Abstract
INTRODUCTION: Retained hemothorax (rHTX) occurs when blood persists in the pleural space beyond 72 hours. While initial management involves chest tube placement, failure often necessitates surgical intervention. Intrapleural fibrinolytic therapy (IPFT) with tissue plasminogen activator (tPA)/DNase is a nonoperative alternative, but failure rates remain high (>20%). Prior work in pleural infections suggests fibrinolytic failure results from plasminogen degradation by neutrophil proteases. We hypothesized that rHTX is a similarly inflamed environment where plasminogen depletion impairs fibrinolysis. METHODS: Hemothorax fluid and plasma were collected from trauma patients (n = 19) at a Level 1 trauma center. Elastase antigen and plasminogen activator inhibitor 1 (PAI-1) activity were measured via enzyme-linked immunosorbent assay-based assays. Western blot assessed full-length plasminogen and degradation fragments. Turbidity clot lysis assays evaluated rHTX fibrinolytic potential +/- supplemental plasminogen. Paired t tests were performed with significance at p < 0.05. RESULTS: Elastase levels were approximately 10-fold higher in rHTX compared with plasma (rHTX, 4.76 ± 7.83 μg/mL vs. plasma, 0.45 ± 0.37 μg/mL; p = 0.02). Western blot demonstrated low plasminogen levels in rHTX compared with plasma with evidence of inflammatory degradation. After exogenous treatment of rHTX with 330pM tPA (~1,000-fold lower than clinical doses), there was no meaningful residual PAI-1 activity. Clot lysis assays of rHTX demonstrated markedly improved time to 50% clot lysis in the presence of supplemental plasminogen (rHTX, 31.3 ± 19.2 minutes vs. rHTX-plasminogen, 21.9 ± 4.5 minutes; p = 0.03). Plasminogen activator inhibitor 1 activity, although present at baseline, was rapidly neutralized by low-dose tPA, suggesting that no clinically meaningful tPA inhibition is present in rHTX (rHTX, 48.7 ± 52.3 ng/mL vs. post-tPA-treated rHTX, 2.3 ± 0.6 ng/mL active PAI-1; p = 0.003). CONCLUSION: Retained hemothorax is a highly inflammatory environment with secondary plasminogen depletion that reduces fibrinolytic capacity. Plasminogen activator inhibitor 1 inhibition of tPA appears to be an unlikely mechanism of clinical IPFT failure. These findings challenge the role of IPFT for rHTX and support upfront surgical intervention. Future studies exploring plasminogen supplementation in IPFT as a therapeutic strategy for poor surgical candidates is warranted.