TY - JOUR

T1 - Platelet activation near point-like source of agonist: Experimental insights and computational model

AU - Starodubtseva, Ezhena S.

AU - Karogodina, Tatyana Yu

AU - Moskalensky, Alexander E.

N1 - The study was supported by the Russian Science Foundation (grant #23-75-10049). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Starodubtseva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2024/10/1

Y1 - 2024/10/1

N2 - Disorders of hemostasis resulting in bleeding or thrombosis are leading cause of mortality in the world. Blood platelets are main players in hemostasis, providing the primary response to the vessel wall injury. In this case, they rapidly switch to the activated state in reaction to the exposed chemical substances such as ADP, collagen and thrombin. Molecular mechanisms of platelet activation are known, and detailed computational models are available. However, they are too complicated for large-scale problems (e.g. simulation of the thrombus growth) where less detailed models are required, which still should take into account the variation of agonist concentration and heterogeneity of platelets. In this paper, we present a simple model of the platelet population response to a spatially inhomogeneous stimulus. First, computational nodes modeling platelets are placed randomly in space. Each platelet is assigned the specific threshold for agonist, which determines whether it becomes activated at a given time. The distribution of the threshold value in a population is assumed to be log-normal. The model was validated against experimental data in a specially designed system, where the photorelease of ADP was caused by localized laser stimulus. In this system, a concentration of ADP obeys 2-dimensional Gaussian distribution which broadens due to the diffusion. The response of platelets to the point-like source of ADP is successfully described by the presented model. Our results advance the understanding of platelet function during hemostatic response. The simulation approach can be incorporated into larger computational models of thrombus formation.

AB - Disorders of hemostasis resulting in bleeding or thrombosis are leading cause of mortality in the world. Blood platelets are main players in hemostasis, providing the primary response to the vessel wall injury. In this case, they rapidly switch to the activated state in reaction to the exposed chemical substances such as ADP, collagen and thrombin. Molecular mechanisms of platelet activation are known, and detailed computational models are available. However, they are too complicated for large-scale problems (e.g. simulation of the thrombus growth) where less detailed models are required, which still should take into account the variation of agonist concentration and heterogeneity of platelets. In this paper, we present a simple model of the platelet population response to a spatially inhomogeneous stimulus. First, computational nodes modeling platelets are placed randomly in space. Each platelet is assigned the specific threshold for agonist, which determines whether it becomes activated at a given time. The distribution of the threshold value in a population is assumed to be log-normal. The model was validated against experimental data in a specially designed system, where the photorelease of ADP was caused by localized laser stimulus. In this system, a concentration of ADP obeys 2-dimensional Gaussian distribution which broadens due to the diffusion. The response of platelets to the point-like source of ADP is successfully described by the presented model. Our results advance the understanding of platelet function during hemostatic response. The simulation approach can be incorporated into larger computational models of thrombus formation.

KW - Platelet Activation/drug effects

KW - Adenosine Diphosphate/pharmacology

KW - Humans

KW - Computer Simulation

KW - Blood Platelets/drug effects

KW - Models, Biological

KW - Thrombosis

KW - Thrombin/metabolism

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85206340687&origin=inward&txGid=09df6f31284adc2d284ad6ab719fd45e

UR - https://www.mendeley.com/catalogue/057b6b57-8a0e-388b-b102-2865448200f9/

U2 - 10.1371/journal.pone.0308679

DO - 10.1371/journal.pone.0308679

M3 - Article

C2 - 39361659

VL - 19

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 10

M1 - e0308679

ER -