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.

[1]  P. Carmeliet,et al.  Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. , 1993, The Journal of clinical investigation.

[2]  G. Bergonzelli,et al.  Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[3]  J. Mcdonagh,et al.  Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding. , 1993, Blood.

[4]  Y. Eguchi,et al.  Cellular localization of type 1 plasminogen activator inhibitor messenger RNA and protein in murine renal tissue. , 1993, The American journal of pathology.

[5]  W. Border,et al.  Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. , 1992, Kidney international.

[6]  D. Loskutoff,et al.  Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  D. Collen,et al.  On the role of coagulation and fibrinolysis in atherosclerosis. , 1992, Annals of epidemiology.

[8]  A. V. van Zonneveld,et al.  Inhibition of Plasminogen Activator Inhibitor‐1 Activity Results in Promotion of Endogenous Thrombolysis and Inhibition of Thrombus Extension in Models of Experimental Thrombosis , 1992, Circulation.

[9]  D. Loskutoff,et al.  Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. , 1991, The Journal of clinical investigation.

[10]  T. Astrup Fibrinolysis: Past and Present, a Reflection of Fifty Years , 1991, Seminars in thrombosis and hemostasis.

[11]  D. Loskutoff,et al.  Plasminogen activator inhibitors. , 1991, Trends in cardiovascular medicine.

[12]  E. Kruithof,et al.  A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1. , 1991, Blood.

[13]  P. Quax,et al.  Endotoxin induction of plasminogen activator and plasminogen activator inhibitor type 1 mRNA in rat tissues in vivo. , 1990, The Journal of biological chemistry.

[14]  K. Marotti,et al.  Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene , 1990, Nature.

[15]  P. Verde,et al.  Urokinase-dependent cell surface proteolysis and cancer. , 1990, Seminars in cancer biology.

[16]  D. Collen,et al.  A hamster pulmonary embolism model for the evaluation of the thrombolytic and pharmacokinetic properties of thrombolytic agents , 1990 .

[17]  Raymond,et al.  Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. , 1989, The Journal of clinical investigation.

[18]  F. España,et al.  Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease. , 1988, British heart journal.

[19]  M. Blombäck,et al.  PLASMINOGEN ACTIVATOR INHIBITOR IN PLASMA: RISK FACTOR FOR RECURRENT MYOCARDIAL INFARCTION , 1987, The Lancet.

[20]  H. Heremans,et al.  Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide. , 1987, Journal of immunology.

[21]  C. Kluft,et al.  Plasminogen activator inhibitors. , 1987, Blood.

[22]  F. Werf,et al.  Plasminogen activator inhibitor in the blood of patients with coronary artery disease. , 1985, British medical journal.

[23]  M. Alessi,et al.  Increased PA-Inhibitor Levels in the Postoperative Period – No Cause-Effect Relation with Increased Cortisol , 1985, Thrombosis and Haemostasis.

[24]  L. Tengborn,et al.  Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. , 1985 .

[25]  J. Paramo,et al.  Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. , 1985, The Journal of clinical investigation.

[26]  H. Tyler,et al.  The Measurement of Fibrinolysis in the Rat , 1971, Thrombosis and Haemostasis.

[27]  M. Verstraete,et al.  A rapid enzymatic method for assay of fibrinogen fibrin polymerization time (FPT test). , 1963, Clinica chimica acta; international journal of clinical chemistry.