Plasminogen supplementation improves lysis of inflammatory retained traumatic hemothorax

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 rHIX (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.

LEVEL OF EVIDENCE:

Basic Science; N/A (Basic Science).

Hemothorax is a significant clinical problem in the United States, affecting approximately 300,000 patients annually, with many resulting in a retained hemothorax (rHTX).¹ An rHTX is most commonly associated with thoracic surgery or traumatic injury, with 25% of trauma-related deaths involving thoracic injuries.² By definition, rHTX refers to blood products within the pleural cavity persisting beyond 72 hours.^3–5 Initial management typically involves chest tube thoracostomy to drain the blood products, but this is often inadequate because of the formation of fibrin deposition and loculations, impeding effective drainage.^1,5 When tube thoracostomy fails, surgical intervention, such as video-assisted thoracoscopy or thoracotomy, becomes necessary.^1,2

For patients who are not surgical candidates or wish to avoid it, intrapleural fibrinolytic therapy (IPFT) offers a nonoperative alternative.⁶ This intervention involves administrating 10 mg of tissue plasminogen activator (tPA) and 5 mg of deoxyribonucluease-1 (DNase) into the pleural space via the thoracostomy tube every 12 hours for 3 days.⁶ However, even with this robust regimen, failure rates remain high at approximately 20% to 25% of cases, leading to prolonged hospital stays, increased health care costs, and delayed definitive surgical intervention.^7–9 Prior studies have demonstrated superior outcomes with video-assisted thoracoscopic surgery (VATS) compared with IPFT, including shorter hospital stays and decreased need for additional intervnetions.¹⁰ However, despite these recommendations, IPFT is still frequently used in certain patient populations, making understanding the mechanism behind its success or failure clinically relevant. Moreover, delayed surgical management can complicate the technical aspect of the procedure as dense inflammatory adhesions form over time.

The pathophysiology of rHTX involves a complex interplay between inflammation and coagulation.^5,11–13 The persistent presence of blood in the pleural space leads to inflammation and fibrin deposition, which obstructs effective drainage.^11,12,14,15 Ex vivo, extravascular blood coagulation has been shown to drive neutrophil priming through complement activation, so it follows that similar phenomena may be present in rHTX.¹⁶ Neutrophil activation leads to the release of neutrophil extracellular traps and proteolytic enzymes, such as neutrophil elastase, which may play a key role in fibrinolytic failure.^15,17–19

Under physiologic conditions, fibrinolysis commences when plasminogen is converted into plasmin via tPA on the fibrin clot surface, with plasmin then directly degrading fibrin leading to clot dissolution.²⁰ Prior studies have suggested that elevated plasminogen activator inhibitor 1 (PAI-1) levels (the native inhibitor of tPA) contribute to IPFT failure in empyema and loculated parapneumonic effusions.^21,22 However, PAI-1 is both conformationally labile with a functional half-life of approximately 2 hours and is also highly susceptible to elastase degradation, and it was recently shown that inflammatory plasminogen degradation rather than excess PAI-1 activity is the primary explanation for the overwhelming majority of IPFT failures in infection-related pleural space diseases.^19,23,24 Given that there is some literature to suggest that rHTX may have a similar inflammatory profile to that of infectious pleural space disease, it may be the case that inflammatory plasminogen deficiency also occurs in rHTX, and this may explain any observed failure of IPFT encountered clinically.¹² However, to date, this has not been formally assessed in rHTX.

Given the evidence that rHTX may be an inflamed environment and that neutrophilic inflammatory processes can lead to clot stabilization and fibrinolytic resistance in other contexts, we hypothesized that rHTX creates an inflammatory environment in which neutrophil elastase is locally elevated and depletes full-length plasminogen into nonfunctional fragments and that fibrinolysis could be rescued by addition of supplemental plasminogen. We set out to investigate the underlying biomolecular pathology in rHTX in a series of experiments using pleural fluid and circulating plasma collected from patients with traumatic hemothorax who underwent tube thoracostomy or thoracic surgical intervention.

PATIENTS AND METHODS

Population and Sampling

This study included adult trauma patients with rHTX (n = 19) who presented to a single US level 1 trauma center between May 2024 and January 2025. After receiving institutional review board approval (University of Nebraska Medical Center, IRB 0101–24-FB) and obtaining written informed consent, hemothorax fluid from the pleural space was collected at time of surgery or chest tube placement in 3.2% sodium citrate and centrifuged at 3,000g for 15 minutes at 4°C, aliquoted, and stored at −80°C until use. Blood plasma was obtained from blood samples collected via peripheral venipuncture in 3.2% sodium citrate anticoagulant and serially centrifuged at 3,000g for 15 minutes at 4°C, aliquoted, and stored at −80°C until use as previously described.¹⁶ The study adhered to the STROBE guidelines to ensure comprehensive and transparent reporting (Supplemental Digital Content, Supplementary Data 1, http://links.lww.com/TA/E562).

PAI-1 Activity and Elastase Antigen Assays

To evaluate potential mechanism of fibrinolysis failure, we assessed hemothorax PAI-1 activity using a commercially available assay according to manufacturer instructions (Innovative Research, Novi, MI). Plasminogen activator inhibitor 1 activity was measured in each patient’s circulating blood plasma and their hemothorax fluid. In addition, we also measured PAI-1 activity in each patient’s hemothorax fluid after it was treated with 330pM tPA for 1 hour to match the amount of tPA used in our turbidity assays, which is a much lower dose than is used in clinical IPFT, to demonstrate that PAI-1 activity cannot explain any clinical IPFT failures.¹⁹ In this assay, 1 unit of PAI-1 activity is equivalent to 1.34 ng of active PAI-1, with our results reported as ng/mL active PAI-1 as captured by adsorbed urokinase rather than a capture antibody in this method in order to ensure that only active PAI-1 (rather than total antigen) is being measured.¹⁹

To demonstrate the local acute inflammatory nature of hemothorax relative to the systemic levels of neutrophil-mediated inflammation, neutrophil elastase antigen levels were measured in both hemothorax fluid and each patient’s corresponding plasma using a commercially available enzyme-linked immunosorbent assay according to manufacturer instructions (Abcam, Cambridge, MA).

Western Blot Analysis for Plasminogen and Degradation Fragments

Western blot analysis was performed on hemothorax, and plasma samples were collected on the day of intervention according to the method of Towbin.²⁵ Samples were run under nonreducing conditions and probed with an anti-plasminogen IgM monoclonal antibody at 1:1,000 targeting the N-terminal Kringle domains 1 to 3 (clone GMA-013; Merck Millipore, Billerica, MA). LI-COR fluorescent (IRDye 800CW) anti-IgM secondary antibody was used at 1:15,000 dilution for detection on a LI-COR Odyssey F4 imaging system (LI-COR Inc., Lincoln, NE). A standard protein marker (Bio-Rad precision plus dual color) was used to determine molecular weights. As fluorescent band intensity is linearly proportional to protein concentration on the LI-COR system, band densitometry was performed to compare relative amounts of full-length plasminogen between circulating blood plasma and hemothorax fluid to investigate the degree of any observed plasminogen depletion in hemothorax.²⁶

Turbidity Clot Lysis Assays

To assess fibrinolytic potential of hemothorax fluid, turbidity clot lysis assays were performed by mixing hemothorax fluid ( 1/3 final assay volume) with 1mg/mL purified human fibrinogen (ProLytix, Essex Junction, VT), 330pM recombinant human tPA (Sigma-Aldrich, Saint Louis, MO), and clotting was initiated by addition of 5 nM human thrombin (ProLytix) and 20 mM CaCl₂ with clot formation and fibrinolysis, and then measured via absorption at 620-nm wavelength in a microplate reader over time (rather than 405 nm to avoid free hemoglobin interference) as previously described. To determine whether plasminogen depletion and/or degradation products such as angiostatin contributed to fibrinolytic resistance or failure and if supplementation of plasminogen could improve the fibrinolytic response, the turbidity assays were performed in the presence of absence of 62.5 μg/mL human glu-plasminogen (ProLytix) supplementation, and the time to 50% clot lysis (“transition midpoint” or T_m) was compared between the conditions.^15,19

Statistical Analysis

Statistical analysis was performed using GraphPad Prism version 10 (GraphPad Software, Inc., San Diego, CA). Continuous variables were reported as mean ± SD or n (%). Paired two-tailed t tests were used for pairwise comparisons between hemothorax fluid and plasma assay values, as well as pre– and post–tPA-treated hemothorax fluid. Statistical significance was set at p < 0.05.

RESULTS

Patient Demographics and Clinical Outcomes

A total of 19 patients with blunt trauma–related hemothorax were included (Table 1). The mean age was 68 years, and 18.7% of patients were female. The median Injury Severity Score was 13.5 (interquartile range [IQR], 9–16.8). No patients had in-hospital mortality, but two required thoracic reoperation. The median hospital length of stay was 10.5 days (IQR, 8.3–14.3 days). The median time from injury to initial sample collection was 4 days (IQR, 2–6 days). Demographics, initial laboratory findings, and outcomes are shown in Table 1.

TABLE 1.

Demographics, Clinical Characteristics, Laboratory Values, and Clinical Outcomes of Trauma Patients With Hemothorax (n = 19)

Variable	All Patients n = 19 (%) or Median (IQR)
Demographics
Age, y	64 (61–79)
Male sex, n (%)	16 (84.2%)
Trauma patients, n (%)	19 (100%)
Blunt, n (%)	19 (100%)
Injury Severity Score	13.5 (9–16)
Race
White/Caucasian, n (%)	17 (89.5%)
Black/African American, n (%)	1 (5.3%)
Other/unknown, n (%)	1 (5.3%)
Ethnicity
Non-Hispanic or Latino, n (%)	18 (94.7%)
Comorbidities
BMI, kg/m2	30.2 (22.1–35)
Diabetes, n (%)	6 (31.6%)
Steroid use, n (%)	0 (0%)
No. rib fiactures	7 (4–8)
Underwent surgical rib fixation, n (%)	14 (73.7%)
Age of hemothorax at initial collection, d	4 (2–6)
Day of intervention serum labs
WBC, serum, ×103/μL	10.2 (7.4–12.4)
Glucose, serum, mg/dL	106.5 (95–126.5)
pH, serum, units	7.36 (7.32–7.38)
PaCO2, serum, mm Hg	47.5 (43.8–50)
PaO2, serum, mm Hg	36.5 (26.5–70.5)
HCO3, serum, mmol/L	26 (23–27)
Outcomes
Hospital length of stay, d	10 (7–15)
ICU-free days (at day 28)	28 (24–28)
Ventilator-free days (at day 28)	27 (27–28)
Days to supplemental O2 wean	3 (1–4)
Days to CT removal	3 (3–4)
Required blood transfusion, n (%)	4 (21.1%)
Unplanned readmit, n (%)	2 (10.5%)
Underwent repeat surgery within 3 mo, n (%)	3 (15.8%)
In-hospital mortality, n (%)	0 (0.0%)

BMI, body mass index; WBC, white blood cell.

Elastase Is Increased in rHTX

In order to establish that rHTX is a locally inflamed environment relative to systemic circulation that may proteolytically degrade plasminogen as a mechanism for impaired fibrinolysis, we assessed neutrophil elastase levels in the rHTX fluid and corresponding blood plasma. When compared with corresponding plasma, there was an approximately 10-fold increase in elastase antigen levels in rHTX fluid (rHTX, 4.76 ± 7.83 μg/mL vs. plasma, 0.45 ± 0.37 μg/mL; p = 0.02), indicating a locally inflamed environment (Fig. 1A).

Figure 1.

Retained hemothorax is a locally inflamed environment with secondary plasminogen depletion. (A) Elastase antigen levels are significantly elevated in hemothorax fluid compared with corresponding plasma. (B) Western blot densitometry analysis demonstrated consistently and significantly reduced levels of full-length plasminogen in rHTX relative to plasma, with the degree of plasminogen depletion varying between patients. (C) Representative Western blot image of rHTX samples compared with each of their corresponding plasma samples illustrating decreased band intensity of both glu- and lys-plasminogen in rHTX samples. Results shown with the line at the median, the box at the IQR, and whiskers at the range. Comparisons were made via paired two-tailed t tests;*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. All remaining samples shown in Supplemental Digital Content (Supplementary Fig. S1, http://links.lww.com/TA/E563).

PAI-1 Activity Is Rapidly Depleted by Low-Dose tPA

Previous literature in pleural space diseases has implicated PAI-1 as the cause of ineffective fibrinolysis in the pleural space.^6,14 Plasminogen activator inhibitor 1 activity was present and relatively high in rHTX samples at baseline, likely secondary to the underlying inflammatory environment (Fig. 2). However, as expected based on recent work,¹⁹ PAI-1 was neutralized to nominal activity values by addition of just 330pM of tPA—an amount 1,000-fold lower than the standard clinical dose used in IPFT (rHTX, 48.7 ± 52.3 ng/mL vs. post–tPA-treated rHTX, 2.3 ± 0.6 ng/mL active PAI-1; p = 0.003) (Fig. 2).

Figure 2.

Plasminogen activator inhibitor 1 activity in rHTX is neutralized by low-dose tPA. Baseline PAI-1 activity (ng/mL active PAI-1) is present in rHTX fluid. However, after treatment of rHTX fluid by 330pM tPA, an approximately 1,000-fold lower tPA dose than is used clinically in IPFT, neutralized PAI-1 activity. Results shown with the line at the median, the box at the IQR, and whiskers at the range. Comparisons were made via paired two-tailed t tests;*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Plasminogen Is Depleted in Hemothorax Fluid

Western blot analysis revealed significantly lower levels of full-length plasminogen in rHTX samples compared with corresponding plasma, with less than half the band intensity present in hemothorax fluid (plasma plasminogen, 37.1 ± 17.5 vs. rHTX plasminogen, 14.2 ± 11.0 relative units; p < 0.0001) (Fig. 1B and C, Fig. 3). While most rHTX fluid had some detectable level of full-length plasminogen, there was variability. Additionally, multiple lower-molecular-weight bands were present, representing plasminogen degradation fragments of different weights. Some patients exhibited near-total degradation, suggesting elastase-mediated cleavage, especially in our older hemothorax samples (Fig. 3). Western blot of all patient samples is shown in Supplemental Digital Content (Supplementary Fig. S1, http://links.lww.com/TA/E563).

Figure 3.

Western blot demonstrates presence of plasminogen degradation fragments in rHTX. Western blot analysis against the N-terminus of plasminogen demonstrates the presence of plasminogen degradation fragments that are consistent with those observed as a result of inflammatory protease degradation.

Plasminogen Supplementation Restores Fibrinolysis

Turbidity clot lysis assays were performed to test whether rHTX fluid was capable of generating a fibrinolytic response to tPA and whether supplemental plasminogen would improve the fibrinolytic capacity. When compared with rHTX fluid without supplemental plasminogen, there was a 30.0% reduction in the time to achieve 50% clot lysis when supplemental plasminogen was added (rHTX T_m, 31.3 ± 19.2 minutes vs. rHTX-plasminogen T_m, 21.9 ± 4.5 minutes; p = 0.03) (Fig. 4). There was a continuum of lytic capabilities of patient rHTX in response to tPA, with some patients having very little response to tPA that could be corrected with supplemental plasminogen, some patients had lytic ability but still demonstrated improved lytic ability with the additional plasminogen, while some patients got no appreciable lytic benefit to supplemental plasminogen (Fig. 4A–C).

Figure 4.

Turbidity clot lysis assays demonstrate plasminogen supplementation improves fibrinolysis in rHTX. Turbidity clot lysis assays mixing rHTX with a source of clottable fibrinogen, thrombin, calcium, and tPA +/− supplemental plasminogen demonstrated that some patients’ rHTX has little fibrinolytic potential and this could be rescued with supplemental plasminogen (A), while some patients had moderate fibrinolytic potential that could similarly be improved with supplemental plasminogen (B), and others had robust fibrinolytic potential with no meaningful changes by addition of supplemental plasminogen (C). Overall, we observed an average improvement (reduction) in time to 50% clot lysis of 30.0% for our cohort (D). Results for individual turbidity assays are shown as their individual absorption values over time, with the combined overall cohort data quantifying the time (in minutes) to 50% clot lysis shown with the line at the median, the box at the IQR, and whiskers at the range. Comparisons were made via paired two-tailed t tests;*p < 0.05, *p < 0. 01, ***p < 0.001, ****p < 0.0001.

DISCUSSION

Retained hemothorax remains a common clinical challenge, particularly when initial drainage via tube thoracostomy is insufficient and surgical intervention carries added risk. However, failure to evacuate large rHTX risks complications including empyema and/or fibrothorax,^1,3,27 both of which can be catastrophic for patients as uncontrolled sepsis or irreversible restrictive lung disease can occur. An alternative strategy to avoid operation has been employed using IPFT in patients with rHTX that fails to adequately drain via tube thoracostomy but whom are poor operative candidates or decline operative intervention. However, the results of this are variable, with many patients failing to improve via such an approach.

Given recent work in empyema and parapneumonic effusions showing that the inflamed environment leads to inflammatory plasminogen depletion such that fibrinolysis in response to tPA is not possible with restoration of plasminogen,¹⁹ and some limited literature that rHTX may have a similar inflammatory environment to these intrapleural infections,¹² we hypothesized that a similar phenomena may occur in rHTX.

While polytrauma patients are known to have elevated systemic levels of neutrophil-inflammation,¹⁶ we found that the rHTX fluid had an approximately 10-fold increase in neutrophil elastase relative to systemic circulation, indicating a highly inflamed local environment full of a protease known to degrade plasminogen and cause failure of fibrinolysis. Furthermore, given that historical literature of pleural space disease has suggested that PAI-1 is the primary reason for IPFT failure,^21,22 we sought to investigate whether such an explanation may be applicable for fibrinolytic resistance in rHTX. While PAI-1 activity was present at relatively high levels in rHTX samples, it was depleted to a nominal value in all cases by the addition of a single dose of exogenous tPA at concentrations nearly 1,000-fold lower than what is clinically used in IPFT (Fig. 2). This suggests that PAI-1 is unlikely to be a significant contributor to therapeutic failure of IPFT in rHTX.

To then investigate whether the highly inflamed local environment in rHTX may lead to a plasminogen deficiency secondary to degradation, as is seen in empyema, we performed Western blotting of rHTX and its corresponding circulating blood plasma for plasminogen, where we found a more than two-fold depletion in band intensity of full-length plasminogenand evidence of degradation fragments in rHTX. To then investigate whether this observed depletion had a functional consequence, we performed turbidity clot lysis assays that mixed rHTX fluid with a fresh source of clottable fibrinogen, which was then clotted and challenged with tPA in the presence or absence of supplemental plasminogen. While some patients rHTX retained robust lytic capability, many patients demonstrated a marked improvement in their lytic response to tPA in the presence of supplemental plasminogen, most notably in those patients in whom little fibrinolysis was observed in response to tPA in the absence of supplemental plasminogen (Fig. 4A–C).

Overall, the present data are consistent with our hypothesis that inflammatory degradation and depletion of full-length, functional plasminogen in rHTX fluid may drive clinical IPFT failure. While some patients appeared to have a robust lytic response of their rHTX fluid to tPA, some did not, and in those where fibrinolysis was blunted, it could be rescued in all cases with plasminogen supplementation. This aligns with the recent findings in empyema/parapneumonic effusion, where a proteolytic, inflammatory pleural environment depleted of plasminogen is the hallmark of fibrinolytic resistance,¹⁵ although, importantly, in the present study of rHTX, it is clear that there is a less uniform blunting of fibrinolysis with some patients clearly retaining sufficient plasminogen levels to generate robust fibrinolysis in response to tPA.

Clinical Implications

Our findings have important clinical implications. First, in patients with rHTX where tube thoracostomy alone leads to insufficient drainage, our data suggest that, if IPFT is attempted and fails, plasminogen depletion may be the mechanism of failure. Without adequate plasminogen, tPA has no effective substrate to convert into plasmin, rendering fibrinolytic therapy ineffective. While human plasminogen was recently approved by the Food and Drug Administration, its current indication is for treatment of congenital plasminogen deficiency, a rare disorder with a population incidence of just 1 in 1.6 million people.²⁸ Therefore, until clinical trials for safety and efficacy using intrapleural plasminogen supplementation during IPFT are performed, this approach remains clinically unavailable.

Current guidelines from the Eastern Association for the Surgery of Trauma recommend considering early video-assisted thoracoscopic surgery within 4 days for patients with large-volume hemothorax, particularly in cases where chest tube drainage is inadequate. Failure to operate in these cases leads to increased hospital length of stay and increased risk of thoracic complications, including “trapped lung” (fibrothorax) and empyema.^1,27 Our data provide a molecular biologic rationale for this approach. Finally, these findings raise new therapeutic questions. Future research investigating the role of plasminogen supplementation is needed in IPFT in the form of clinical trials. Our turbidity clot lysis assays potentially support this, showing that restoring plasminogen can rescue fibrinolysis ex vivo in rHTX samples that have little response to tPA without it.

Limitations

This study has several limitations. First, this was an exploratory study from a single center with a small sample size (n = 19), limiting statistical power and generalizability. Second, while our ex vivo analysis of rHTX samples provided mechanistic insight, they do not fully replicate the in vivo pleural environment. The complex interplay of cytokines, mesothelial cells, and mechanical factors may further influence fibrinolysis in ways not accounted for in our assays. Future studies using animal models will be essential to validate these findings. We also had variability among our patient population; a small subset of patients underwent multiple thoracic procedures during hospitalization, which may have influenced their pleural inflammatory profiles and introduced variability into our results. Finally, while our findings support plasminogen depletion as a mechanism of fibrinolytic failure, we were unable to assess plasminogen consumption dynamics over time. Additionally, the variability in timing of sample collection relative to injury may influence the degree of plasminogen depletion and disease process. Although we attempted to correlate sample age with fibrinolytic profile, the sample size was not sufficient to draw definitive conclusions and remains an area for future research.

CONCLUSION

This study provides novel insights into the failure of IPFT in rHTX, identifying neutrophilic inflammation and plasminogen depletion as a key mechanistic barrier (summarized in Fig. 5). While PAI-1 may inhibit endogenous fibrinolysis and contribute to loculation and organization in rHTX and other complex pleural space diseases, our findings challenge the conventional view that PAI-1 is the primary mechanism of IPFT failure in the pleural space and instead suggest that this may be driven by plasminogen depletion secondary to inflammatory proteolytic activity through neutrophil elastase. In summary, our results may offer a potential mechanistic rationale to support earlier surgical intervention in patients with rHTX and highlight the potential for future plasminogen-based therapeutics, which warrants further investigation in clinical trials.

Figure 5.

Schematic diagram for proposed mechanism of blunted fibrinolytic potential in rHTX.

Supplementary Material

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.jtrauma.com).