Abstract
Although reversible platelet aggregation observed in response to ADP stimulation in the presence of calcium is a well-known phenomenon, its mechanisms are not entirely clear. To study them, we developed a simple kinetic mass-action-law-based mathematical model to use it in combination with experiments. Light transmission platelet aggregometry (LTA) induced by ADP was performed for platelet-rich plasma or washed platelets using both conventional light transmission and aggregate size monitoring method based on optical density fluctuations. Parameter values of the model were determined by means of parameter estimation techniques implemented in COPASI software. The mathematical model was able to describe reversible platelet aggregation LTA curves without assuming changes in platelet aggregation parameters over time, but with the assumption that platelet can enter the aggregate only once. In the model, the mean size of platelet aggregates correlated with the solution transparency. This corresponded with flow cytometry analysis and with optical density fluctuations data on aggregate size. The predicted values of model parameters correlated with ADP concentration used in experiments. These data suggest that, at the start of the aggregation, when platelet integrins switch “on”, large unstable platelet aggregates are rapidly formed, which leads to an increase in light transmission. However, upon fragmentation of these aggregates, the probability of the post-aggregate platelets’ attachment to each other decreases preventing new aggregation and resulting in the reversible aggregation phenomenon.
Highlights
Platelets are anuclear cells that circulate in blood for approximately 7–9 days after production in bone marrow
There was a dose-dependent increase of reversible aggregation in heparinized or hirudinated platelet rich plasma (PRP) in response to ADP, with transition reversible/irreversible aggregation at 1.25–5 μM (Fig. 1A)
In response to ADP fibrinogen binding to a single platelet increases step-like (Fig. S3), so we can assume that the probabilities of platelet attachment to each other do not change with time
Summary
Platelets are anuclear cells that circulate in blood for approximately 7–9 days after production in bone marrow. The Smoluchowski approach could be the most “correct” one, it is quite computationally expensive when solved with deterministic methods, and still contain too many unknown parameters when solved with stochastic methods[24,25] and, computational modelling of aggregometry data with Smoluchowski equation could not be readily performed alongside with personalized parameter estimation yet[26]. Another commonly used approach is the lattice models[27,28], which is based on a construction of a lattice with a particle in each cell of the mesh. Most of them were developed for irreversible aggregation, and focus on the level of aggregation as the main parameter, and pre-define which parameter values should depend on the level of activation[31,32]
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