PMID- 10090937
OWN - NLM
STAT- MEDLINE
DCOM- 19990419
LR  - 20091119
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 93
IP  - 7
DP  - 1999 Apr 1
TI  - Alpha2-antiplasmin gene deficiency in mice is associated with enhanced
      fibrinolytic potential without overt bleeding.
PG  - 2274-81
AB  - alpha2-antiplasmin (alpha2-AP) is the main physiologic plasmin inhibitor in
      mammalian plasma. Inactivation of the murine alpha2-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 alpha2-AP allele was observed,
      and homozygous deficient (alpha2-AP-/-) mice displayed normal fertility,
      viability, and development. Reverse transcription-polymerase chain reaction
      confirmed the absence of alpha2-AP mRNA in kidney and liver from alpha2-AP-/-
      mice, in contrast to wild-type (alpha2-AP+/+) mice. Immunologic and functional
      alpha2-AP levels were undetectable in plasma of alpha2-AP-/- mice, and were about
      half of wild-type in heterozygous littermates (alpha2-AP+/-). Other hemostasis
      parameters, including plasminogen activator inhibitor-1, plasminogen, fibrinogen,
      hemoglobin, hematocrit, and blood cell counts were comparable for alpha2-AP+/+,
      alpha2-AP+/-, and alpha2-AP-/- mice. After amputation of tail or toe tips,
      bleeding stopped spontaneously in alpha2-AP+/+, as well as in alpha2-AP+/- and
      alpha2-AP-/- mice. Spontaneous lysis after 4 hours of intravenously injected
      125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in
      alpha2-AP+/+ mice when injecting clots prepared from alpha2-AP+/+ plasma (78% +/-
      5% v 46% +/- 9%; mean +/- SEM, n = 6 to 7; P =.02) or from alpha2-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 alpha2-AP-/- mice, as compared with alpha2-AP+/+ mice (P </=.005). Thus,
      alpha2-AP-/- mice develop and reproduce normally; they have an enhanced
      endogenous fibrinolytic capacity without overt bleeding.
FAU - Lijnen, H R
AU  - Lijnen HR
AD  - Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
      roger.lignen@med.kuleuven.ac.be
FAU - Okada, K
AU  - Okada K
FAU - Matsuo, O
AU  - Matsuo O
FAU - Collen, D
AU  - Collen D
FAU - Dewerchin, M
AU  - Dewerchin M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (alpha-2-Antiplasmin)
SB  - AIM
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Disease Models, Animal
MH  - Fertility
MH  - Fibrinolysis/*genetics
MH  - Genotype
MH  - Hemorrhage
MH  - Hemorrhagic Disorders/genetics
MH  - Hemostasis/genetics
MH  - Humans
MH  - Kidney/metabolism
MH  - Liver/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Plasminogen Activator Inhibitor 1/metabolism
MH  - alpha-2-Antiplasmin/deficiency/*genetics
EDAT- 1999/03/26 00:00
MHDA- 1999/03/26 00:01
CRDT- 1999/03/26 00:00
PHST- 1999/03/26 00:00 [pubmed]
PHST- 1999/03/26 00:01 [medline]
PHST- 1999/03/26 00:00 [entrez]
PST - ppublish
SO  - Blood. 1999 Apr 1;93(7):2274-81.