Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

Abstract Despite the common use of thrombolytic drugs, especially in stroke treatment, there are many conflicting studies on factors affecting fibrinolysis. Because of the complexity of the fibrinolytic system, mathematical models closely tied with experiments can be used to understand relationships...

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Autores principales:	Brittany E. Bannish, Irina N. Chernysh, James P. Keener, Aaron L. Fogelson, John W. Weisel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d863aaf2dbc74d158f8a400faec97703
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spelling	oai:doaj.org-article:d863aaf2dbc74d158f8a400faec977032021-12-02T11:52:21ZMolecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments10.1038/s41598-017-06383-w2045-2322https://doaj.org/article/d863aaf2dbc74d158f8a400faec977032017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06383-whttps://doaj.org/toc/2045-2322Abstract Despite the common use of thrombolytic drugs, especially in stroke treatment, there are many conflicting studies on factors affecting fibrinolysis. Because of the complexity of the fibrinolytic system, mathematical models closely tied with experiments can be used to understand relationships within the system. When tPA is introduced at the clot or thrombus edge, lysis proceeds as a front. We developed a multiscale model of fibrinolysis that includes the main chemical reactions: the microscale model represents a single fiber cross-section; the macroscale model represents a three-dimensional fibrin clot. The model successfully simulates the spatial and temporal locations of all components and elucidates how lysis rates are determined by the interplay between the number of tPA molecules in the system and clot structure. We used the model to identify kinetic conditions necessary for fibrinolysis to proceed as a front. We found that plasmin regulates the local concentration of tPA through forced unbinding via degradation of fibrin and tPA release. The mechanism of action of tPA is affected by the number of molecules present with respect to fibrin fibers. The physical mechanism of plasmin action (crawling) and avoidance of inhibition is defined. Many of these new findings have significant implications for thrombolytic treatment.Brittany E. BannishIrina N. ChernyshJames P. KeenerAaron L. FogelsonJohn W. WeiselNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brittany E. Bannish Irina N. Chernysh James P. Keener Aaron L. Fogelson John W. Weisel Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
description	Abstract Despite the common use of thrombolytic drugs, especially in stroke treatment, there are many conflicting studies on factors affecting fibrinolysis. Because of the complexity of the fibrinolytic system, mathematical models closely tied with experiments can be used to understand relationships within the system. When tPA is introduced at the clot or thrombus edge, lysis proceeds as a front. We developed a multiscale model of fibrinolysis that includes the main chemical reactions: the microscale model represents a single fiber cross-section; the macroscale model represents a three-dimensional fibrin clot. The model successfully simulates the spatial and temporal locations of all components and elucidates how lysis rates are determined by the interplay between the number of tPA molecules in the system and clot structure. We used the model to identify kinetic conditions necessary for fibrinolysis to proceed as a front. We found that plasmin regulates the local concentration of tPA through forced unbinding via degradation of fibrin and tPA release. The mechanism of action of tPA is affected by the number of molecules present with respect to fibrin fibers. The physical mechanism of plasmin action (crawling) and avoidance of inhibition is defined. Many of these new findings have significant implications for thrombolytic treatment.
format	article
author	Brittany E. Bannish Irina N. Chernysh James P. Keener Aaron L. Fogelson John W. Weisel
author_facet	Brittany E. Bannish Irina N. Chernysh James P. Keener Aaron L. Fogelson John W. Weisel
author_sort	Brittany E. Bannish
title	Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
title_short	Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
title_full	Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
title_fullStr	Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
title_full_unstemmed	Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments
title_sort	molecular and physical mechanisms of fibrinolysis and thrombolysis from mathematical modeling and experiments
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d863aaf2dbc74d158f8a400faec97703
work_keys_str_mv	AT brittanyebannish molecularandphysicalmechanismsoffibrinolysisandthrombolysisfrommathematicalmodelingandexperiments AT irinanchernysh molecularandphysicalmechanismsoffibrinolysisandthrombolysisfrommathematicalmodelingandexperiments AT jamespkeener molecularandphysicalmechanismsoffibrinolysisandthrombolysisfrommathematicalmodelingandexperiments AT aaronlfogelson molecularandphysicalmechanismsoffibrinolysisandthrombolysisfrommathematicalmodelingandexperiments AT johnwweisel molecularandphysicalmechanismsoffibrinolysisandthrombolysisfrommathematicalmodelingandexperiments
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Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments

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