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Spontaneous thrombosis in mice carrying the factor V Leiden mutation.

A polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with coinheritance of other prothrombotic gene mutations. However, the potential contribution of additional genetic risk factors in the majority of patients remains unknown. To gain insight into the molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene. Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed among FvQ/Q, FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a mixed 129Sv-C57BL/6J genetic background, FvQ/Q mice develop disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within FV among mammalian species and suggest an important contribution of other genetic factors to the thrombosis associated with FVL in humans. (Blood. 2000;96:4222-4226)

Pubmed ID: 11110695


  • Cui J
  • Eitzman DT
  • Westrick RJ
  • Christie PD
  • Xu ZJ
  • Yang AY
  • Purkayastha AA
  • Yang TL
  • Metz AL
  • Gallagher KP
  • Tyson JA
  • Rosenberg RD
  • Ginsburg D



Publication Data

December 15, 2000

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL-035989
  • Agency: NHLBI NIH HHS, Id: HL-036195
  • Agency: PHS HHS, Id: P01-41484

Mesh Terms

  • Activated Protein C Resistance
  • Amino Acid Substitution
  • Animals
  • Animals, Newborn
  • Crosses, Genetic
  • Disease Models, Animal
  • Disseminated Intravascular Coagulation
  • Epistasis, Genetic
  • Factor V
  • Female
  • Fertility
  • Fibrin
  • Gene Targeting
  • Genes, Lethal
  • Longevity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Phenotype
  • Point Mutation
  • RNA Splicing
  • Risk Factors
  • Thrombosis