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Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis

In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are stu...

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Autores principales: Danforth, Christopher M., Orfeo, Thomas, Everse, Stephen J., Mann, Kenneth G., Brummel-Ziedins, Kathleen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271084/
https://www.ncbi.nlm.nih.gov/pubmed/22319567
http://dx.doi.org/10.1371/journal.pone.0030385
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author Danforth, Christopher M.
Orfeo, Thomas
Everse, Stephen J.
Mann, Kenneth G.
Brummel-Ziedins, Kathleen E.
author_facet Danforth, Christopher M.
Orfeo, Thomas
Everse, Stephen J.
Mann, Kenneth G.
Brummel-Ziedins, Kathleen E.
author_sort Danforth, Christopher M.
collection PubMed
description In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual's thrombin generation potential. A novel graphical method is used to integrate standard measures that characterize thrombin generation in both empirical and computational models (e.g max rate, max level, total thrombin, time to 2 nM thrombin (“clot time”)) to visualize how normal range variation in coagulation factors results in unique thrombin generation phenotypes. Unique ensembles of the 8 coagulation factors encompassing the limits of normal range variation were used as initial conditions for the computational modeling, each ensemble representing “an individual” in a theoretical healthy population. These “individuals” with unremarkable proteome composition was then compared to actual normal and “abnormal” individuals, i.e. factor ensembles measured in apparently healthy individuals, actual coagulopathic individuals or artificially constructed factor ensembles representing individuals with specific factor deficiencies. A sensitivity analysis was performed to rank either individual factors or all possible pairs of factors in terms of their contribution to the overall distribution of thrombin generation phenotypes. Key findings of these analyses include: normal range variation of coagulation factors yields thrombin generation phenotypes indistinguishable from individuals with some, but not all, coagulopathies examined; coordinate variation of certain pairs of factors within their normal ranges disproportionately results in extreme thrombin generation phenotypes, implying that measurement of a smaller set of factors may be sufficient to identify individuals with aberrant thrombin generation potential despite normal coagulation proteome composition.
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spelling pubmed-32710842012-02-08 Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis Danforth, Christopher M. Orfeo, Thomas Everse, Stephen J. Mann, Kenneth G. Brummel-Ziedins, Kathleen E. PLoS One Research Article In terms of its soluble precursors, the coagulation proteome varies quantitatively among apparently healthy individuals. The significance of this variability remains obscure, in part because it is the backdrop against which the hemostatic consequences of more dramatic composition differences are studied. In this study we have defined the consequences of normal range variation of components of the coagulation proteome by using a mechanism-based computational approach that translates coagulation factor concentration data into a representation of an individual's thrombin generation potential. A novel graphical method is used to integrate standard measures that characterize thrombin generation in both empirical and computational models (e.g max rate, max level, total thrombin, time to 2 nM thrombin (“clot time”)) to visualize how normal range variation in coagulation factors results in unique thrombin generation phenotypes. Unique ensembles of the 8 coagulation factors encompassing the limits of normal range variation were used as initial conditions for the computational modeling, each ensemble representing “an individual” in a theoretical healthy population. These “individuals” with unremarkable proteome composition was then compared to actual normal and “abnormal” individuals, i.e. factor ensembles measured in apparently healthy individuals, actual coagulopathic individuals or artificially constructed factor ensembles representing individuals with specific factor deficiencies. A sensitivity analysis was performed to rank either individual factors or all possible pairs of factors in terms of their contribution to the overall distribution of thrombin generation phenotypes. Key findings of these analyses include: normal range variation of coagulation factors yields thrombin generation phenotypes indistinguishable from individuals with some, but not all, coagulopathies examined; coordinate variation of certain pairs of factors within their normal ranges disproportionately results in extreme thrombin generation phenotypes, implying that measurement of a smaller set of factors may be sufficient to identify individuals with aberrant thrombin generation potential despite normal coagulation proteome composition. Public Library of Science 2012-02-02 /pmc/articles/PMC3271084/ /pubmed/22319567 http://dx.doi.org/10.1371/journal.pone.0030385 Text en Danforth et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Danforth, Christopher M.
Orfeo, Thomas
Everse, Stephen J.
Mann, Kenneth G.
Brummel-Ziedins, Kathleen E.
Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title_full Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title_fullStr Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title_full_unstemmed Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title_short Defining the Boundaries of Normal Thrombin Generation: Investigations into Hemostasis
title_sort defining the boundaries of normal thrombin generation: investigations into hemostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271084/
https://www.ncbi.nlm.nih.gov/pubmed/22319567
http://dx.doi.org/10.1371/journal.pone.0030385
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