%0 Journal Article
%T Modeling of human factor Va inactivation by activated protein C
%A Maria Bravo
%A Thomas Orfeo
%A Kenneth G Mann
%A Stephen J Everse
%J BMC Systems Biology
%D 2012
%I BioMed Central
%R 10.1186/1752-0509-6-45
%X A model of human APC inactivation of prothrombinase was constructed in a stepwise fashion by analyzing time courses of FVa inactivation in empirical reaction systems with increasing number of interacting components and generating corresponding model constructs of each reaction system. Reaction mechanisms, rate constants and equilibrium constants informing these model constructs were initially derived from various research groups reporting on APC inactivation of FVa in isolation, or in the presence of FXa or prothrombin. Model predictions were assessed against empirical data measuring the appearance and disappearance of multiple FVa degradation intermediates as well as prothrombinase activity changes, with plasma proteins derived from multiple preparations. Our work integrates previously published findings and through the cooperative analysis of in vitro experiments and mathematical constructs we are able to produce a final validated model that includes 24 chemical reactions and interactions with 14 unique rate constants which describe the flux in concentrations of 24 species.This study highlights the complexity of the inactivation process and provides a module of equations describing the Protein C pathway that can be integrated into existing comprehensive mathematical models describing tissue factor initiated coagulation.One of the critical events in blood coagulation is the conversion of large amounts of the zymogen prothrombin to the enzyme thrombin by the enzymatic complex prothrombinase. The prothrombinase complex is formed by the non-covalent interaction between the enzyme factor Xa (FXa) and the non-enzymatic cofactor factor Va (FVa) on a phospholipid surface in the presence of calcium [1-3]. The procofactor, factor V, is activated by thrombin to generate a calcium-associated two chain molecule, composed of a heavy chain (FVaHC) and light chain (FVaLC) (Figure 1) [4,5]. The prothrombinase complex increases thrombin generation over FXa alone by 5 orders of magn
%K Coagulation
%K Factor Va
%K Activated protein C
%K Prothrombinase
%K Prothrombin
%K Factor Xa
%K Mathematical modeling
%U http://www.biomedcentral.com/1752-0509/6/45