Restoration of Thrombolytic Potential in Plasminogen-Deficient Mice by Bolus Administration of Plasminogen

• Published in: Blood 1996-08, Vol.88 (3), p.870-876
• Main Authors: Lijnen, H.Roger, Carmeliet, Peter, Bouchέ, Ann, Moons, Lieve, Ploplis, Victoria A., Plow, Edward F., Collen, Desire
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Female; Fibrin - analysis; Fibrinolysis - drug effects; Hematologic and hematopoietic diseases; Liver - chemistry; Liver - pathology; Lung - chemistry; Lung - pathology; Male; Medical sciences; Mice; Mice, Knockout; Plasminogen - administration & dosage; Plasminogen - deficiency; Plasminogen - pharmacology; Plasminogen - therapeutic use; Platelet diseases and coagulopathies; Thromboembolism - drug therapy; Thromboembolism - pathology; Thrombolytic Therapy; Tissue Plasminogen Activator - deficiency; Tissue Plasminogen Activator - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V88.3.870.870

Homozygous plasminogen-deficient (Plg-/-) mice had a significantly reduced thrombolytic capacity toward intravenously injected 125l-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 μg/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 α2-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.