title: C4b-binding protein inhibits the factor V-dependent but not the factor V-independent cofactor activity of protein S in the activated protein C-mediated inactivation of factor VIIIa.
abstract: Activated protein C (APC) is an important inactivator of coagulation factors Va and VIIIa. In the inactivation of factors Va and VIIIa, protein S serves as a cofactor to APC. Protein S can bind to C4b-binding protein (C4BP), and thereby loses its cofactor activity to APC. By modulating free protein S levels, C4BP is an important regulator of protein S cofactor activity. In the factor VIIIa inactivation, protein S and factor V act as synergistic cofactors to APC. We investigated the effect of C4BP on both the factor V-independent and factor V-dependent cofactor activity of protein S in the factor VIIIa inactivation using a purified system. Protein S increased the APC-mediated inactivation of factor VIIIa to 60% and in synergy with protein S, factor V at equimolar concentrations increased this effect further to 90%. The protein S/factor V synergistic effect was inhibited by preincubation of protein S and factor V with a four-fold molar excess of C4BP. However, C4BP did not inhibit the factor V-independent protein S cofactor activity in the purified system whereas it inhibited the cofactor activity in plasma. We conclude that C4BP-bound protein S retains its cofactor activity to APC in the factor VIIIa inactivation.
authors.affiliation: Department of Haematology, University Medical Center, Utrecht, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: van de Poel
authors.forename: J C
authors.initials: JC
authors.lastname: Meijers
authors.forename: B N
authors.initials: BN
authors.lastname: Bouma
mesh_terms: D000925:Anticoagulants / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005165:Factor V / Q000494:pharmacology*; D015944:Factor VIIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008567:Membranes, Artificial; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011486:Protein C / Q000378:metabolism / Q000494:pharmacology*; D017293:Protein S / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D016167:Integrin alphaXbeta2; D008567:Membranes, Artificial; D010743:Phospholipids; D011486:Protein C; D017293:Protein S; D015944:Factor VIIIa; D005165:Factor V