Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: a proof of concept study

Kenji Tsushima; Koichi Yamaguchi; Yuta Kono; Toshiki Yokoyama; Keishi Kubo; Takuma Matsumura; Yasunori Ichimura; Mitsuhiro Abe; Jiro Terada; Koichiro Tatsumi

doi:10.1016/j.pupt.2014.04.008

Thrombomodulin for acute exacerbations of idiopathic pulmonary fibrosis: a proof of concept study

Pulm Pharmacol Ther. 2014 Dec;29(2):233-40. doi: 10.1016/j.pupt.2014.04.008. Epub 2014 May 14.

Authors

Affiliations

¹ Department of Pulmonary Medicine, Shinonoi General Hospital, 666-1 Ai Shinonoi, Nagano 388-8004, Japan; Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Electronic address: tsushimakenji@yahoo.co.jp.
² Department of Pulmonary Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
³ First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan.
⁴ Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

PMID: 24836398
DOI: 10.1016/j.pupt.2014.04.008

Abstract

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-IPF-patients 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-IPF-patients.

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 thrombin-antithrombin 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.

Keywords: Acute exacerbation of idiopathic pulmonary fibrosis; High-mobility group box-1; Recombinant human soluble thrombomodulin; SpO(2)/F(I)O(2); Thrombin–antithrombin complex.

Publication types

Clinical Trial

MeSH terms

Acute Disease
Aged
C-Reactive Protein / analysis
Disseminated Intravascular Coagulation / drug therapy
Disseminated Intravascular Coagulation / etiology
Female
Humans
Idiopathic Pulmonary Fibrosis / complications
Idiopathic Pulmonary Fibrosis / drug therapy*
Idiopathic Pulmonary Fibrosis / mortality
L-Lactate Dehydrogenase / blood
Leukocyte Count
Male
Prospective Studies
Recombinant Proteins
Retrospective Studies
Thrombomodulin / therapeutic use*

Substances

Recombinant Proteins
THBD protein, human
Thrombomodulin
C-Reactive Protein
L-Lactate Dehydrogenase