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Thromb Haemost 2000; 83(01): 70-77
DOI: 10.1055/s-0037-1613760
Commentary
Schattauer GmbH

Rescue of Fatal Neonatal Hemorrhage in Factor V Deficient Mice by Low Level Transgene Expression

Tony L. Yang
1   From the Department of Human Genetics, University of Michigan
,
Jisong Cui
2   Howard Hughes Medical Institute
3   Merck & Co., Inc., Rahway, NJ
,
Jeremy M. Taylor
4   Department of Biostatistics, University of Michigan, Ann Arbor, MI
,
Angela Yang
2   Howard Hughes Medical Institute
,
Stephen B. Gruber
5   Department of Internal Medicine, University of Michigan
6   Department of Epidemiology, University of Michigan, USA
,
David Ginsburg
1   From the Department of Human Genetics, University of Michigan
2   Howard Hughes Medical Institute
5   Department of Internal Medicine, University of Michigan
› Author AffiliationsSupport provided by NIH Grant 1P01HL57346-01A1(D.G.) and the Howard Hughes Medical Institute. Transgenic Animal Model Core support was provided by the University of Michigan Comprehensive Cancer Center (CA46592), the University of Michigan Multipurpose Arthritis Center (AR20557), and the University of Michigan Center for Organogenesis.
Further Information

Publication History

Received 03 May 1999

Accepted after revision 02 September 1999

Publication Date:
06 December 2017 (online)

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Summary

Factor V (FV) is a critical component of the coagulation cascade. FV-deficient patients suffer moderate to severe bleeding, though residual FV activity is detectable in nearly all cases. In contrast, FVdeficient mice die either during mid-embryogenesis, or of massive perinatal hemorrhage. In order to examine the requirements for FV in murine embryogenesis and hemostasis, we generated transgenic mouse lines expressing a Fv minigene under control of either the tissue-specific albumin (Malb) or rat platelet factor 4 (Rpf4) promoter. A total of 12 Malb and 3 Rpf4 lines were analyzed. Though expression in the target tissue was detectable in most lines by RT-PCR, only low levels of transgene expression were achieved (<3% of endogenous Fv in all lines). Despite a low level of Fv transgene expression, rescue of the lethal Fv −/− phenotype was observed with one of the Malb transgenic (Tg+) lines. However, rescue appeared to be incomplete with continued loss of >1/2 of expected Tg+, Fv −/− mice in early embryogenesis. Rescued Tg+, Fv −/− mice have undetectable FV (<0.1%) in both plasma and platelet compartments, but survive the perinatal period and mature to adulthood without spontaneous hemorrhage. We conclude that FV present at <0.1% is sufficient to support postnatal survival. Failure of the Malb transgene to rescue the midembryonic block suggests that FV expression is required during mammalian development at higher levels or with a different tissue-specific or temporal pattern. Taken together, these data may explain the observation of residual FV activity in most human FV-deficient patients due to early embryonic lethality in those absolutely deficient, and suggest that minimal levels of FV expression, below the level of detection, also may be sufficient to support survival in humans.

Keywords

Transgenic - mice - factor V

Current address: Dr. J. Cui, Merck & Co., Inc., Rahway, NJ, USA


 

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