Mathematical models of coagulation - Are we there yet?

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 regulate haemostasis. However, current models vary in the reactions they capture, in reaction rates used, and their validation is restricted by a lack of large coherent datasets, resulting in questioning of their utility.

OBJECTIVES AND METHODS: To address this debate, we systematically assessed current models against a large dataset, using plasma coagulation factor levels from 348 individuals with normal haemostasis as inputs, and compared model predictions with measured thrombin generation. To identify the causes of these variations, we quantified and compared 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 haemostatic response across the whole cohort, and 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 those reactions of high influence on measured thrombin generation, such as the contribution of Factor XI.

CONCLUSIONS: 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 haemostatic profile could be used for assessing antithrombotics or as a tool for precision medicine.