Shibeko2012 - Model of IIa generation
Model Identifier
MODEL1808150001
Short description
Mathematical model of blood coagulation investigating the effects of varied rFVIIa and TF concentration.
Format
SBML
(L2V4)
Related Publication
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Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids.
- Shibeko AM, Woodle SA, Lee TK, Ovanesov MV
- Blood , 7/ 2012 , Volume 120 , Issue 4 , pages: 891-899 , PubMed ID: 22563088
- Office of Blood Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892, USA.
- Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: (1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF) binding, and (2) a high-dose-requiring phospholipid-related pathway of FVIIa action. In the present study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVII-deficient human plasma. From mathematical simulations of our model of FX activation, which were confirmed by thrombin-generation experiments, we conclude that the action of rFVIIa at pharmacologic doses is dominated by the TF-dependent pathway with a minor contribution from a phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In the present study, we present a pathway to reconcile the 2 major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogs currently under development.
Contributors
Submitter of the first revision: Matthew Roberts
Submitter of this revision: Matthew Roberts
Modellers: Matthew Roberts
Submitter of this revision: Matthew Roberts
Modellers: Matthew Roberts
Metadata information
isDescribedBy (1 statement)
isVersionOf (1 statement)
isVersionOf (1 statement)
Curation status
Non-curated
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
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Model files |
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| Shibeko2012_Model_IIa_Generation.xml | SBML L2V4 representation of Shibeko2012 - Model of IIa generation | 45.02 KB | Preview | Download |
Additional files |
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| Shibeko2012_Model_IIa_Generation.cps | Model COPASI file for IIa generation. Parameters k_a^FVIIai_TF,FXa_TFPI and k_d^FVIIai_TF_FXa_TFPI missing and arbitrarily set to 0.1 and 0.01 respectively. ODE for TF has term " 'k_d^FVIIa_TF' * FVII_TF" which was changed to " 'k_d^FVIIa_TF' * FVIIa_TF". Initial conditions given as a range. rFVIIa simulated by changing VIIa initial condition. Clot time was defined by curator as the time of max IIa. | 74.16 KB | Preview | Download |
| Shibeko2012_Model_Xa_Generation.cps | Model COPASI file for Xa generation model. Parameters k_a^FVIIai_TF,FXa_TFPI and k_d^FVIIai_TF_FXa_TFPI missing and arbitrarily set to 0.1 and 0.01 respectively. ODE for TF has term " 'k_d^FVIIa_TF' * FVII_TF" which was changed to " 'k_d^FVIIa_TF' * FVIIa_TF". Initial conditions given as a range. rFVIIa simulated by changing VIIa initial condition. | 82.53 KB | Preview | Download |
| fig6B.png | Attempt at reproducing figure 6. Clot time was defined by curator as time of max IIa. | 16.47 KB | Preview | Download |
- Model originally submitted by : Matthew Roberts
- Submitted: Aug 15, 2018 4:07:31 PM
- Last Modified: Aug 15, 2018 4:07:31 PM
Revisions
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Version: 2
- Submitted on: Aug 15, 2018 4:07:31 PM
- Submitted by: Matthew Roberts
- With comment: Edited model metadata online.