From the Authors:
We appreciate the insightful letter by Bogatkevich and colleagues, and strongly concur with their conclusions to carefully consider the potential unique antifibrotic effects of inhibiting individual components of the coagulation cascade, especially thrombin. Indeed, the unique effects of individual members of the coagulation cascade, compared with the cascade as a whole, deserve additional respect in light of the unsuccessful AntiCoagulant Effective in Idiopathic Pulmonary Fibrosis (ACE-IPF) trial (1, 2).
At the time of our trial development, we were charged with designing a trial using available, FDA-approved, therapeutic interventions for pathways involved in fibrosis. We believe the ACE trial does demonstrate that the coagulation cascade (or other vitamin K–dependent proteins) plays a role in IPF, in that use of warfarin did lead to worsened outcomes (2). The notion of a more selective blockade of thrombin activity is an attractive idea.
Our understanding of thrombin activity and protease-activated receptor (PAR)-mediated lung inflammation and fibrosis is growing rapidly. The authors of the letter to the editor have contributed significantly to this understanding through their findings that the thrombin inhibitor, dabigatran, has antifibrotic effects on lung fibroblasts and in a murine lung fibrosis model (3, 4). Moreover, Wygrecka and colleagues demonstrate that knockdown of PAR-1 and PAR-3 together, rather than PAR-1 alone, was necessary to inhibit thrombin-mediated epithelial to mesenchymal transition (5). The PARs remain an interesting antifibrotic target, and understanding their complex biological effects may be critical in the selection of a successful therapy. Given the availability of dabigatran etexilate, we would fully support a clinical trial to evaluate its activity. We hope that a validation of the biological effect on the correct target in vivo, would be a key part of any such clinical outcome trial in IPF, so that we can further advance this promising field.
Footnotes
Author disclosures are available with the text of this letter at www.atsjournals.org.
References
- 1.Chambers RC, Scotton CJ. Coagulation cascade proteinases in lung injury and fibrosis. Proc Am Thorac Soc. 2012;9:96–101. doi: 10.1513/pats.201201-006AW. [DOI] [PubMed] [Google Scholar]
- 2.Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, Kaner RJ, Olman MA Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet) A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186:88–95. doi: 10.1164/rccm.201202-0314OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum. 2009;60:3455–3464. doi: 10.1002/art.24935. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bogatkevich GS, Ludwicka-Bradley A, Nietert PJ, Akter T, van Ryn J, Silver RM. Antiinflammatory and antifibrotic effects of the oral direct thrombin inhibitor dabigatran etexilate in a murine model of interstitial lung disease. Arthritis Rheum. 2011;63:1416–1425. doi: 10.1002/art.30255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Wygrecka M, Didiasova M, Berscheid S, Piskulak K, Taborski B, Zakrzewicz D, Kwapiszewska G, Preissner KT, Markart P. Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. Thromb Haemost. 2013;110:295–307. doi: 10.1160/TH12-11-0854. [DOI] [PubMed] [Google Scholar]