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Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers

We describe a mouse model of fetal loss in factor V Leiden (FvL) mothers in which fetal loss is triggered when the maternal prothrombotic state coincides with fetal gene defects that reduce activation of the protein C anticoagulant pathway within the placenta. Fetal loss is caused by disruption of p...

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Autores principales: Sood, Rashmi, Zogg, Mark, Westrick, Randal J., Guo, Yi-he, Kerschen, Edward J., Girardi, Guillermina, Salmon, Jane E., Coughlin, Shaun R., Weiler, Hartmut
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118565/
https://www.ncbi.nlm.nih.gov/pubmed/17438064
http://dx.doi.org/10.1084/jem.20062566
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author Sood, Rashmi
Zogg, Mark
Westrick, Randal J.
Guo, Yi-he
Kerschen, Edward J.
Girardi, Guillermina
Salmon, Jane E.
Coughlin, Shaun R.
Weiler, Hartmut
author_facet Sood, Rashmi
Zogg, Mark
Westrick, Randal J.
Guo, Yi-he
Kerschen, Edward J.
Girardi, Guillermina
Salmon, Jane E.
Coughlin, Shaun R.
Weiler, Hartmut
author_sort Sood, Rashmi
collection PubMed
description We describe a mouse model of fetal loss in factor V Leiden (FvL) mothers in which fetal loss is triggered when the maternal prothrombotic state coincides with fetal gene defects that reduce activation of the protein C anticoagulant pathway within the placenta. Fetal loss is caused by disruption of placental morphogenesis at the stage of labyrinth layer formation and occurs in the absence of overt placental thrombosis, infarction, or perfusion defects. Platelet depletion or elimination of protease-activated receptor 4 (Par4) from the mother allows normal placentation and prevents fetal loss. These findings establish a cause–effect relationship for the observed epidemiologic association between maternal FvL status and fetal loss and identify fetal gene defects as risk modifiers of pregnancy failure in prothrombotic mothers. Pregnancy failure is mediated by Par4-dependent activation of maternal platelets at the fetomaternal interface and likely involves a pathogenic pathway independent of occlusive thrombosis. Our results further demonstrate that the interaction of two given thrombosis risk factors produces markedly disparate consequences on disease manifestation (i.e., thrombosis or pregnancy loss), depending on the vascular bed in which this interaction occurs.
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spelling pubmed-21185652007-12-13 Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers Sood, Rashmi Zogg, Mark Westrick, Randal J. Guo, Yi-he Kerschen, Edward J. Girardi, Guillermina Salmon, Jane E. Coughlin, Shaun R. Weiler, Hartmut J Exp Med Articles We describe a mouse model of fetal loss in factor V Leiden (FvL) mothers in which fetal loss is triggered when the maternal prothrombotic state coincides with fetal gene defects that reduce activation of the protein C anticoagulant pathway within the placenta. Fetal loss is caused by disruption of placental morphogenesis at the stage of labyrinth layer formation and occurs in the absence of overt placental thrombosis, infarction, or perfusion defects. Platelet depletion or elimination of protease-activated receptor 4 (Par4) from the mother allows normal placentation and prevents fetal loss. These findings establish a cause–effect relationship for the observed epidemiologic association between maternal FvL status and fetal loss and identify fetal gene defects as risk modifiers of pregnancy failure in prothrombotic mothers. Pregnancy failure is mediated by Par4-dependent activation of maternal platelets at the fetomaternal interface and likely involves a pathogenic pathway independent of occlusive thrombosis. Our results further demonstrate that the interaction of two given thrombosis risk factors produces markedly disparate consequences on disease manifestation (i.e., thrombosis or pregnancy loss), depending on the vascular bed in which this interaction occurs. The Rockefeller University Press 2007-05-14 /pmc/articles/PMC2118565/ /pubmed/17438064 http://dx.doi.org/10.1084/jem.20062566 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Articles
Sood, Rashmi
Zogg, Mark
Westrick, Randal J.
Guo, Yi-he
Kerschen, Edward J.
Girardi, Guillermina
Salmon, Jane E.
Coughlin, Shaun R.
Weiler, Hartmut
Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title_full Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title_fullStr Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title_full_unstemmed Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title_short Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
title_sort fetal gene defects precipitate platelet-mediated pregnancy failure in factor v leiden mothers
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118565/
https://www.ncbi.nlm.nih.gov/pubmed/17438064
http://dx.doi.org/10.1084/jem.20062566
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