Reaction Mechanisms and Kinetic Constants used in Mechanistic Models of Coagulation and Fibrinolysis

Abstract

Computational modeling has gained a strong foothold as a tool for understanding and simulating biological phenomena like blood coagulation. However, exceptional complexity of these phenomena (that include hundreds of individual biochemical processes and a few biophysical processes) complicates development of reliable models and interpretation of the results. It is thus of great importance that a model of hemostasis designed for a particular application should be reproducible, apart from making robust predictions. Such a model would further reflect useful pharmacological implications not only with respect to identifying drug targets but also in understanding drug effects on their respective targets. We show, using a sample model, that model predictions vary significantly with the use of different values available in the literature for the same kinetic constant. We thus highlight the importance of having consensus of kinetic constants used in the formulation of mechanistic models for coagulation, and document values for each kinetic constant that can be used in such models, and for varying reaction conditions (synthetic, in vitro, in vivo).

Mathematics of Pharmacokinetics and Pharmacodynamics: Diversity of Topics, Models and Methods

“…Under these settings, M is the number of cell producing IFN, x k denotes the cell location, ρ is the production rate, α the degradation/absorbtion rate of IFN. There is a non-homogeneity in diffusion coefficients D (1,2,3) = D * , D (4) = 0.1D * , D (5) = 0.01D * as suggested by experimentally observed differences of small molecular tracers distribution in LN domains [14]. The regions of LNs that contain T lymphocytes (the cortical and para-cortical zones or the Ω 5 region) are characterised by weak molecular diffusion, which is associated with poor hydraulic conductivity [14].…”

A mathematical model to quantify the effects of platelet count, shear rate, and injury size on the initiation of blood coagulation under venous flow conditions

“…Among the challenges that face the use of mathematical modelling as a tool to conduct robust quantitative studies of thrombus are the disparities in the values of blood coagulation kinetic constants reported in the literature. These disparities stem their origin from different settings in which these parameters are measured, which calls into question the validity of the predictions made by the models of thrombus formation [25]. Furthermore, difficulties in performing in vivo and in vitro experiments of thrombus growth represent an important challenge, that must be overcome for the validation of computational models.…”