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Original Research: Diffuse Lung Disease |

Recombinant Human Thrombomodulin in Acute Exacerbation of Idiopathic Pulmonary FibrosisRecombinant Human Thrombomodulin in AE-IPF FREE TO VIEW

Kensuke Kataoka, MD, PhD; Hiroyuki Taniguchi, MD, PhD; Yasuhiro Kondoh, MD, PhD; Osamu Nishiyama, MD, PhD; Tomoki Kimura, MD, PhD; Toshiaki Matsuda, MD; Toshiki Yokoyama, MD, PhD; Koji Sakamoto, MD, PhD; Masahiko Ando, MD, PhD
Author and Funding Information

From the Department of Respiratory Medicine and Allergy (Drs Kataoka, Taniguchi, Kondoh, Kimura, Matsuda, and Yokoyama), Tosei General Hospital, Seto; Department of Respiratory Medicine and Allergology (Dr Nishiyama), Kinki University, Faculty of Medicine, Osaka; Department of Respiratory Medicine (Dr Sakamoto), Nagoya University Graduate School of Medicine, Nagoya; and Center for Advanced Medicine and Clinical Research (Dr Ando), Nagoya University Hospital, Nagoya, Japan.

CORRESPONDENCE TO: Hiroyuki Taniguchi, MD, PhD, Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi 489-8642, Japan; e-mail: taniguchi@tosei.or.jp


FUNDING/SUPPORT: This study was partially supported by a grant to the Diffuse Lung Disease Research Group from the Ministry of Health, Labor and Welfare, Japan, and the NPO Respiratory Disease Conference.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(2):436-443. doi:10.1378/chest.14-2746
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BACKGROUND:  Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening closely associated with endothelial damage and disordered coagulopathy. Recombinant human soluble thrombomodulin (rhTM) regulates the coagulation pathway mainly by reducing thrombin-mediated clotting and enhancing protein C activation. We investigated the efficacy of rhTM for the treatment of patients with AE-IPF.

METHODS:  This historical control study comprised 40 patients with AE-IPF. Twenty patients treated with rhTM (0.06 mg/kg/d) for about 6 days (rhTM group) and 20 patients treated without rhTM (control group) were evaluated. The predictors of 3-month mortality (logistic regression model) were evaluated.

RESULTS:  There was no difference in baseline characteristics between the control group and the rhTM group. Three-month mortality of the rhTM group and control group was 30.0% and 65.0%, respectively. In univariate analysis, C-reactive protein and rhTM therapy were significant determinants for 3-month survival. In multivariate analysis, rhTM therapy (OR, 0.219; 95% CI, 0.049-0.978; P = 0.047) was an independent significant determinant for 3-month survival.

CONCLUSIONS:  We found that rhTM therapy improved 3-month survival of AE-IPF. The results observed here warrant further investigation of rhTM in randomized control trials.

Figures in this Article

Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) presents as episodes of acute respiratory worsening of unknown etiology and is associated with a high rate of short-term mortality. Published clinical trials have revealed that AE is one of the leading causes of death of patients with IPF.1 Although little is known about the pathophysiology of AE-IPF, several studies suggest that disordered coagulation and fibrinolysis play important roles in AEs.2,3 Studies of patients with IPF have demonstrated a procoagulant and antifibrinolytic alveolar environment in AE-IPF.46 A similar environment has been described in ARDS, in which pathophysiologic responses are caused by microvascular thrombosis7,8 and endothelial injury.9

Treatment of AE-IPF has generally consisted of high-dose corticosteroids, although there are no data from controlled trials to prove their efficacy.1012 Thrombomodulin is a transmembrane glycoprotein expressed on the surface of vascular endothelial cells. Expression of thrombomodulin is tightly regulated to maintain homeostasis and to ensure a rapid and localized hemostatic and inflammatory response to injury. A novel biologic agent, recombinant human soluble thrombomodulin (rhTM), exhibits a range of physiologically important antiinflammatory, anticoagulant, and antifibrinolytic properties via complex interactions with thrombin, protein C, thrombin-activatable fibrinolysis inhibitor, complement components, the Lewis Y antigen, and the cytokine high-mobility group protein B1.13,14 The clinical efficacy of rhTM in the treatment of intravascular coagulation was demonstrated in a randomized controlled trial,15 and it has been approved for clinical use in Japan since 2008. Retrospective analyses reported that rhTM might improve survival rate and respiratory dysfunction in patients with severe sepsis.16,17 Based on these findings, we hypothesized that rhTM may be effective against AE-IPF. The purpose of this pilot retrospective study was to investigate the efficacy of rhTM in the treatment of patients with AE-IPF.

Subjects

This was a historical control study of patients admitted for episodes of AE-IPF to Tosei General Hospital, Aichi, Japan. From August 2009 to December 2011, 22 consecutive patients with AE-IPF were treated with rhTM (rhTM group) (Fig 1). To match numbers, we used a historical control group comprising 22 consecutive patients with AE-IPF from May 2007 to July 2009 (Fig 1). AE-IPF was defined using reported criteria for AE-IPF,10 which state that all of the following conditions must be satisfied for previous or concurrent diagnosis of IPF: unexplained worsening or development of dyspnea within 30 days; new, bilateral, ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia pattern on CT imaging; and no evidence of pulmonary infection by endotracheal aspirate or BAL. Patients with obvious causes, such as left-sided heart failure or pulmonary embolism as an identifiable cause of acute lung injury, were excluded.

Figure Jump LinkFigure 1 –  Flowchart of study design. AE-IPF = acute exacerbation of idiopathic pulmonary fibrosis; rhTM = recombinant human soluble thrombomodulin.Grahic Jump Location

Transthoracic echocardiography was performed in all patients. Cultures of sputum, blood, and urine examined for mycobacteria, fungi, and bacteria were negative in all patients. All serologic studies for respiratory viruses such as herpes simplex virus, cytomegalovirus, varicella-zoster virus, adenovirus, influenza virus, and respiratory syncytial virus, and for chlamydophila, mycoplasma, and legionella were negative. Of 40 patients who met the inclusion criteria, BAL was performed at acute exacerbation in 37. BAL could not be performed in the other three patients because of severe hypoxemic respiratory failure. Cultures of BAL fluid (BALF) for respiratory viruses were performed. In BALF samples, additional stains were used: Ziehl-Neelsen staining for mycobacteria and Grocott’s methenamine silver stain for fungi and Pneumocystis jirovecii. In addition, polymerase chain reaction DNA test for P jirovecii in BALF was performed.

The exclusion criteria in this study were as follows: more than one previous episode of AE-IPF, fatal or life-threatening bleeding (intracranial, GI, or pulmonary bleeding), history of cerebrovascular disorder (cerebral bleeding or cerebral infarction) within 1 year, age ≤ 15 years, history of hypersensitivity to protein preparations or low-molecular-weight heparin (LMWH), complication of severe disease other than AE-IPF, pregnancy or breastfeeding, and decompensated liver cirrhosis or other serious liver disorder. These data were collected retrospectively from medical records. This study was carried out in accord with the principles of the Declaration of Helsinki and approved by the institutional review board at Tosei General Hospital (IRB no. 293).

Interventions

In the rhTM group, administration of rhTM infusion (0.06 mg/kg/d) was started when patients fulfilled the criteria for AE-IPF and after they had given informed consent. RhTM therapy was continued for about 6 days, followed by continuous IV infusion of LMWH (750,000 International Units/kg/d). The control group was treated with continuous IV infusion of LMWH (750,000 International Units/kg/d) as standard anticoagulant therapy. In both groups, discontinuation of anticoagulant therapy was considered if any adverse events were present.

Data Collection

We collected information on the characteristics of the underlying IPF and treatment of IPF prior to AE. For respiratory function prior to AE, we collected respiratory data for the 6 months before AE. Patients were followed until 3 months after entry into the study. The variables at AE used to assess comparability between the two groups were age, sex, Pao2/Fio2, respiratory rate, APACHE (Acute Physiology and Chronic Health Evaluation) II score, WBC count, serologic tests (C-reactive protein [CRP], lactate dehydrogenase [LDH], Krebs von der Lungen-6 [KL-6], surfactant protein D [SP-D], D-dimer, thrombomodulin, and brain natriuretic peptide) and BALF data (total cell count, cell fraction, and D-dimer, thrombomodulin, and albumin levels). We evaluated 3-month mortality and physiologic and biochemical variables. The presence of adverse events related to coagulation and fibrinolysis that led to discontinuation of the administered anticoagulant therapy was recorded. These data were collected retrospectively from medical records.

Statistical Analysis

Continuous variables were described by median and interquartile range. Categorical variables were described by frequency and percentage. Comparisons between groups were done with the Mann-Whitney U test. Associated factors of 3-month mortality were analyzed by univariate analysis and multivariate logistic regression. Variables with a P value < .1 at univariate analysis were included in the multivariate analysis. ORs and 95% CIs were calculated. To evaluate the robustness of the results concerning efficacy of rhTM, we performed another multivariate logistic regression analysis including treatment group (rhTM/control) and propensity score to adjust for potential confounding factors as covariates. The propensity score was calculated from the logistic regression model including age; sex; Pao2/Fio2; respiratory rate; APACHE II score; WBC count; and CRP, LDH, KL-6, SP-D, and D-dimer levels. Statistical analysis was performed using SPSS 21.0 (IBM Corp). A P value < .05 was considered to be statistically significant.

Baseline Characteristics

A patient flow diagram is shown in Figure 1. In the study period, 44 consecutive patients were admitted for AE-IPF. Four of these patients were excluded, including two with previous episodes of AE, one with complication of severe acute cholecystitis, and one who refused further medical treatment. The remaining 40 patients met the inclusion criteria. They included 36 men and four women, with a median age of 72 years (range, 43-90 years) (interquartile range, 66-78 years). Median Pao2/Fio2 at diagnosis for AE-IPF was 226 (range, 76-298). The baseline characteristics of the study population are shown in Table 1. There were no significant differences in characteristics and treatment prior to AE between the rhTM group and control group (Table 2). In univariate logistic regression analysis, duration of IPF, FVC, and diffusing capacity were not significant predictors for 3-month survival (P = .209, P = .540, and P = .999, respectively).

Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics

Data are expressed as group median (interquartile range) or No. (%). APACHE = Acute Physiology and Chronic Health Evaluation; CRP = C-reactive protein; KL-6 = Krebs von der Lungen-6; LDH = lactate dehydrogenase; rhTM = recombinant human soluble thrombomodulin; SP-D = surfactant protein D.

a 

P value: rhTM group vs control group.

b 

n = 38.

c 

n = 19 due to missing data.

Table Graphic Jump Location
TABLE 2 ]  Patient Characteristics of Underlying IPF Prior to Acute Exacerbation

Data are expressed as group median (interquartile range) or No. (%). Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis. See Table 1 legend for expansion of other abbreviation.

a 

P value: rhTM group vs control group.

b 

n = 33.

c 

n = 17.

d 

n = 16.

e 

n = 32.

f 

n = 15 due to missing data.

In 32 patients (80%), mild abnormality was detected in coagulation or fibrinolysis parameters in peripheral blood tests. Pulmonary embolism was excluded by using CT pulmonary angiography. As indicated in Table 3, in BAL from patients with AE-IPF, a high total number of cells and elevation of D-dimer levels and thrombomodulin were found. For comparison, D-dimer levels were below the detection sensitivity limit in BALF of patients with stable IPF (data not shown).

Table Graphic Jump Location
TABLE 3 ]  BAL Fluid Data

Data are expressed as group median (interquartile range). See Table 1 legend for expansion of abbreviation.

a 

P value: rhTM group vs control group.

Therapeutic Intervention of AE-IPF

Twenty patients were treated with rhTM (rhTM group), and 20 patients were treated without rhTM (control group) (Table 4). The median duration of treatment was 6 days with rhTM (range, 3-6 days) followed by 8 days with LMWH (range, 0-17 days) in the rhTM group. On the other hand, the median duration of treatment was 10 days with LMWH (range, 7-22 days) in the control group. All patients received high-dose IV corticosteroids (methylprednisolone, 1 g/d) for 3 days. Corticosteroid therapy was followed by a tapered dosage and was combined with oral administration of an immunosuppressant (cyclosporine 3 mg/kg/d). All patients received empirical antibiotic therapy until negative bacterial cultures were confirmed. Seven patients continued to receive pirfenidone, which had been administered since before the onset of AE, together with the treatment of AE.

Table Graphic Jump Location
TABLE 4 ]  Therapeutic Interventions for Acute Exacerbation of IPF

Data are expressed as No. (%). IMV = invasive mechanical ventilation; LMWH = low-molecular-weight heparin; mPSL = pulse, IV methylprednisolone 1 g/d for 3 d; NIV = noninvasive ventilation. See Table 1 and 2 legends for expansion of other abbreviations.

a 

P value: rhTM group vs control group.

Noninvasive ventilation (NIV) was the first-line intervention for all patients. Endotracheal intubation on day 1 was performed in only one patient. The 3-month mortality of the rhTM group and control group was 30.0% (six of 20 patients) and 65.0% (13 of 20 patients), respectively. The cause of death in all these cases was respiratory failure.

Univariate and Multivariate Analysis of Predictors of 3-Month Mortality

In univariate analysis, CRP and rhTM therapy were significant predictors for 3-month mortality (Table 5). The results of the multivariate analysis are listed in Table 5. Based on multivariate analysis including respiratory rate, CRP, and rhTM therapy, 3-month mortality was independently associated with rhTM therapy (OR, 0.219; 95% CI, 0.049-0.978; P = .047). A supportive logistic regression analysis with adjustment for propensity score, which was calculated from all the variables assessed in univariate analysis, confirmed the advantage in 3-month mortality for rhTM therapy (OR, 0.21; 95% CI, 0.05-0.91; P = 0.038). Figure 2 shows the Kaplan-Meier curves at 3 months in both the rhTM and control groups.

Table Graphic Jump Location
TABLE 5 ]  Univariate and Multivariate Analyses of Predictors of 3-Mo Mortality

See Table 1 legend for expansion of abbreviations.

Figure Jump LinkFigure 2 –  Kaplan-Meier distribution for the probability of progression-free survival. The P value was calculated using the log-rank test. The solid line represents patients in the rhTM group, and the dotted line represents patients in the control group. Survival was significantly better in the rhTM group than the control group (P = .0024). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location
Adverse Events

Two adverse events related to coagulation and fibrinolysis occurred in each group. In the rhTM group, one episode of hemosputum occurred on day 5 (administration of rhTM was discontinued and the patient recovered), and one episode of acute DVT of the leg emerged newly on day 4 (the patient was switched from rhTM to LMWH and recovered; rhTM has no proven benefit in the treatment of DVT). In the control group, there was bleeding from the central venous catheter insertion site on day 3 in one patient and subcutaneous bleeding on day 8 in another (administration of LMWH was promptly stopped in these two patients, and they recovered from the complication within 24 h).

This is the first study, to our knowledge, to investigate the efficacy of rhTM for AE-IPF. We showed that rhTM was associated with a better outcome for 3-month mortality (30%). Using a logistic regression model, it was also shown to improve 3-month survival. Administration of rhTM appeared to be safe without any major adverse effects.

We found high levels of D-dimer in BALF in patients with AE-IPF, which reflect a disturbance in intraalveolar-activated coagulation. We also showed an elevated level of thrombomodulin in BALF, which reflects a release of thrombomodulin from the lung microvascular endothelium into the alveolar space in the setting of endothelial injury.9 These findings are compatible with a previous report showing the presence of disordered coagulation, fibrinolysis, and endothelial damage in autopsy samples of AE-IPF.18 Because rhTM binds to thrombin to inactivate coagulation, and the thrombin rhTM complex activates protein C to produce activated protein C, it can play an important role in regulating coagulation.

Collard et al3 studied the plasma biomarker profile of AE-IPF and found that mechanical ventilation and log change in thrombomodulin were significant predictors of survival at AE-IPF. These findings support the hypothesis that microvascular dysfunction may be the key to the development and prognosis of AE-IPF and that microcoagulation should be a principal therapeutic target. We suppose that via suppression of the coagulation abnormality, rhTM administration at AE-IPF in this study prevented the progressive and fatal process of AE-IPF. Although a clinical trial demonstrated that treatment with warfarin is associated with no clinical benefit in patients with chronic phase IPF,19 we investigated the role of anticoagulation therapies for the treatment of AE-IPF in this study.10

In this study, higher CRP levels were a poor prognostic factor for AE-IPF. Similarly, Song et al20 found that higher CRP levels were a poor prognostic factor for AE-IPF in a multivariate analysis. These findings suggest a crucial role for inflammation in the pathologic mechanism of AE-IPF and that the effect of rhTM in AE-IPF might be due to its antiinflammatory actions. In addition to regulation of the coagulation pathway, rhTM has antiinflammatory effects including lypopolysaccharide adsorption,21 high-mobility group protein B1 adsorption and degradation,22 inhibition of neutrophil adhesion to endothelial cells, inhibition of complement activation,23 and inactivation of bradykinin, C3a, and C5a.24

Currently, treatment of AE-IPF generally consists of high-dose corticosteroids or combination therapy with high-dose corticosteroids and cyclosporine, but there are no controlled trials from which to judge the efficacy of these treatments.2527 According to IPF guidelines,11 there is no gold standard for the management of AE-IPF; however, a common management strategy was applied for AE-IPF in this series. First, all patients were treated with high-dose IV corticosteroids and oral administration of cyclosporine unless contraindicated. Second, NIV was used as a first-line respiratory management for AE-IPF to avoid intubation. Guidelines on the diagnosis and management of IPF recommend that the majority of patients with respiratory failure due to IPF should not receive mechanical ventilation and state that NIV may be appropriate in some patients.11,28

We recognize that there are some limitations to this study. First this is a retrospective, historical control study, not a randomized control study, and it is possible that this might somehow have biased results or that multiple unmeasured variables may have affected the outcomes. It is also possible that knowledge of an interesting new intervention might have influenced other aspects of management, including the level of support and the timing of key tests. However, as indicated in Table 4, there was not a significant difference in the major therapeutic interventions for AE-IPF. Second, this is a single-center study with rather small sample size. Third, all patients in this study are Japanese, and racial differences may need to be considered in the effectiveness of this drug. Finally, we included three patients with suspected AE-IPF who had not undergone BAL evaluation. However, there were no differences in the results of two models in which these three suspected cases were included and excluded (data not shown).

In conclusion, we found that rhTM therapy improved 3-month survival of AE-IPF in this case-control study. The results observed here warrant further investigation of rhTM in randomized control trials.

Author contributions: K. K. served as principal author, had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis. Y. K., O. N., and K. S. contributed to the study concept and design; T. K., T. M., and T. Y. contributed to data collection; H. T., T. K., T. M., T. Y., and M. A. contributed to data analysis; T. K., T. M., and T. Y. contributed to preparation and review of the manuscript; Y. K., O. N., K. S., and M. A. contributed to the writing and revising of the manuscript; and H. T. contributed to final approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Taniguchi has received lecture fees from Asahi Kasei Pharma Corp. Dr Kondoh has received lecture fees from Asahi Kasei Pharma Corp. Drs Kataoka, Nishiyama, Kimura, Matsuda, Yokoyama, Sakamoto, and Ando have reported that no potential conflicts of interest with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

AE

acute exacerbation

APACHE

Acute Physiology and Chronic Health Evaluation

BALF

BAL fluid

CRP

C-reactive protein

IPF

idiopathic pulmonary fibrosis

KL-6

Krebs von der Lungen-6

LDH

lactate dehydrogenase

LMWH

low-molecular-weight heparin

NIV

noninvasive ventilation

rhTM

recombinant human soluble thrombomodulin

SP-D

surfactant protein D

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Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005;128(3):1475-1482. [CrossRef] [PubMed]
 
Collard HR, Calfee CS, Wolters PJ, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L3-L7. [CrossRef] [PubMed]
 
Günther A, Mosavi P, Ruppert C, et al. Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease. Thromb Haemost. 2000;83(6):853-860. [PubMed]
 
Olman MA. Mechanisms of fibroproliferation in acute lung injury.. In:Matthay MA, Lenfant C., eds. Acute Respiratory Distress Syndrome. New York, NY: Marcel Dekker; 2003:313-354.
 
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Figures

Figure Jump LinkFigure 1 –  Flowchart of study design. AE-IPF = acute exacerbation of idiopathic pulmonary fibrosis; rhTM = recombinant human soluble thrombomodulin.Grahic Jump Location
Figure Jump LinkFigure 2 –  Kaplan-Meier distribution for the probability of progression-free survival. The P value was calculated using the log-rank test. The solid line represents patients in the rhTM group, and the dotted line represents patients in the control group. Survival was significantly better in the rhTM group than the control group (P = .0024). See Figure 1 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Patient Characteristics

Data are expressed as group median (interquartile range) or No. (%). APACHE = Acute Physiology and Chronic Health Evaluation; CRP = C-reactive protein; KL-6 = Krebs von der Lungen-6; LDH = lactate dehydrogenase; rhTM = recombinant human soluble thrombomodulin; SP-D = surfactant protein D.

a 

P value: rhTM group vs control group.

b 

n = 38.

c 

n = 19 due to missing data.

Table Graphic Jump Location
TABLE 2 ]  Patient Characteristics of Underlying IPF Prior to Acute Exacerbation

Data are expressed as group median (interquartile range) or No. (%). Dlco = diffusing capacity of the lung for carbon monoxide; IPF = idiopathic pulmonary fibrosis. See Table 1 legend for expansion of other abbreviation.

a 

P value: rhTM group vs control group.

b 

n = 33.

c 

n = 17.

d 

n = 16.

e 

n = 32.

f 

n = 15 due to missing data.

Table Graphic Jump Location
TABLE 3 ]  BAL Fluid Data

Data are expressed as group median (interquartile range). See Table 1 legend for expansion of abbreviation.

a 

P value: rhTM group vs control group.

Table Graphic Jump Location
TABLE 4 ]  Therapeutic Interventions for Acute Exacerbation of IPF

Data are expressed as No. (%). IMV = invasive mechanical ventilation; LMWH = low-molecular-weight heparin; mPSL = pulse, IV methylprednisolone 1 g/d for 3 d; NIV = noninvasive ventilation. See Table 1 and 2 legends for expansion of other abbreviations.

a 

P value: rhTM group vs control group.

Table Graphic Jump Location
TABLE 5 ]  Univariate and Multivariate Analyses of Predictors of 3-Mo Mortality

See Table 1 legend for expansion of abbreviations.

References

Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431-440. [CrossRef] [PubMed]
 
Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. 2005;128(3):1475-1482. [CrossRef] [PubMed]
 
Collard HR, Calfee CS, Wolters PJ, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2010;299(1):L3-L7. [CrossRef] [PubMed]
 
Günther A, Mosavi P, Ruppert C, et al. Enhanced tissue factor pathway activity and fibrin turnover in the alveolar compartment of patients with interstitial lung disease. Thromb Haemost. 2000;83(6):853-860. [PubMed]
 
Olman MA. Mechanisms of fibroproliferation in acute lung injury.. In:Matthay MA, Lenfant C., eds. Acute Respiratory Distress Syndrome. New York, NY: Marcel Dekker; 2003:313-354.
 
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