Mathematical models of coagulation—are we there yet?

Owen, Matt J.; Wright, Joy R.; Tuddenham, Edward G.D.; King, John R.; Goodall, Alison H.; Dunster, Joanne L.

Abstract

Background
Mathematical models of coagulation have been developed to mirror thrombin generation in plasma, with the aim of investigating how variation in coagulation factor levels regulates hemostasis. However, current models vary in the reactions they capture and the reaction rates used, and their validation is restricted by a lack of large coherent datasets, resulting in questioning of their utility.

Objectives
To address this debate, we systematically assessed current models against a large dataset, using plasma coagulation factor levels from 348 individuals with normal hemostasis to identify the causes of these variations.

Methods
We compared model predictions with measured thrombin generation, quantifying and comparing the ability of each model to predict thrombin generation, the contributions of the individual reactions, and their dependence on reaction rates.

Results
We found that no current model predicted the hemostatic response across the whole cohort and all produced thrombin generation curves that did not resemble those obtained experimentally. Our analysis has identified the key reactions that lead to differential model predictions, where experimental uncertainty leads to variability in predictions, and we determined reactions that have a high influence on measured thrombin generation, such as the contribution of factor XI.

Conclusion
This systematic assessment of models of coagulation, using large dataset inputs, points to ways in which these models can be improved. A model that accurately reflects the effects of the multiple subtle variations in an individual’s hemostatic profile could be used for assessing antithrombotics or as a tool for precision medicine.

Citation

Owen, M. J., Wright, J. R., Tuddenham, E. G., King, J. R., Goodall, A. H., & Dunster, J. L. (2024). Mathematical models of coagulation—are we there yet?. Journal of Thrombosis and Haemostasis, 22(6), 1689-1703. https://doi.org/10.1016/j.jtha.2024.03.009

• Journal Article Type: Article
• Acceptance Date: Mar 12, 2024
• Online Publication Date: Mar 21, 2024
• Publication Date: 2024-06
• Deposit Date: Jun 12, 2024
• Publicly Available Date: Jun 12, 2024
• Journal: Journal of Thrombosis and Haemostasis
• Print ISSN: 1538-7933
• Electronic ISSN: 1538-7836
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 22
• Issue: 6
• Pages: 1689-1703
• DOI: https://doi.org/10.1016/j.jtha.2024.03.009
• Keywords: coagulation factors; kinetics; mathematical models; systems biology; thrombin
• Public URL: https://nottingham-repository.worktribe.com/output/33012158
• Publisher URL: https://www.jthjournal.org/article/S1538-7836(24)00167-3/fulltext
• Additional Information: This article is maintained by: Elsevier; Article Title: Mathematical models of coagulation—are we there yet?; Journal Title: Journal of Thrombosis and Haemostasis; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.jtha.2024.03.009; Content Type: article; Copyright: © 2024 The Authors. Published by Elsevier Inc. on behalf of International Society on Thrombosis and Haemostasis.