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


RESULTS
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.


CONCLUSIONS
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.
Reilly
C F
CF
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Fujita
T
T
Hutzelmann
J E
JE
Mayer
E J
EJ
Shebuski
R J
RJ
D000818:Animals; D000933:Antifibrinolytic Agents / Q000378:metabolism; D004285:Dogs; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects*; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D015849:Plasminogen Inactivators / Q000378:metabolism / Q000494:pharmacology*; D011655:Pulmonary Embolism / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D005338:Fibrin Fibrinogen Degradation Products; D007457:Iodine Radioisotopes; D015849:Plasminogen Inactivators; C036309:fibrin fragment D; D010959:Tissue Plasminogen Activator