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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4222-4226
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Spontaneous thrombosis in mice carrying the factor V
Leiden mutation
Jisong Cui,
Daniel T. Eitzman,
Randal J. Westrick,
Patricia D. Christie,
Zuojun J. Xu,
Angela Y. Yang,
Anjali A. Purkayastha,
Tony L. Yang,
Alan L. Metz,
Kim P. Gallagher,
Julia A. Tyson,
Robert D. Rosenberg, and
David Ginsburg
From the Divisions of Medical Genetics and Cardiology,
Department of Internal Medicine, Department of Human Genetics, and the
Howard Hughes Medical Institute, University of Michigan Medical Center,
Ann Arbor MI; Parke-Davis Pharmaceutical Research Division,
Warner-Lambert Co, Ann Arbor, MI; and the Department of Biology,
Massachusetts Institute of Technology, Cambridge, MA.
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.
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