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 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.
Sood
Rashmi
R
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA. rashmi.sood@bcw.edu
Zogg
Mark
M
Westrick
Randal J
RJ
Guo
Yi-He
YH
Kerschen
Edward J
EJ
Girardi
Guillermina
G
Salmon
Jane E
JE
Coughlin
Shaun R
SR
Weiler
Hartmut
H
D020016:Activated Protein C Resistance / Q000150:complications* / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004195:Disease Models, Animal; D005165:Factor V / Q000235:genetics*; D005260:Female; D005313:Fetal Death / Q000209:etiology* / Q000473:pathology; D005315:Fetal Diseases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000098:blood supply / Q000473:pathology*; D017354:Point Mutation / Q000235:genetics; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000235:genetics; D018179:Receptors, Thrombin / Q000378:metabolism; D012307:Risk Factors; D018180:Thrombomodulin / Q000235:genetics
D018179:Receptors, Thrombin; D018180:Thrombomodulin; C095381:factor V Leiden; D005165:Factor V; C112908:protease-activated receptor 4