Restoration of thrombolytic potential in plasminogen-deficient mice by bolus administration of plasminogen.
Homozygous plasminogen-deficient (Plg-/-) mice had a significantly reduced thrombolytic capacity toward intravenously injected 125I-fibrin labeled plasma clots prepared from Plg-/- murine plasma (9% +/- 3% lysis after 8 hours; (mean +/- SEM, n = 6), as compared with 82% +/- 8% in wild-type mice; P < .0001). Bolus injection of 1 mg purified murine plasminogen in 10- to 17-week-old Plg-/- mice increased the plasminogen antigen and activity levels at 8 hours to normal levels (130 +/- 5 micrograms/mL). Plasminogen administration was associated with significant restoration of thrombolytic potential (64% +/- 7% spontaneous clot lysis; P < .0001 versus lysis without plasminogen injection). Bolus injection of 1 mg plasminogen in homozygous tissue-type plasminogen activator-deficient (t-PA-/-) mice doubled the plasminogen antigen and activity levels after 8 hours and increased 125I-fibrin clot lysis at 8 hours from 13% +/- 3% to 34% +/- 5% (P = .008). Fibrinogen, t-PA antigen and alpha 2-antiplasmin activity levels after 8 hours were not significantly different in the groups with or without plasminogen injection. Injection of plasminogen induced a variable increase (on average 7- to 10-fold) of PAI-1, but no correlation with the extent of spontaneous clot lysis was observed. Histopathologic examination at the end of the experiments revealed that fibrin deposition in the liver of Plg-/- mice was slightly reduced 8 hours after bolus plasminogen injection (P = .007) and markedly reduced after 24 hours (P < .0001). Plasminogen antigen levels in liver extracts were comparable with those found in wild-type mice at 8 hours (130 +/- 20 versus 110 +/- 15 ng/mg protein) and decreased to 25 +/- 3.2 ng/mg protein at 24 hours. Thus, restoration of normal plasminogen levels in Plg-/- mice normalized the thrombolytic potential toward experimentally induced pulmonary emboli, and resulted in removal of endogenous fibrin deposits within 24 hours.
Lijnen
H R
HR
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Carmeliet
P
P
Bouché
A
A
Moons
L
L
Ploplis
V A
VA
Plow
E F
EF
Collen
D
D
D000818:Animals; D005260:Female; D005337:Fibrin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000473:pathology; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010958:Plasminogen / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology* / Q000627:therapeutic use; D013923:Thromboembolism / Q000188:drug therapy* / Q000473:pathology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics
D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator