Journal Article

A mathematical model of lipid‐mediated thrombin generation

Sharene D. Bungay, Patricia A. Gentry and Rodney D. Gentry

in Mathematical Medicine and Biology: A Journal of the IMA

Published on behalf of Institute of Mathematics and its Applications

Volume 20, issue 1, pages 105-129
Published in print March 2003 | ISSN: 1477-8599
Published online March 2003 | e-ISSN: 1477-8602 | DOI: http://dx.doi.org/10.1093/imammb/20.1.105
A mathematical model of lipid‐mediated thrombin generation

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Thrombin is an enzyme that is generated in both vascular and non‐vascular systems. In blood coagulation, a fundamental process in all species, thrombin induces the formation of a fibrin clot. A dynamical model of thrombin generation in the presence of lipid surfaces is presented. This model also includes the self‐regulating thrombin feedback reactions, the thrombomodulin–protein C‐protein S inhibitory system, tissue factor pathway inhibitor (TFPI), and the inhibitor, antithrombin (AT). The dynamics of this complex system were found to be highly lipid dependent, as would be expected from experimental studies. Simulations of this model indicate that a threshold lipid level is required to generate physiologically relevant amounts of thrombin. The dependence of the onset, the peak levels, and the duration of thrombin generation on lipid was saturable. The lipid concentration affects the way in which the inhibitors modulate thrombin production. A novel feature of this model is the inclusion of the dynamical protein C pathway, initiated by thrombin feedback. This inhibitory system exerts its effects on the lipid surface, where its substrates are formed. The maximum impact of TFPI occurs at intermediate vesicle concentrations. Inhibition by AT is only indirectly affected by the lipid since AT irreversibly binds only to solution phase proteins. In a system with normal plasma concentrations of the proteins involved in thrombin formation, the combination of these three inhibitors is sufficient both to effectively stop thrombin generation prior to the exhaustion of its precursor, prothrombin, and to inhibit all thrombin formed. This model can be used to predict thrombin generation under extreme lipid conditions that are difficult to implement experimentally and to examine thrombin generation in non‐vascular systems.

Keywords: thrombin; kinetic model; lipid vesicle; coagulation; inhibition

Journal Article.  0 words. 

Subjects: Applied Mathematics ; Biomathematics and Statistics

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