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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14 May 2007
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April 16 2007
Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers
Rashmi Sood,
Rashmi Sood
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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Mark Zogg,
Mark Zogg
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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Randal J. Westrick,
Randal J. Westrick
2University of Michigan, Ann Arbor, MI 48109
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Yi-he Guo,
Yi-he Guo
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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Edward J. Kerschen,
Edward J. Kerschen
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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Guillermina Girardi,
Guillermina Girardi
3Hospital for Special Surgery and Weill Medical College, Cornell University, New York, NY 10021
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Jane E. Salmon,
Jane E. Salmon
3Hospital for Special Surgery and Weill Medical College, Cornell University, New York, NY 10021
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Shaun R. Coughlin,
Shaun R. Coughlin
4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143
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Hartmut Weiler
Hartmut Weiler
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
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Rashmi Sood
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
Mark Zogg
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
Randal J. Westrick
2University of Michigan, Ann Arbor, MI 48109
Yi-he Guo
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
Edward J. Kerschen
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
Guillermina Girardi
3Hospital for Special Surgery and Weill Medical College, Cornell University, New York, NY 10021
Jane E. Salmon
3Hospital for Special Surgery and Weill Medical College, Cornell University, New York, NY 10021
Shaun R. Coughlin
4Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143
Hartmut Weiler
1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226
CORRESPONDENCE Rashmi Sood: [email protected] OR Hartmut Weiler: [email protected]
Abbreviations used: dpc, days post coitum; FvL, factor V Leiden; Par4, protease-activated receptor 4; Procr, endothelial protein C receptor; TAT, thrombin–antithrombin; Tfpi, tissue factor pathway inhibitor; Thbd, thrombomodulin.
Received:
December 06 2006
Accepted:
March 21 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (5): 1049–1056.
Article history
Received:
December 06 2006
Accepted:
March 21 2007
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Citation
Rashmi Sood, Mark Zogg, Randal J. Westrick, Yi-he Guo, Edward J. Kerschen, Guillermina Girardi, Jane E. Salmon, Shaun R. Coughlin, Hartmut Weiler; Fetal gene defects precipitate platelet-mediated pregnancy failure in factor V Leiden mothers . J Exp Med 14 May 2007; 204 (5): 1049–1056. doi: https://doi.org/10.1084/jem.20062566
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