Kinetic Modeling Sheds Light on the Mode of Action of Recombinant Factor VIIa on Thrombin Generation
ARMY MEDICAL RESEARCH AND MATERIEL COMMAND FORT DETRICK MD TELEMEDICINE AND ADVANCED TECH RESEARCH CENTER
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Introduction. The therapeutic potential of a hemostatic agent can be assessed by investigating its effects on the quantitative parameters of thrombin generation. For recombinant activated factor VII rFVIIa - a promising hemostasis-inducing biologic - experimental studies addressing its effects on thrombin generation yielded disparate results. To elucidate the inherent ability of rFVIIa to modulate thrombin production, it is necessary to identify rFVIIa-induced effects that are compatible with the available biochemical knowledge about thrombin generation mechanisms. Materials and Methods. The existing body of knowledge about coagulation biochemistry can be rigorously represented by a computational model that incorporates the known reactions and parameter values constituting the biochemical network. We used a thoroughly validated numerical model to generate activated factor VII FVIIa titration curves in the cases of normal blood composition, hemophilia A and B blood, blood lacking factor VII, blood lacking tissue factor pathway inhibitor, and diluted blood. We utilized the generated curves to perform systematic fold-change analyses for five quantitative parameters characterizing thrombin accumulation. Results. The largest fold changes induced by increasing FVIIa concentration were observed for clotting time thrombin peak time, and maximum slope of the thrombin curve. By contrast, thrombin peak height was much less affected by FVIIa titrations, and the area under the thrombin curve stayed practically unchanged. Comparisons with experimental data demonstrated that the computationally derived patterns can be observed in vitro. Conclusions. rFVIIa modulates thrombin generation primarily by accelerating the process, without significantly affecting the total amount of generated thrombin.
- Medicine and Medical Research