PB1147 - Novel continuum model reveals the potential mechanisms regulating dynamics of a heterogeneous arterial thrombus

Background: The mechanisms responsible for both spatial heterogeneity of arterial thrombus and its three-stage dynamics are poorly understood. It was recently shown that the combination of spatial confinement of thrombin activity and depletion of dense granule pool in the thrombus core might play an important role in overall thrombus dynamics. However, the mechanisms regulating the size of both thrombus core and shell are unclear.

Aims: To investigate the potential mechanisms regulating the dynamics of thrombus core and shell we took advantage of a novel computational model.

Methods: We developed a continuum model of thrombus formation that describes thrombus heterogeneity, thrombin-induced platelet dense granule secretion and thrombus propagation through thrombin and ADP-induced platelet activation. The model parameters were taken from the published data and it was validated using experimental analysis of microvascular thrombus formation in mice.

Results: The model recapitulated the three-stage dynamics of thrombus observed in vivo (Figure 1). In line with earlier results, such behavior of a thrombus was the consequence of the burst-like release of ADP (Figure 2). The model predicted the confinement of thrombus core as a result of thrombin transport and threshold-like dependence of platelet activation on thrombin concentration. The maximal shell size was regulated by transport of ADP and the kinetics of thrombin-dependent secretion of dense granules. Model predicted that partial propagation of thrombin inside the thrombus shell caused irreversible platelet activation by low-dose thrombin and defined the residual shell size. Model was also applied to describe FeCl3-induced thrombosis in macrocirculation, allowing to study the occlusion scenario, and predicting that time to occlusion depended on the thrombin flux from the injury site.

Conclusion(s): The new continuum model offers a mechanism for the observed stabilization of the thrombus shell and allows to investigate thrombus dynamics in macrovasculature.
This work was supported by Russian Science Foundation grant 23-74-00057.