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Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8
Contents lists available at ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: A proof of concept study Q3
Q1
Kenji Tsushima a, d, *,1, Koichi Yamaguchi b, 2, Yuta Kono b, 2, Toshiki Yokoyama c, 3, Keishi Kubo c, 3, Takuma Matsumura d, 4, Yasunori Ichimura d, 4, Mitsuhiro Abe d, 4, Jiro Terada d, 4, Koichiro Tatsumi d, 4 a
Department of Pulmonary Medicine, Shinonoi General Hospital, 666-1 Ai Shinonoi, Nagano 388-8004, Japan Department of Pulmonary Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan d Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2014 Received in revised form 24 April 2014 Accepted 27 April 2014
Introduction: The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as a potential new strategy for treating disseminated intravascular coagulation in Japan. This preliminary study was to evaluate whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM for AE-IPF-patients has any beneficial effects on inflammatory mediators and activated coagulation. Methods: We retrospectively compared the clinical data of AE-IPF-patients, idiopathic pulmonary fibrosis (IPF) with pneumonia-patients and slowly progressive IPF-patients. As a subsequent study, AE-IPFpatients were prospectively treated with a bolus of rhTM intravenously for six days under mechanical ventilation. We historically investigated the improvement of the serial clinical data in both oxygenation and intravascular coagulation disturbance between treated AE-IPF-patients and untreated AE-IPFpatients. Results: Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In 20 treated AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The levels of oxygenation rapidly increased on day 1 and continued to improve until day 7 in the survival AE-IPF-patients. The thrombineantithrombin complex levels and inflammatory cytokine levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. Conclusion: AE-IPF-patients were found to have significantly higher levels of coagulation. The rhTM administration in the surviving AE-IPF-patients led to significant differences in the oxygenation and intravascular coagulation disturbance. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Acute exacerbation of idiopathic pulmonary fibrosis Recombinant human soluble thrombomodulin High-mobility group box-1 SpO2/FIO2 Thrombineantithrombin complex
1. Introduction
* Corresponding author. Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: þ81 43 226 2800. E-mail address: [email protected] (K. Tsushima). 1 Tel.: þ81 26 292 2261. 2 Tel.: þ81 3 3342 6111. 3 Tel.: þ81 263 37 2631. 4 Tel.: þ81 43 226 2800.
Idiopathic pulmonary fibrosis (IPF) is a chronic, diffuse interstitial pulmonary disease associated with the histologic appearance of usual interstitial pneumonia. The median survival of IPF-patients is four to five years after the development of symptoms of cough and shortness of breath [1]. Additionally, the time between symptom onset and diagnosis is approximately three years [2,3]. Some IPF-patients show acute respiratory deterioration, termed acute exacerbation of IPF (AE-IPF) [4]. AE-IPF-patients show severe hypoxemia and respiratory failure requiring mechanical ventilation. In fact respiratory failure due to AE-IPF is usually considered as
http://dx.doi.org/10.1016/j.pupt.2014.04.008 1094-5539/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tsushima K, et al., Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: A proof of concept study, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.008
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a contraindication to mechanical ventilation in view of the poor prognosis of ventilated patients. At best, it might be considered for noninvasive ventilation [5]. In a retrospective review, the 2-year incidence of acute exacerbation of the disease was reported to be 9.6% and the mortality rate was reported to be 78% [6]. The time to development of acute exacerbation from the initial visit was between three and 60 months [6]. The outcomes of AE-IPF-patients are poor, with 1-month and 3-month mortality rates of approximately 60% and 67%, respectively [7]. The treatment of AE-IPF generally consists of high-dose corticosteroids, although there are no data from controlled trials to prove their efficacy. Cytotoxic agents such as cyclosporine A have been studied; however, no convincing evidence of benefits has been demonstrated [8]. The loss of alveolar epithelial cell integrity and injury may play an important role in AE-IPF, leading to remodeling and the extrusion of fibrin onto the alveolar surface [9]. Disordered coagulation and fibrinolysis may be important components of AE-IPF [10]. The modulation of coagulation and fibrinolysis may have complex effects on both hemostatic and inflammatory pathways in the pathogenesis of AE-IPF. Thrombomodulin (TM) (RecomodulinÒ, Asahi Kasei Pharma Corporation, Tokyo, Japan)is a transmembrane protein expressed on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation [11]. TM binds to thrombin and activates coagulation. The thrombin-TM complex activates protein C, and in the presence of protein S, inactivates factors VIIIa and Va, thereby inhibiting further thrombin formation. A novel biological agent, recombinant human soluble thrombomodulin (rhTM), has been approved for clinical use for the treatment of disseminated intravascular coagulation (DIC) in Japan. In 86 consecutive patients with sepsis-induced DIC who required ventilator management, rhTM administration had a significantly beneficial effect on both mortality and the respiratory dysfunction [12]. Therefore, anticoagulation therapy is beginning to be recognized as a potential new strategy for treating AE-IPF-patients. The aim of the present preliminary study was to evaluate whether a coagulation dysfunction is detectable, also whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM has any beneficial effect on the inflammatory mediators and activated coagulation between treated AE-IPFpatients and untreated AE-IPF-patients according to a historical analysis. 2. Methods The research protocol was approved by the human ethics committee of Shinonoi General Hospital. All subjects and/or their family gave written informed consent. This trial registration number is UMIN000012590.
2.2. Laboratory data The AE-IPF-patients, IPF with pneumonia-patients and slowly progressive IPF-patients were measured at the initial admission; white blood cell (WBC) count and platelet count and the levels of fibrinogen degradation products (FDP, normal range:
YPUPT1374_proof ■ 16 May 2014 ■ 1/8
Pulmonary Pharmacology & Therapeutics xxx (2014) 1e8
Contents lists available at ScienceDirect
Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt
Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: A proof of concept study Q3
Q1
Kenji Tsushima a, d, *,1, Koichi Yamaguchi b, 2, Yuta Kono b, 2, Toshiki Yokoyama c, 3, Keishi Kubo c, 3, Takuma Matsumura d, 4, Yasunori Ichimura d, 4, Mitsuhiro Abe d, 4, Jiro Terada d, 4, Koichiro Tatsumi d, 4 a
Department of Pulmonary Medicine, Shinonoi General Hospital, 666-1 Ai Shinonoi, Nagano 388-8004, Japan Department of Pulmonary Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan d Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2014 Received in revised form 24 April 2014 Accepted 27 April 2014
Introduction: The mortality of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is high. Anticoagulation therapy (recombinant human soluble thrombomodulin (rhTM)) is recognized as a potential new strategy for treating disseminated intravascular coagulation in Japan. This preliminary study was to evaluate whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM for AE-IPF-patients has any beneficial effects on inflammatory mediators and activated coagulation. Methods: We retrospectively compared the clinical data of AE-IPF-patients, idiopathic pulmonary fibrosis (IPF) with pneumonia-patients and slowly progressive IPF-patients. As a subsequent study, AE-IPFpatients were prospectively treated with a bolus of rhTM intravenously for six days under mechanical ventilation. We historically investigated the improvement of the serial clinical data in both oxygenation and intravascular coagulation disturbance between treated AE-IPF-patients and untreated AE-IPFpatients. Results: Eleven AE-IPF, 21 IPF with pneumonia and 16 slowly progressive IPF-patients were enrolled, and the coagulatory levels of the AE-IPF-patients were found to be significantly higher than in the other patients. In 20 treated AE-IPF-patients, the 28-day mortality and in-hospital mortality were 35% and 45%, respectively. The levels of oxygenation rapidly increased on day 1 and continued to improve until day 7 in the survival AE-IPF-patients. The thrombineantithrombin complex levels and inflammatory cytokine levels in the survivors on day 7 were significantly different from those observed in the nonsurvivors. Conclusion: AE-IPF-patients were found to have significantly higher levels of coagulation. The rhTM administration in the surviving AE-IPF-patients led to significant differences in the oxygenation and intravascular coagulation disturbance. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Acute exacerbation of idiopathic pulmonary fibrosis Recombinant human soluble thrombomodulin High-mobility group box-1 SpO2/FIO2 Thrombineantithrombin complex
1. Introduction
* Corresponding author. Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Tel.: þ81 43 226 2800. E-mail address: [email protected] (K. Tsushima). 1 Tel.: þ81 26 292 2261. 2 Tel.: þ81 3 3342 6111. 3 Tel.: þ81 263 37 2631. 4 Tel.: þ81 43 226 2800.
Idiopathic pulmonary fibrosis (IPF) is a chronic, diffuse interstitial pulmonary disease associated with the histologic appearance of usual interstitial pneumonia. The median survival of IPF-patients is four to five years after the development of symptoms of cough and shortness of breath [1]. Additionally, the time between symptom onset and diagnosis is approximately three years [2,3]. Some IPF-patients show acute respiratory deterioration, termed acute exacerbation of IPF (AE-IPF) [4]. AE-IPF-patients show severe hypoxemia and respiratory failure requiring mechanical ventilation. In fact respiratory failure due to AE-IPF is usually considered as
http://dx.doi.org/10.1016/j.pupt.2014.04.008 1094-5539/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tsushima K, et al., Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: A proof of concept study, Pulmonary Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pupt.2014.04.008
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a contraindication to mechanical ventilation in view of the poor prognosis of ventilated patients. At best, it might be considered for noninvasive ventilation [5]. In a retrospective review, the 2-year incidence of acute exacerbation of the disease was reported to be 9.6% and the mortality rate was reported to be 78% [6]. The time to development of acute exacerbation from the initial visit was between three and 60 months [6]. The outcomes of AE-IPF-patients are poor, with 1-month and 3-month mortality rates of approximately 60% and 67%, respectively [7]. The treatment of AE-IPF generally consists of high-dose corticosteroids, although there are no data from controlled trials to prove their efficacy. Cytotoxic agents such as cyclosporine A have been studied; however, no convincing evidence of benefits has been demonstrated [8]. The loss of alveolar epithelial cell integrity and injury may play an important role in AE-IPF, leading to remodeling and the extrusion of fibrin onto the alveolar surface [9]. Disordered coagulation and fibrinolysis may be important components of AE-IPF [10]. The modulation of coagulation and fibrinolysis may have complex effects on both hemostatic and inflammatory pathways in the pathogenesis of AE-IPF. Thrombomodulin (TM) (RecomodulinÒ, Asahi Kasei Pharma Corporation, Tokyo, Japan)is a transmembrane protein expressed on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation [11]. TM binds to thrombin and activates coagulation. The thrombin-TM complex activates protein C, and in the presence of protein S, inactivates factors VIIIa and Va, thereby inhibiting further thrombin formation. A novel biological agent, recombinant human soluble thrombomodulin (rhTM), has been approved for clinical use for the treatment of disseminated intravascular coagulation (DIC) in Japan. In 86 consecutive patients with sepsis-induced DIC who required ventilator management, rhTM administration had a significantly beneficial effect on both mortality and the respiratory dysfunction [12]. Therefore, anticoagulation therapy is beginning to be recognized as a potential new strategy for treating AE-IPF-patients. The aim of the present preliminary study was to evaluate whether a coagulation dysfunction is detectable, also whether the coagulation factors increase or decrease in AE-IPF-patients, and whether the additional administration of rhTM has any beneficial effect on the inflammatory mediators and activated coagulation between treated AE-IPFpatients and untreated AE-IPF-patients according to a historical analysis. 2. Methods The research protocol was approved by the human ethics committee of Shinonoi General Hospital. All subjects and/or their family gave written informed consent. This trial registration number is UMIN000012590.
2.2. Laboratory data The AE-IPF-patients, IPF with pneumonia-patients and slowly progressive IPF-patients were measured at the initial admission; white blood cell (WBC) count and platelet count and the levels of fibrinogen degradation products (FDP, normal range:
