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 m utation carriers experience clinically significant thrombosis in their life time. In a small subset of patients, thrombosis is associated with coinheri tance of other prothrombotic gene mutations. However, the potential contrib ution of additional genetic risk factors in the majority of patients remain s unknown. To gain insight into the molecular basis for the variable expres sivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv ge ne. Adult heterozygous (FVQ/+) and homozygous (FVQ/Q) mice are viable and f ertile and exhibit normal survival. Compared with wild-type mice, adult FVQ /Q mice demonstrate a marked increase in spontaneous tissue fibrin depositi on. No differences in fetal development or survival are observed among FVQ/ Q, FVQ/+ or control littermates on the C57BL/6J genetic background. In cont rast, on a mixed 129Sv-C57BL/6J genetic background, FvQ/Q mice develop diss eminated intravascular thrombosis in the perinatal period, resulting in sig nificant mortality shortly after birth. These results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site w ithin FV among mammalian species and suggest an important contribution of o ther genetic factors to the thrombosis associated with FVL in humans. (C) 2 000 by The American Society of Hematology.