The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory Distress Syndrome


Background: Recombinant human soluble thrombomodulin (rhTM) was approved for the treatment of disseminated intravascular coagulation in Japan, and rhTM has anti-inflammatory effects. Disordered coagulation is a part of the acute respiratory distress syndrome (ARDS) pathophysiology and thus we hypothesize that anticoagulant therapy may help. This preliminary study was to observe the safety of rhTM administration and the improvement on biomarker levels after the therapy for ARDS-patients. Objectives: Case series of ARDS-patients. Methods: Seventeen ARDS-patients that required ventilatory management were treated with rhTM and clinical and laboratory data were collected including platelets, thrombin-antithrombin complex (TAT), fibrinogen degradation products, oxygen saturation/the fraction of inspired oxygen (SpO2/FIO2), and high-mobility group-1 (HMG-1). The administration of rhTM was started during 6 days at a bolus dose of 0.06 mg/kg/day immediately after the diagnosis of ARDS. Results: Eleven of the 17 ARDS-patients were alive at 28 days after the beginning of the administration of rhTM. The serial pattern of the SpO2/FIO2 showed remarkable differences between the survivors and nonsurvivors from day 5 to day 7. The TAT in the survivors significantly decreased after treatment, and there were significantly lower levels in the TAT on day 7 in comparison to that of the nonsurvivors. The serial changes of HMG-1 showed increased levels in the nonsurvivors until day 5 after the administration of rhTM. Conclusions: Additional rhTM administration can safely improve the parameters in survival ARDS-patients, as demonstrated by significant improvements in the SpO2/FIO2, HMG-1 and TAT.

Share and Cite:

K. Tsushima, T. Yokoyama, T. Koizumi, K. Kubo and K. Tatsumi, "The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory Distress Syndrome," International Journal of Clinical Medicine, Vol. 4 No. 11, 2013, pp. 488-495. doi: 10.4236/ijcm.2013.411086.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] M. Van de Wouwer, D. Collen and E. M. Conway, “Thrombomodulin-Protein C-EPCR System: Integrated to Regulate Coagulation and Inflammation,” Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 24, 2004, pp. 1374-1383.
[2] H. Saito, I. Maruyama, S. Shimazaki, Y. Yamamoto, N. Akikawa, R. Ohno, A. Hirayama, T. Matsuda, H. Asakura, M. Nakashima and N. Aoki, “Efficacy and Safety of Recombinant Human Soluble Thrombomodulin (ART-123) in Disseminated Intravascular Coagulation: Results of a Phase III, Randomized, Double-Blind Clinical Trial,” Journal of Thrombosis and Haemostasis, Vol. 5, No. 1, 2007, pp. 31-41.
[3] S. C. Sebag, J. A. Bastarache and L. B. Ware, “Therapeutic Modulation of Coagulation and Fibrinolysis in Acute Lung Injury and the Acute Respiratory Distress Syndrome,” Current Pharmaceutical Biotechnology, Vol. 12, No. 9, 2011, pp. 1481-1496.
[4] J. H. Finigan, “The Coagulation System and Pulmonary Endothelial Function in Actre Lung Injury,” Microvascular Research, Vol. 77, No. 1, 2009, pp. 35-38.
[5] H. Lum and A. B. Malik, “Regulation of Vascular Endothelial Barrier Function,” American Journal of Physiology —Lung Cellular and Molecular Physiology, Vol. 267, 1994, pp. L233-241.
[6] G. Cirino, C. Cicala, M. R. Bucci, L. Sorrentino, J. M. Maraganore, and S. R. Stone, “Thrombin Functions as an Inflammatory Mediator through Activation of Its Receptor,” The Journal of Experimental Medicine, Vol. 183, No. 3, 1996, pp. 821-827.
[7] The ARDS Definition Task Force, “Acute Respiratory Distress Syndrome Berlin Definition,” JAMA, Vol. 307, No. 23, 2012, pp. 1-8.
[8] K. D. Liu, J. Levitt, H. Zhuo, R. H. Kallet, S. Brady, J. Steingrub, M. Tidswell, M. D. Siegel, G. Soto, M. W. Peterson, M. S. Chesnutt, C. Phillips, A. Weinacker, B. T. Thompson, M. D. Eisner and M. A. Matthay, “Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury,” American Journal of Respiratory and Critical Care Medicine, Vol. 178, No. 6, 2008, pp. 618-623.
[9] M. Mohri, Y. Gonda, M. Oka, Y. Aoki, K. Gomi, T. Kiyota, T. Sugihara, S. Yamamoto, T. Ishida and I. Maruyama, “The Antithrombotic Effects of Recombinant Human Soluble Thrombomodulin (rhsTM) on Tissue Factor-Induced Disseminated Intravascular Coagulation in Crab-Eating Monkeys (Macaca fascicularis),” Blood Coagul Fibrinolysis, Vol. 8, 1997, pp. 274-283.
[10] K. Abeyama, D. M. Stern, Y. Ito, K. Kawahara, Y. Yoshimoto, M. Tanaka, T. Uchimura, N. Ida, Y. Yamazaki, S. Yamada, Y. Yamamoto, H. Yamamoto, S. Iino, N. Taniguchi and I. Maruyama, “The N-Terminal Domain of Thrombomodulin Sequesters High-Mobility Group-B1 Protein, a Novel Antiinflammatory Mechanism,” Journal of Clinical Investigation, Vol. 115, No. 5, 2005, pp. 1267-1274.
[11] C. S. Shi, G. Y. Shi, S. M. Hsiao, Y. C. Kao, K. L. Kuo, C. Y. Ma, C. H. Kuo, B. I. Chang, C. F. Chang, C. H. Lin, C. H. Wong and H. L. Wu, “Lectin-Like Domain of Thrombomodulin Binds to Its Specific Ligand Lewis Y Antigen and Neutralizes Lipopolysaccharide-Induced Inflammatory Response,” Blood, Vol. 112, No. 9, 2008, pp. 3661-3670.
[12] M. Van de Wouwer, S. Plaisance, A. De Vriese, E. Waelkens, D. Collen, J. Persson, M. R. Daha and E. M. Conway, “The Lectin-Like Domain of Thrombomodulin Interferes with Complement Activation and Protects against Arthritis,” Journal of Thrombosis and Haemostasis, Vol. 4, No. 8, 2006, pp. 1813-1824.
[13] M. Nagato, K. Okamoto, Y. Abe, A. Higure and K. Yamaguchi, “Recombinant Human Soluble Thrombomodulin Decreases the Plasma High-Mobility Group Box-1 Protein Levels, Whereas Improving the Acute Liver Injury and Survival Rates in Experimental Endotoxemia,” Critical Care Medicine, Vol. 37, No. 7, 2009, pp. 2181-2186.
[14] E. Abraham, J. Arcaroli, A. Carmody, H. Wang and K. J. Tracey, “HMG-1 as Mediator of Acute Lung Inflammation,” The Journal of Immunology, Vol. 165, No. 6, 2000, pp. 2950-2954.
[15] A. Ishizaka, T. Matsuda, K. H. Albertine, H. Koh, S. Tasaka, N. Hasegawa, N. Kohno, T. Kotani, H. Morisaki, J. Takeda, M. Nakamura, X. Fang, T. R. Martin, M. A. Matthay and S. Hashimoto, “Elevation of KL-6, a Lung Epithelial Cell Marker, in Plasma and Epithelial Lining Fluid in Acute Respiratory Distress Syndrome,” American Journal of Physiology—Lung Cellular and Molecular Physiology, Vol. 286, 2004, pp. L1088-1094.
[16] P. J. Offner and E. E. Moore, “Lung Injury Severity Scoring in the Era of Lung Protective Mechanical Ventilation: The PaO2/FIO2 Ratio,” Journal of Trauma, Vol. 55, No. 2, 2003, pp. 285-289.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.