Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis.
The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limited but significantly different (P < 0.001) spontaneous lysis within 3 h (6 +/- 1 vs 3 +/- 1%, respectively). A 25-microliters 125I-fibrin-labeled normal murine plasma clot, injected into a jugular vein, was lysed for 47 +/- 5, 66 +/- 3, and 87 +/- 7% within 8 h in PAI-1+/+, heterozygous PAI-1-deficient (PAI-1+/-), and PAI-1-/- mice, respectively (P = 0.002 for PAI-1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PAI-1+/+ and PAI-1-/- mice, were 35 +/- 5 and 91 +/- 3% within 4 h, respectively (P < 0.001). 11 out of 26 PAI-1+/+ but only 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 micrograms endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PAI-1-/- mice after partial amputation of the tail or of the caecum. Thus, disruption of the PAI-1 gene in mice appears to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis.
Carmeliet
P
P
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Stassen
J M
JM
Schoonjans
L
L
Ream
B
B
van den Oord
J J
JJ
De Mol
M
M
Mulligan
R C
RC
Collen
D
D
D000704:Analysis of Variance; D000818:Animals; D002432:Cecum / Q000502:physiology; D004731:Endotoxins / Q000633:toxicity; D004906:Erythrocyte Count; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006470:Hemorrhage / Q000097:blood / Q000503:physiopathology*; D006487:Hemostasis; D051379:Mice; D008815:Mice, Inbred Strains; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency* / Q000235:genetics*; D010976:Platelet Count; D011655:Pulmonary Embolism / Q000097:blood / Q000503:physiopathology; D013927:Thrombosis / Q000097:blood / Q000473:pathology / Q000503:physiopathology*
D004731:Endotoxins; D006454:Hemoglobins; D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin