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Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages
Shiori Koseki-Kuno1, Mitsunori Yamakawa, Gerhard Dickneite
1Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Iida-Nishi 2-2-2, Yamagata 990-9585 Japan. aichinos@med.id.yamagata-u.ac.jp
Abstract:
To understand the molecular pathology of factor XIII (FXIII) deficiency in vivo, its A subunit (FXIIIA)-knockout (KO) mice were functionally analyzed. Although homozygous FXIIIA female KO mice were capable of becoming pregnant, most of them died due to excessive vaginal bleeding during gestation. Abdominal incisions revealed that the uteri of the dead mice were filled with blood and that some embryos were much smaller than others within a single uterus. A series of histologic examinations of the pregnant animals suggested that massive placental hemorrhage and subsequent necrosis developed in the uteri of the FXIIIA KO mice on day 10 of gestation. This was true regardless of the genotypes of fetuses. These results are reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and indicate that maternal FXIII plays a critical role in uterine hemostasis and maintenance of the placenta during gestation.
Insights
Maternal factor XIII (FXIII) deficiency in mice causes fatal uterine bleeding during pregnancy. This highlights FXIII's crucial role in maintaining uterine hemostasis and placental integrity to prevent miscarriage.
Area of Science:
- Reproductive biology
- Hematology
- Molecular pathology
Background:
- Factor XIII (FXIII) is essential for blood clot stabilization.
- FXIII deficiency can lead to bleeding disorders, but its role in pregnancy is not fully understood.
- FXIII's A subunit (FXIIIA) is critical for its enzymatic activity.
Purpose of the Study:
- To investigate the in vivo role of maternal FXIIIA in pregnancy.
- To elucidate the molecular mechanisms underlying pregnancy complications in FXIII deficiency.
- To establish a mouse model for studying FXIII deficiency during gestation.
Main Methods:
- Generation and functional analysis of FXIIIA-knockout (KO) mice.
- Monitoring of pregnant homozygous FXIIIA female KO mice.
- Histological examination of uterine tissues and embryos.
Main Results:
- Homozygous FXIIIA female KO mice experienced excessive vaginal bleeding and mortality during gestation.
- Uterine hemorrhage and placental necrosis were observed by day 10 of gestation.
- Embryonic development was impaired, irrespective of fetal genotype.
Conclusions:
- Maternal FXIII is critical for uterine hemostasis during pregnancy.
- FXIIIA deficiency leads to placental hemorrhage and impaired fetal development, mimicking human miscarriage.
- FXIII plays a vital role in maintaining placental integrity throughout gestation.