Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.

A highly reduced extrinsic pathway coagulation model (8 ODEs) under flow considered a thin 15-micron platelet layer where transport limitations were largely negligible (except for fibrinogen) and where cofactors (FVIIa, FV, FVIII) were not rate-limiting. By including thrombin feedback activation of...

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Autores principales:	Jason Chen, Scott L Diamond
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/24a5a9b68f8e492d9294362b4a83f107
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spelling	oai:doaj.org-article:24a5a9b68f8e492d9294362b4a83f1072021-12-02T20:16:14ZSensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.1932-620310.1371/journal.pone.0260366https://doaj.org/article/24a5a9b68f8e492d9294362b4a83f1072021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0260366https://doaj.org/toc/1932-6203A highly reduced extrinsic pathway coagulation model (8 ODEs) under flow considered a thin 15-micron platelet layer where transport limitations were largely negligible (except for fibrinogen) and where cofactors (FVIIa, FV, FVIII) were not rate-limiting. By including thrombin feedback activation of FXI and the antithrombin-I activities of fibrin, the model accurately simulated measured fibrin formation and thrombin fluxes. Using this reduced model, we conducted 10,000 Monte Carlo (MC) simulations for ±50% variation of 5 plasma zymogens and 2 fibrin binding sites for thrombin. A sensitivity analysis of zymogen concentrations indicated that FIX activity most influenced thrombin generation, a result expected from hemophilia A and B. Averaging all MC simulations confirmed both the mean and standard deviation of measured fibrin generation on 1 tissue factor (TF) molecule per μm2. Across all simulations, free thrombin in the layer ranged from 20 to 300 nM (mean: 50 nM). The top 2% of simulations that produced maximal fibrin were dominated by conditions with low antithrombin-I activity (decreased weak and strong sites) and high FIX concentration. In contrast, the bottom 2% of simulations that produced minimal fibrin were dominated by low FIX and FX. The percent reduction of fibrin by an ideal FXIa inhibitor (FXI = 0) ranged from 71% fibrin reduction in the top 2% of MC simulations to only 34% fibrin reduction in the bottom 2% of MC simulations. Thus, the antithrombotic potency of FXIa inhibitors may vary depending on normal ranges of zymogen concentrations. This reduced model allowed efficient multivariable sensitivity analysis.Jason ChenScott L DiamondPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 11, p e0260366 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jason Chen Scott L Diamond Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
description	A highly reduced extrinsic pathway coagulation model (8 ODEs) under flow considered a thin 15-micron platelet layer where transport limitations were largely negligible (except for fibrinogen) and where cofactors (FVIIa, FV, FVIII) were not rate-limiting. By including thrombin feedback activation of FXI and the antithrombin-I activities of fibrin, the model accurately simulated measured fibrin formation and thrombin fluxes. Using this reduced model, we conducted 10,000 Monte Carlo (MC) simulations for ±50% variation of 5 plasma zymogens and 2 fibrin binding sites for thrombin. A sensitivity analysis of zymogen concentrations indicated that FIX activity most influenced thrombin generation, a result expected from hemophilia A and B. Averaging all MC simulations confirmed both the mean and standard deviation of measured fibrin generation on 1 tissue factor (TF) molecule per μm2. Across all simulations, free thrombin in the layer ranged from 20 to 300 nM (mean: 50 nM). The top 2% of simulations that produced maximal fibrin were dominated by conditions with low antithrombin-I activity (decreased weak and strong sites) and high FIX concentration. In contrast, the bottom 2% of simulations that produced minimal fibrin were dominated by low FIX and FX. The percent reduction of fibrin by an ideal FXIa inhibitor (FXI = 0) ranged from 71% fibrin reduction in the top 2% of MC simulations to only 34% fibrin reduction in the bottom 2% of MC simulations. Thus, the antithrombotic potency of FXIa inhibitors may vary depending on normal ranges of zymogen concentrations. This reduced model allowed efficient multivariable sensitivity analysis.
format	article
author	Jason Chen Scott L Diamond
author_facet	Jason Chen Scott L Diamond
author_sort	Jason Chen
title	Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
title_short	Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
title_full	Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
title_fullStr	Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
title_full_unstemmed	Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.
title_sort	sensitivity analysis of a reduced model of thrombosis under flow: roles of factor ix, factor xi, and γ'-fibrin.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/24a5a9b68f8e492d9294362b4a83f107
work_keys_str_mv	AT jasonchen sensitivityanalysisofareducedmodelofthrombosisunderflowrolesoffactorixfactorxiandgfibrin AT scottldiamond sensitivityanalysisofareducedmodelofthrombosisunderflowrolesoffactorixfactorxiandgfibrin
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Sensitivity analysis of a reduced model of thrombosis under flow: Roles of Factor IX, Factor XI, and γ'-Fibrin.

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