Precision-guided, Personalized Intrapleural Fibrinolytic Therapy for Empyema and Complicated Parapneumonic Pleural Effusions: The Case for The Fibrinolytic Potential

Abstract

Complicated pleural effusions and empyema with loculation and failed drainage are common clinical problems. In adults, intrapleural fibrinolytic therapy is commonly used with variable results and therapy remains empiric. Despite the intrapleural use of various plasminogen activators; fibrinolysins, for about sixty years, there is no clear consensus about which agent is most effective. Emerging evidence demonstrates that intrapleural administration of plasminogen activators is subject to rapid inhibition by plasminogen activator inhibitor-1 and that processing of fibrinolysins is importantly influenced by other factors including the levels and quality of pleural fluid DNA. Current therapy for loculation that accompanies pleural infections also includes surgery, which is invasive and for which patient selection can be problematic. Most of the clinical literature published to date has used flat dosing of intrapleural fibrinolytic therapy in all subjects but little is known about how that strategy influences the processing of the administered fibrinolysin or how this influences outcomes. We developed a new test of pleural fluids ex vivo, which is called the Fibrinolytic Potential or FP, in which a dose of a fibrinolysin is added to pleural fluids ex vivo after which the fibrinolytic activity is measured and normalized to baseline levels. Testing in preclinical and clinical empyema fluids reveals a wide range of responses, indicating that individual patients will likely respond differently to flat dosing of fibrinolysins. The test remains under development but is envisioned as a guide for dosing of these agents, representing a novel candidate approach to personalization of intrapleural fibrinolytic therapy.

Phase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyema

“…Next, we tested the concept of fibrinolytic potential (FP) as a personalized predictor of the response to LTI-01 IPFT (21,22). Supplementation of the predose (baseline and at 23 hours) PFs with 2-chain uPA (the FP) generated robust levels of fibrinolytic activity (median 0.7-1.3 AU; P < 0.01 versus unsupplemented baseline levels).…”

“…Correlation (D) between fibrinolytic potential (FP) and clinical outcome after IPFT with LTI-01 (n = 8; r = -0.79; P < 0.05 by Spearman's rank correlation). FP was determined in samples of PF collected prior to IPFT as previously described (21,22). Percent changes in relative pleural density on chest X-ray prior to and after IPFT with LTI-01 were calculated as previously described (5).…”

“…Levels of PAI-1 antigen and activity levels were also assessed (18), as were levels of bioactive A2M-uPA complexes (13). FP measurement of fibrinolytic activity after supplementation of baseline PFs with 2-chain uPA was determined in samples of PF collected prior to the IPFT as previously described (21,22). A total of n = 8 PFs were available for these analyses.…”

Medical and Surgical Management of Empyema

“…98,113,114 PAI-1 irreversibly inactivates tPA in 1:1 fashion and human empyema PAI-1 levels are highly heterogenous, 98,115,116 suggesting that IPFT dosing relative to measures of fibrin formation may be useful. 117 Phase I investigation of the fibrinolytic drug single-chain urokinase plasminogen activator (scuPA) that is relatively resistant to inhibition by PAI-1 is underway. 118 In patients who failed to respond to the 3-day MIST2 regimen, an extended course of IPFT does not appear to be of benefit.…”

Dual intracavitary therapy for pleural infections: leaving reluctance behind

“…Additionally, whether urokinase or new fibrinolytics, such as single chain urokinase plasminogen activator (scuPA) [22], may replace tPA in dual intrapleural regimens has not yet been tested. Individualised dosages of fibrinolytics based on pleural fluid plasminogen activator activity is an attractive notion that needs to be explored [23]. If the classical MIST2 protocol is truly cost-effective, then the application of more simplified administration protocols will be even more so.…”