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


CONCLUSIONS
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.
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.
Kenji
K
Tsushima
Department of Pulmonary Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Koichi
K
Yamaguchi
Department of Pulmonary Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
Yuta
Y
Kono
First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan.
Toshiki
T
Yokoyama
First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi Matsumoto, Nagano 390-8621, Japan.
Keishi
K
Kubo
Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Takuma
T
Matsumura
Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Yasunori
Y
Ichimura
Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Mitsuhiro
M
Abe
Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Jiro
J
Terada
Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Koichiro
K
Tatsumi
D000208:Acute Disease; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy / Q000209:etiology; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007958:Leukocyte Count; D008297:Male; D011446:Prospective Studies; D011994:Recombinant Proteins; D012189:Retrospective Studies; D018180:Thrombomodulin / Q000627:therapeutic use*
D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; D002097:C-Reactive Protein; D007770:L-Lactate Dehydrogenase
Acute exacerbation of idiopathic pulmonary fibrosis; High-mobility group box-1; Recombinant human soluble thrombomodulin; SpO(2)/F(I)O(2); Thrombin–antithrombin complex