{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:23:27Z","timestamp":1774031007630,"version":"3.50.1"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-74-00057"],"award-info":[{"award-number":["23-74-00057"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    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\n                    <jats:italic>in vivo<\/jats:italic>\n                    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\n                    <jats:italic>in silico<\/jats:italic>\n                    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\n                    <jats:sub>3<\/jats:sub>\n                    -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 \u0441larification to the core-and-shell model of arterial thrombus organization, as well as a possible role of the large thrombus shell in hemostasis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014062","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T17:33:21Z","timestamp":1774028001000},"page":"e1014062","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thrombin activity confinement and dense granule release drive the dynamics of arterial thrombus"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1606-0029","authenticated-orcid":true,"given":"Efim S.","family":"Bershadsky","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8677-129X","authenticated-orcid":true,"given":"Dmitry Y.","family":"Nechipurenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"issue":"10","key":"pcbi.1014062.ref001","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/nm782","article-title":"Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse","volume":"8","author":"S Falati","year":"2002","journal-title":"Nat Med"},{"issue":"10","key":"pcbi.1014062.ref002","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1182\/blood-2012-09-457739","article-title":"Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network","volume":"121","author":"TJ Stalker","year":"2013","journal-title":"Blood"},{"issue":"3","key":"pcbi.1014062.ref003","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1111\/jth.13600","article-title":"Hierarchical organization of the hemostatic response to penetrating injuries in the mouse macrovasculature","volume":"15","author":"JD Welsh","year":"2017","journal-title":"J Thromb Haemost"},{"issue":"11","key":"pcbi.1014062.ref004","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1182\/blood-2014-01-550335","article-title":"A systems approach to hemostasis: 1. 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