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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2274-2281
 2-Antiplasmin Gene Deficiency in Mice Is Associated
With Enhanced Fibrinolytic Potential Without Overt Bleeding
H.R. Lijnen,
K. Okada,
O. Matsuo,
D. Collen, and
M. Dewerchin
From the Center for Molecular and Vascular Biology, University of
Leuven, and the Center for Transgene Technology and Gene Therapy,
Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium;
and the Department of Physiology, Kinki University School of Medicine,
Osaka, Japan.
 2-antiplasmin (2-AP) is
the main physiologic plasmin inhibitor in mammalian plasma.
Inactivation of the murine
2-AP gene was
achieved by replacing, through homologous recombination in embryonic
stem cells, a 7-kb genomic sequence encoding the entire murine protein
(exon 2 through part of exon 10, including the stop codon) with the
neomycin resistance expression cassette. Germline transmission
of the mutated allele was confirmed by Southern blot analysis.
Mendelian inheritance of the inactivated
2-AP allele was
observed, and homozygous deficient
(2-AP /) mice displayed normal
fertility, viability, and development. Reverse transcription-polymerase
chain reaction confirmed the absence of
2-AP mRNA in kidney
and liver from 2-AP/ mice, in contrast
to wild-type (2-AP+/+) mice.
Immunologic and functional 2-AP levels were undetectable in plasma of 2-AP/ mice, and were
about half of wild-type in heterozygous littermates (2-AP+/). Other hemostasis
parameters, including plasminogen activator inhibitor-1, plasminogen,
fibrinogen, hemoglobin, hematocrit, and blood cell counts were
comparable for 2-AP+/+,
2-AP+/, and
2-AP/ mice. After amputation of tail
or toe tips, bleeding stopped spontaneously in
2-AP+/+, as well as in
2-AP+/ and
2-AP/ mice. Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma
clots was significantly higher in
2-AP/ than in
2-AP+/+ mice when injecting clots
prepared from 2-AP+/+ plasma
(78% ± 5% v 46% ± 9%; mean ± SEM, n = 6 to
7; P = .02) or from 2-AP/
plasma (81% ± 5% v 46% ± 5%; mean ± SEM,
n = 5; P = .008). Four to 8 hours after endotoxin
injection, fibrin deposition in the kidneys was significantly reduced
in 2-AP/ mice, as compared with
2-AP+/+ mice (P  .005).
Thus, 2-AP/ mice develop and reproduce
normally; they have an enhanced endogenous fibrinolytic capacity
without overt bleeding.
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