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Blood coagulation factor X deficiency causes partial embryonic lethality and fatal neonatal bleeding in mice
M Dewerchin1, Z Liang, L Moons
1Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Abstract:
Mice with a total deficiency in blood coagulation Factor X (FX) were generated by targeted replacement of an 18-kb fragment of the FX gene, comprising all exons encoding the mature FX protein, with a neo(r) cassette. The genotype distribution among the offspring from heterozygous breeding pairs suggested that FX deficiency resulted in partial embryonic lethality, with approximately one-third of the FX-/- embryos dying around embryonic day (E) 11.5-12.5. Two of 44 non-resorbed FX-/- embryos analyzed at these stages showed signs of massive bleeding, one of which into the brain ventricles, but no histological defects in the vasculature of these embryos or their yolk sac were observed. The remainder of the FX-/- embryos appeared normal and survived to term, but the majority of neonates (90%) died within 5 days, most frequently from intraabdominal bleeding. The remaining FX-/- animals succumbed between postnatal day (P)5 and P20 with intraabdominal, subcutaneous, or intracranial bleeding or a combination thereof. The lethal phenotype of the FX-/- mice illustrates the importance of FX function in embryonic and postnatal survival and demonstrates that these mice serve as effective models of the bleeding disorders observed in severe FX deficiency in humans.
Insights
Mice lacking blood coagulation Factor X (FX) experienced embryonic lethality and severe bleeding disorders post-birth. These FX-deficient mice serve as a crucial model for human bleeding conditions.
Area of Science:
- Hematology
- Genetics
- Developmental Biology
Background:
- Factor X (FX) is a critical protein in the blood coagulation cascade.
- FX deficiency leads to severe bleeding disorders in humans.
Purpose of the Study:
- To generate and characterize mice with a complete deficiency in Factor X (FX).
- To investigate the role of FX in embryonic and postnatal survival.
Main Methods:
- Targeted gene replacement was used to create FX-deficient (FX-/-) mice.
- Genotype distribution and survival rates were analyzed in offspring.
- Phenotypic analysis included assessment of bleeding and histological examination.
Main Results:
- FX deficiency caused partial embryonic lethality around E11.5-12.5, with some embryos showing massive bleeding.
- Most FX-/- neonates (90%) died within 5 days due to intraabdominal bleeding.
- Surviving FX-/- mice exhibited various bleeding events, leading to death between P5 and P20.
Conclusions:
- Complete FX deficiency is incompatible with normal embryonic and postnatal survival in mice.
- FX-deficient mice are a valuable model for studying severe FX deficiency and associated bleeding disorders in humans.