Thrombin activity confinement and dense granule release drive the dynamics of arterial thrombus

The mechanisms driving spatial heterogeneity of arterial thrombus and its three-stage dynamics are poorly understood. To investigate the potential principles regulating the size of the thrombus core and shell we developed a 3D continuum computational model that describes thrombus heterogeneity, thrombin-induced platelet dense granule secretion and clot propagation through thrombin and ADP-induced platelet activation. The continuum model predicted that spatial confinement of the thrombus core was a result of thrombin transport and a threshold-like dependence of platelet activation on thrombin concentration. This new model recapitulated three-stage dynamics observed in vivo and explained it with a burst-like ADP concentration dynamics due to the confinement of thrombus core propagation and rapid dense granule pool depletion within the core. The maximal shell size in silico was regulated by the transport of ADP and the kinetics of thrombin-dependent dense granules secretion. Simulations also predicted that partial propagation of thrombin inside the thrombus shell caused irreversible platelet activation by the low-dose thrombin and defined the residual shell size. Moreover, our results provided an explanation for the reduced size of a thrombus core observed in the mouse models of Hermansky-Pudlak syndrome. The continuum model was then applied to describe a FeCl 3 -induced thrombosis in macrocirculation, and described the thrombin-flux-depending switch between occlusive and non-occlusive thrombosis scenarios in mouse carotid artery. Finally, our simulations reinforced the hypothesis suggesting the importance of the large ADP-dependent thrombus shell for sealing the breach in case of a penetrating injury. Taken together, our results suggest a novel mechanism that may regulate arterial thrombus dynamics and offer several insights and сlarification to the core-and-shell model of arterial thrombus organization, as well as a possible role of the large thrombus shell in hemostasis.