Plasminogen activator inhibitor-1 suppresses endogenous fibrinolysis in a canine model of pulmonary embolism

• Published in: Circulation (New York, N.Y.) Vol. 84; no. 1; pp. 287 - 292
• Main Authors: REILLY, C. F, FUJITA, T, HUTZELMANN, J. E, MAYER, E. J, SHEBUSKI, R. J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-07-1991
• Subjects: 550201 - Biochemistry- Tracer Techniques; 550901 - Pathology- Tracer Techniques; ANIMALS; Antifibrinolytic Agents - metabolism; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BIOCHEMICAL REACTION KINETICS; Biological and medical sciences; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BLOOD COAGULATION; BLOOD COAGULATION FACTORS; BODY FLUIDS; Cardiology. Vascular system; CHEMICAL REACTIONS; Chronic cor pulmonale; COAGULANTS; DAYS LIVING RADIOISOTOPES; DECOMPOSITION; DISEASES; DOGS; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; ENZYME INHIBITORS; Female; FIBRIN; Fibrin Fibrinogen Degradation Products - metabolism; FIBRINOLYSIS; Fibrinolysis - drug effects; Heart; HEMATOLOGIC AGENTS; HEMOSTATICS; INHIBITION; INTERMEDIATE MASS NUCLEI; INTERNAL CONVERSION RADIOISOTOPES; IODINE 125; IODINE ISOTOPES; Iodine Radioisotopes - metabolism; ISOTOPE APPLICATIONS; ISOTOPES; KINETICS; Male; MAMMALS; MATERIALS; Medical sciences; Microcirculation; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; PATHOGENESIS; Plasminogen Inactivators - metabolism; Plasminogen Inactivators - pharmacology; Pneumology; PROTEINS; PROTEOLYSIS; Pulmonary Embolism - metabolism; Pulmonary Embolism - physiopathology; Pulmonary Embolism - therapy; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; RADIOISOTOPES; REACTION KINETICS; RESPIRATORY SYSTEM DISEASES; SCLEROPROTEINS; Thrombolytic Therapy; Tissue Plasminogen Activator - pharmacology; TRACER TECHNIQUES; VASCULAR DISEASES; VERTEBRATES; Fissipedia; Pharmacologic test; Carnivora; Enzyme; Thrombus; Cardiovascular disease; Exploration; Plasminogen activator; Experimental study; Fibrinolysis; Pulmonary embolism; Vertebrata; Mammalia; Endogenous; Animal; Dog
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.84.1.287

Plasminogen activator inhibitor-1 (PAI-1), the specific, fast-acting inhibitor of tissue-type plasminogen activator (t-PA), binds to fibrin and has been found in high concentrations within arterial thrombi. These findings suggest that the localization of PAI-1 to a thrombus protects that same thrombus from fibrinolysis. In this study, clot-bound PAI-1 was assessed for its ability to suppress clot lysis in vivo.
Autologous, canine whole blood clots were formed in the presence of increasing amounts of activated PAI-1 (0-30 micrograms/ml). Approximately 6-8% of the PAI-1 bound to the clots under the experimental conditions. Control and PAI-1-enriched clots containing iodine-125-labeled fibrin (ogen) were homogenized, washed to remove nonbound elements, and delivered to the lungs of anesthetized dogs where the homogenates subsequently underwent lysis by the endogeneous fibrinolytic system. 125I-labeled fibrin degradation products appeared in the blood of control animals within 10 minutes and were maximal by 90 minutes. PAI-1 reduced fibrin degradation product release in a dose-responsive manner at all times between 30 minutes and 5 hours (greater than or equal to 76% inhibition at 30 minutes, PAI-1 greater than or equal to 6 micrograms/ml). PAI-1 also suppressed D-dimer release from clots containing small amounts of human fibrin (ogen). t-PA administration attenuated the effects of PAI-1, whereas latent PAI-1 (20 micrograms/ml) had no effect on clot lysis. Blood levels of PA and PAI activity remained unaltered during these experiments.
The results indicate that PAI-1 markedly inhibits endogenous fibrinolysis in vivo and, moreover, suggest that the localization of PAI-1 to a forming thrombus is an important physiological mechanism for subsequent thrombus stabilization.