title: Simulation model for thrombin generation in plasma.
abstract: A simulation model for the production of thrombin in plasma is presented. Values of the reaction rate constants as determined in purified systems are used and the model is tested by comparison of simulations of factor Xa, factor Va and thrombin generation curves with experimental data obtained in thromboplastin-activated plasma. Simulations of the effect of hirudin indicate that factor V is predominantly activated by thrombin and not by factor Xa. The model predicts a threshold value for the factor Xa production which, if exceeded, results in explosive and complete activation of prothrombinase. The dependence of this threshold value on different negative feedback reactions, e.g. the inactivation of thrombin and factor Xa by antithrombin III (+ heparin), is investigated. The threshold value, for control plasma in the range of 1-10 pM total factor Xa production, can be raised two orders of magnitude by accelerated inactivation of factor Xa and prothrombinase but is hardly affected by a tenfold increase in the rate of thrombin inactivation or by increased production of activated protein C. This latter effect, however, results in a more gradual input-response relation between factor Xa input and the extent of prothrombinase activation.
authors.affiliation: Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: G M
authors.initials: GM
authors.lastname: Willems
authors.forename: T
authors.initials: T
authors.lastname: Lindhout
authors.forename: W T
authors.initials: WT
authors.lastname: Hermens
authors.forename: H C
authors.initials: HC
authors.lastname: Hemker
mesh_terms: D003198:Computer Simulation; D004789:Enzyme Activation; D015943:Factor Va / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D005246:Feedback; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011486:Protein C / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D006629:Hirudins; D011486:Protein C; D015943:Factor Va; D011516:Prothrombin; D013925:Thromboplastin; D013917:Thrombin; D015951:Factor Xa