Orfeo2010 - Simulating the effects of fondaparinux and Rivaroxaban on thrombin generation
Reused mathematical model (Hockin et al., 2002) of blood coagulation simulating the effects of coagulation factor inhibitors, fondaparinux (synthetic heparin) and Rivaroxaban. Fondaparinux (Fpx) simulated to reversibly bind with ATIII before irreversibly binding to Xa, IXa, mIIa, TF:VIIa, Xa:Va and IIa. Rivaroxaban simulated to bind reversibly to Xa and Xa:Va.
- Anticoagulation by factor Xa inhibitors.
- Orfeo T, Butenas S, Brummel-Ziedins KE, Gissel M, Mann KG
- Journal of thrombosis and haemostasis : JTH , 8/ 2010 , Volume 8 , Issue 8 , pages: 1745-1753
- Department of Biochemistry, University of Vermont, Colchester, VT, USA.
- Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders, with the selective targeting of factor (F) Xa emerging as a promising approach.To assess anticoagulant strategies targeting FXa.A deterministic computational model of tissue factor (Tf)-initiated thrombin generation and two empirical experimental systems (a synthetic coagulation proteome reconstruction using purified proteins and a whole blood model) were used to evaluate clinically relevant examples of the two available types of FXa-directed anticoagulants [an antithrombin (AT)-dependent agent, fondaparinux, and an AT-independent inhibitor, Rivaroxaban] in experimental regimens relevant to long-term (suppression of new Tf-initiated events) and acute (suppression of ongoing coagulation processes) clinical applications.Computational representations of each anticoagulant's efficacy in suppressing thrombin generation over a range of anticoagulant concentrations in both anticoagulation regimens were validated by results from corresponding empirical reconstructions and were consistent with those recommended for long-term and acute clinical applications, respectively. All three model systems suggested that Rivaroxaban would prove more effective in the suppression of an ongoing coagulation process than fondaparinux, reflecting its much higher reactivity toward the prothrombinase complex.The success of fondaparinux in acute settings in vivo is not explained solely by its properties as an FXa inhibitor. We have reported that FIXa contributes to the long-term capacity of clot-associated catalysts to restart a coagulation process, suggesting that the enhanced anti-FIXa activity of fondaparinux-AT may be critical to its success in acute settings in vivo.
|Orfeo2010.xml||SBML L2V4 representation of Orfeo2010 - Simulating the effects of fondaparinux and Rivaroxaban on thrombin generation||161.37 KB||Preview | Download|
|fig.jpg||Simulation results either peak at the wrong time (figure 3, Riva:4nM) or the change in thrombin occurs too rapidly (figure 2, Fpx:125nM).||25.24 KB||Preview | Download|
|Orfeo2010.cps||Model CPASI file. Reused Hockin2002 model with TF initial concentration set to 25pM. 9 new reactions from table 1 added. Simulation results either peak at the wrong time (figure 3, Riva:4nM) or the change in thrombin occurs too rapidly (figure 2, Fpx:125nM).||210.67 KB||Preview | Download|