absence of APC. Thrombin generation experiments in normal plasma and in plasma deficient in tissue factor pathway inhibitor (TFPI) and/or protein S demonstrated that protein S stimulates the inhibition of TF by TFPI. Kinetic analysis in model systems containing purified proteins showed that protein S enhances the formation of the binary FXa:TFPI complex by reducing the Ki of TFPI from approximately 4 nM to approximately 0.5 nM. Enhancement of inhibitory activity of TFPI by protein S is only observed with full-length TFPI and in the presence of a negatively charged phospholipid surface. The Ki decrease brings the TFPI concentration necessary for FXa:TFPI complex formation within range of the plasma TFPI concentration which increases FXa:TFPI complex formation and accelerates feedback inhibition of the TF pathway by enhancing the formation of the quaternary TFPI:FXa:TF:FVIIa complex. Thus, protein S is not only a cofactor of APC, but also of TFPI. A reduced TFPI cofactor activity may contribute to the increased risk of venous thrombosis in protein-S deficient individuals. Using calibrated automated thrombography we have developed two assays that enable quantification of the functional activity of the TFPI/protein S system in plasma. These assays show that the activity of the TFPI/protein S system is greatly impaired in oral contraceptive users.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. j.rosing@bioch.unimaas.nl
authors.forename: J
authors.initials: J
authors.lastname: Rosing
authors.forename: L F A
authors.initials: LF
authors.lastname: Maurissen
authors.forename: S N
authors.initials: SN
authors.lastname: Tchaikovski
authors.forename: G
authors.initials: G
authors.lastname: Tans
authors.forename: T M
authors.initials: TM
authors.lastname: Hackeng
mesh_terms: D001779:Blood Coagulation Factors / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017293:Protein S / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013927:Thrombosis / Q000473:pathology
chemical_list: D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; D008074:Lipoproteins; D017293:Protein S; D011956:Receptors, Cell Surface; C091963:activated protein C receptor; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D013917:Thrombin