Understanding the systemic effects of intrapleural tPA and DNase by evaluating effects on coagulation

Design

Prospective observational pilot study

N= 17

Objective

To explore whether there is a measurable change in coagulopathy after getting intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) to help better understand these medications’ systemic risks

Study Groups

Inclusion Criteria

Adults (≥18 years) with complicated parapneumonic effusions (pH <7.2, glucose <60, or LDH >1,000) or multiloculated effusions; identified for chest tube placement and intrapleural therapy with tPA and DNase

Exclusion Criteria

Full-dose anticoagulation, recent blood product transfusion, active or recent gastrointestinal bleeding or intracranial hemorrhage, COVID-19 positive

Methods

Patients were given 10 mg alteplase and 5 mg DNase twice daily. The number of doses was individualized by clinicians based on patient need and response to therapy. Data were compiled from electronic medical records, including serologic analysis, demographics, pleural fluid analysis, diagnosis, and adverse events. 

Baseline and post-infusion TEG, PT/INR, aPTT, fibrinogen, and D-Dimer measurement were obtained. Baseline serologic analysis was done before any tPA and DNase infusions or at least 1 hour after chest tube had been allowed to drain from any previous chest tube tPA and DNase infusions. If patient had intrapleural tPA and DNase, a 1-hour washout period was implemented after draining intrapleural tPA and DNase to minimize effects of previous dose. 

Duration

Outcome Measures

Primary: Change in lysis of clot at 30 minutes (LY30) on thromboelastography (TEG) scan

Secondary: Changes in other TEG, prothrombin time/INR (PT/INR), aPTT, fibrinogen, D-Dimer, intrapleural hemorrhage, systemic bleeding, surgical intervention

Baseline Characteristics

tPA + DNase (N= 17)

Age, years (IQR)

Male

White

Body mass index, kg/m² (IQR)

Time from tPA/DNase dose to post-blood draw, minutes (IQR)

Timing of lab draw during tPA and DNase treatment

1st treatment

2nd treatment

3rd treatment

4th treatment

9 (52.9%)

4 (23.5%)

3 (17.7%)

1 (5.9%)

Median number of doses (IQR)

6 (5-6)

Results

Median pre-value

Median post-value

p-value

LY30, %

D-Dimer, ng/mL

Fibrinogen, mg/dL

INR, s

aPTT, 2

No statistically significant difference was identified in LY30. No other parameters, including R-time, K-time, maximum amplitude (MA), or alpha angle, on the TEG scan showed significant changes when comparing pre and post tPA and DNase therapy values. 

Adverse Events

There was one case of intrapleural hemorrhage (5.9%). There were zero cases of systemic bleeding.

Study Author Conclusions

This is the first study to evaluate measurable changes in systemic coagulation after intrapleural tPA and DNase. This data demonstrates no significant difference in coagulation after intrapleural tPA and DNase infusion, suggesting that there may not be clinically significant absorption.

InpharmD Researcher Critique

Strengths: First study to measure systemic coagulation effects of intrapleural tPA and DNase; use of multiple coagulation measures including TEG scans

Limitations: Small sample size; limited definition of intrapleural hemorrhage; potential short-lived systemic effects not captured due to timing of phlebotomy

Bleeding Risk With Combination Intrapleural Fibrinolytic and Enzyme Therapy in Pleural Infection An International, Multicenter, Retrospective Cohort Study

Design

Multicenter, retrospective observational study

N= 1,851

Objective

To assess the bleeding complication risk associated with intrapleural fibrinolytic and enzyme therapy (IET) use in pleural infection

Study Groups

Inclusion Criteria

Adult patients (≥ 18 years) with pleural infection, treated with at least one dose of combination IET after standard medical treatment failure

Exclusion Criteria

Patients who received IET for recurrence of pleural infection after surgical treatment

Methods

Data was collected from 24 centers across the United States and the United Kingdom. Dosing regimens included 10 mg tPA and 5 mg DNase, given twice daily for 3 days.

Duration

Median length of treatment was 2 days and five doses

Outcome Measures

Primary: Overall incidence of pleural bleeding

Secondary: Incidence of pleural bleeding related to dosing regimens, anticoagulation, platelets, and nonbleeding adverse events

Baseline Characteristics

Study Population (n= 1,833)

Age, years

Male

Body mass index, kg/m²

Pleural findings

Culture positive

Pus

pH

Radiologic loculation

44.7%

45.3%

7.12

81.9%

tPA and DNase administration

Concurrent

Sequential

Not stated

75.8%

21.7%

2.5%

The most administered dosing regimen used was 10 mg tPA and 5 mg DNase, given twice daily for 3 days. Reduced dosing of tPA was used in 172 patients (9.4%), in whom the mean dose per administration was 5 ± 1 mg.

Results

Study Population (n= 1,833)

Pleural bleeding events

Using a half-dose regimen (tissue plasminogen activator, 5 mg) did not change this risk significantly (6/172 [3.5%];p= 0.68).

Therapeutic anticoagulation alongside intrapleural fibrinolytic and enzyme therapy was associated with increased bleeding rates (19/197 [9.6%]) compared with temporarily withholding anticoagulation before administration of IET (3/118 [2.6%]; p= 0.017).

In addition to systemic anticoagulation, increasing RAPID score, elevated serum urea, and platelets of < 100 × 10⁹/L were associated with a significant increase in pleural bleeding risk.

Adverse Events

Pain was the most frequently reported adverse event (12.2%). Hemoptysis occurred in 0.4% of patients, comprising 1.2% of all adverse events.

Other adverse events included chest wall hematoma (0.4%); unexplained drop in hemoglobin or acute anemia without pleural bleeding (0.3%); GI bleeding (0.2%); and hypersensitivity (0.2%).

No episodes of major systemic bleeding secondary to IET were reported, but death before hospital discharge was noted as an adverse event in 16 of 1,833 patients (0.9%).

Study Author Conclusions

IET use in pleural infection confers a low overall bleeding risk. Increased rates of pleural bleeding are associated with concurrent use of anticoagulation but can be mitigated by withholding anticoagulation before IET. Concomitant administration of IET and therapeutic anticoagulation should be avoided.

InpharmD Researcher Critique

This study is the largest of its kind, providing robust data on bleeding risks associated with IET. Its strengths include a large sample size, high data completeness, and use of pre-hoc criteria for defining bleeding events. However, as a retrospective study, it is subject to selection bias and lacks a control group for comparison. The study's findings are limited by the absence of data on prophylactic anticoagulation and the small number of patients on antiplatelet therapy.

Intrapleural Alteplase in a Patient with Complicated Pleural Effusion

Design

Case Report

Case Presentation

A 62-year-old white woman with history of hypertension and hyperlipidemia was admitted for respiratory distress and hypertension. Patient was previously hospitalized at another facility for 3 days. Patient had shortness of breath with cough, general weakness, decreased urinary output, and increasing white blood cell count. The patients started on mask ventilation but required endotracheal ventilation due to deteriorating oxygen status. Empiric antibiotics were given for right-sided pneumonia but patient also had large right-sided pleural effusion and compressive atelectasis. The day after, patient was on chest tube to drain 80 mL of fluid over 4 to 5 days. On the 5th day, patient was started on famotidine IV BID due to bloody drainage. To increase chest tube drainage of the pleural effusion, alteplase 16 mg in 100 mL NS was administered via chest tube for 2 hours into the intrapleural space. Afterwards, daily total volume drainage increased to 235 mL, including 100 mL of alteplase. Intrapleural alteplase continued from hospital day 7 through 10. Heparin was not administered until hospital day 15 as a continuous infusion which was switched to a subcutaneous regimen on day 21. The patient continued to have complications related to low Hb/Hct counts and failure to wean off the ventilator due to pneumonia. On hospital day 45, the patient was given comfort measures until she died later that day.

Study Author's Conclusions

This patient’s complicated pleural effusion resolved when intrapleural alteplase was used as an adjunct to chest tube drainage and antibiotics. Controlled trials need to be conducted to investigate fully the efficacy, dosing, and safety of intrapleural alteplase in the treatment of patients with CPE and empyema.