Dataset Information

Zhou2015 - Blood coagulation model predicting effects of factor Xa inhibitors

ABSTRACT: Blood coagulation model investigating effects of Xa-inhibitors (Rivaroxaban and Apixaban). Model is an extension of Pohl1994 and reduced from Wajima2009. Encoding the model from the supplementary files results in 43 species, 82 reactions and 111 parameters. Including the drug (Xa-inhibitor) and drug-Xa complexes results in 46 species, 84 reactions and 115 parameters (+1 dummy variable to change inhibitory kinetic parameters depending on which drug is simulated). The publication lists there being 45 species, 84 reactions and 116 parameters. Publication figure 2 has 45 species present however the complex VIIa:Xa (reaction 51 involving Xa and VIIa) is not shown. This figure also has numerous small errors such as listing IXa:ATIII complex twice (instead of one being XIa:ATIII), not showing XIa:ATIII, typo ('Va' -> Va), typo (IXa + VIIIa -> IXA:'VIIa'). Rate laws for Xa-drug interactions were assumed to be mass action.

SUBMITTER: Matthew Roberts

PROVIDER: MODEL1806070001 | BioModels | 2018-06-07

REPOSITORIES: BioModels

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	MODEL1806070001?filename=Zhou2015.cps	Other
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A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics.

Zhou X X Huntjens Drh D Gilissen Rahj R

CPT: pharmacometrics & systems pharmacology 20151009 11

Factor Xa (FXa) emerged as a promising target for effective anticoagulation and several FXa inhibitors are now available for the prevention of venous thromboembolism. However, in previously reported pharmacokinetic/pharmacodynamic (PK/PD) models, the complex coagulation processes and detailed information of drug action are usually unclear, which makes it difficult to predict clinical outcome at the drug discovery stage. In this study, a large-scale systems pharmacology model was developed based ...[more]

PMID: 26783501

Similar Datasets

Project description:This model is from the article: A model for the stoichiometric regulation of blood coagulation. Hockin MF, Jones KC, Everse SJ, Mann KG. Journal of Biological ChemistryVolume 277, Issue 21, 24 May 2002, Pages 18322 -18333 11893748, Abstract: We have developed a model of the extrinsic blood coagulation system that includes the stoichiometric anticoagulants. The model accounts for the formation, expression, and propagation of the vitamin K-dependent procoagulant complexes and extends our previous model by including: (a) the tissue factor pathway inhibitor (TFPI)-mediated inactivation of tissue factor (TF).VIIa and its product complexes; (b) the antithrombin-III (AT-III)-mediated inactivation of IIa, mIIa, factor VIIa, factor IXa, and factor Xa; (c) the initial activation of factor V and factor VIII by thrombin generated by factor Xa-membrane; (d) factor VIIIa dissociation/activity loss; (e) the binding competition and kinetic activation steps that exist between TF and factors VII and VIIa; and (f) the activation of factor VII by IIa, factor Xa, and factor IXa. These additions to our earlier model generate a model consisting of 34 differential equations with 42 rate constants that together describe the 27 independent equilibrium expressions, which describe the fates of 34 species. Simulations are initiated by "exposing" picomolar concentrations of TF to an electronic milieu consisting of factors II, IX, X, VII, VIIa, V, and VIIII, and the anticoagulants TFPI and AT-III at concentrations found in normal plasma or associated with coagulation pathology. The reaction followed in terms of thrombin generation, proceeds through phases that can be operationally defined as initiation, propagation, and termination. The generation of thrombin displays a nonlinear dependence upon TF, AT-III, and TFPI and the combination of these latter inhibitors displays kinetic thresholds. At subthreshold TF, thrombin production/expression is suppressed by the combination of TFPI and AT-III; for concentrations above the TF threshold, the bolus of thrombin produced is quantitatively equivalent. A comparison of the model with empirical laboratory data illustrates that most experimentally observable parameters are captured, and the pathology that results in enhanced or deficient thrombin generation is accurately described.

Project description:Jones1994_BloodCoagulation This model is built based on the experimental findings described in Lawson et al., 1994 (PMID:8083241) This model is described in the article: A model for the tissue factor pathway to thrombin. II. A mathematical simulation. Jones KC, Mann KG. J. Biol. Chem. 1994 Sep; 269(37): 23367-23373 Abstract: A mathematical simulation of the tissue factor pathway to the generation of thrombin has been developed using a combination of empirical, estimated, and deduced rate constants for reactions involving the activation of factor IX, X, V, and VIII, in the formation of thrombin, as well as rate constants for the assembly of the coagulation enzyme complexes which involve factor VIIIa-factor IXa (intrinsic tenase) and factor Va-Xa (prothrombinase) assembled on phospholipid membrane. Differential equations describing the fate of each species in the reaction were developed and solved using an interactive procedure based upon the Runge-Kutta technique. In addition to the theoretical considerations involving the reactions of the tissue factor pathway, a physical constraint associated with the stability of the factor VIIIa-factor IXa complex has been incorporated into the model based upon the empirical observations associated with the stability of this complex. The model system provides a realistic accounting of the fates of each of the proteins in the coagulation reaction through a range of initiator (factor VIIa-tissue factor) concentrations ranging from 5 pM to 5 nM. The model is responsive to alterations in the concentrations of factor VIII, factor V, and their respective activated species, factor VIIIa and factor Va, and overall provides a reasonable approximation of empirical data. The computer model permits the assessment of the reaction over a broad range of conditions and provides a useful tool for the development and management of reaction studies. This model is hosted on BioModels Database and identified by: BIOMD0000000336. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.