Extravascular fibrin deposition is common at sites of pleural injury and has been related to loculation of pleural fluids. Although thrombolytic therapy has been used to treat pleural loculations, it has not been compared with pleural administration of anticoagulant therapy. We therefore tested interventional strategies designed to compare the relative effects of in vivo anticoagulation or supplemented fibrinolysis on pleural injury, and to characterize the local tissue responses to these modalities. Early intrapleural instillation of saline (Group 1), heparin 1,000 IU (Group 2), or urokinase (uPA) 1,500 IU (Group 3) every 12 h for 3 d was used to interrupt pleural adhesion formation and pleural fibrosis induced by tetracycline hydrochloride in rabbits. Procoagulant and fibrinolytic activities were determined in pleural effusion samples obtained serially every 12 h after the last administered intrapleural dose. Pleural fluid procoagulant activity was blocked by intrapleural heparin (p < 0.001), but plasminogen-dependent fibrinolytic activity was rarely increased by intrapleural urokinase. Most plasminogen activator activity in the pleural fluids was found at high-molecular-weight regions by enzymography, suggesting that it was bound to inhibitor(s). Pathologic analysis at 14 d demonstrated that the number of pleural adhesions in the heparin (8.4 +/- 3.4, mean +/- standard error) and uPA groups (6.1 +/- 2.5) was less than in saline-treated tetracycline controls (20.7 +/- 4.7) (both p < 0.02). Visceral pleural thickness did not differ between groups (p = NS). We conclude that intrapleural heparin or uPA are equally effective in decreasing intrapleural adhesions in tetracycline-induced pleural injury. The data indicate that early anticoagulation or fibrinolytic intervention can attenuate subsequent pleural symphysis in this model.