Rationale for Anticoagulant Therapy of Pulmonary Fibrosis
Authors: Galina S. Bogatkevich, Paul J. Nietert, Richard M. Silver, Kristin B. Highland
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

To the Editor:

We read with interest the article regarding warfarin in idiopathic pulmonary fibrosis by Noth and colleagues (1). Despite an overall negative result, the value of the data collected is very high because it leads to a very important conclusion: namely, that the general inhibition of the coagulation cascade is not a good strategy for the treatment of pulmonary fibrosis. Our laboratory has investigated the profibrotic effects of thrombin for more than a decade. Based on our work, we have come to a very similar conclusion with important implications for potential therapy for idiopathic pulmonary fibrosis (IPF) and other fibrosing lung diseases, which is that there is no need to inhibit the coagulation cascade to inhibit the profibrotic effects of thrombin.

Activation of thrombin is one of the earliest events after tissue injury. Thrombin promotes differentiation of fibroblasts to a myofibroblast phenotype, increases fibroblast proliferation, and enhances the proliferative effect of fibrinogen on fibroblasts. Thrombin is also a potent inducer of fibrogenic cytokines, including transforming growth factor-β, connective tissue growth factor, platelet-derived growth factor (PDGF), as well as various chemokines and extracellular matrix proteins like collagen, fibronectin, and tenascin (reviewed in Reference 2). There is compelling evidence that thrombin is an important mediator of interstitial lung diseases, including both IPF and scleroderma-associated interstitial lung disease (SSc-ILD). Our laboratory and others have demonstrated dramatically increased levels of thrombin in bronchoalveolar lavage fluid (BALF) from patients with SSc-ILD and other fibrosing lung diseases (3, 4). BALF samples from normal subjects have a low level of thrombin activity, while BALF samples from patients with SSc-ILD express up to 100-fold higher thrombin activity. Elevated thrombin activity is also observed in the bleomycin rodent model of pulmonary fibrosis. In this setting, highly concentrated thrombin binds to the protease-activated receptor 1 and initiates profibrotic signaling. We recently demonstrated that inhibition of thrombin using dabigatran etexilate has marked antiinflammatory and antifibrotic effects in the bleomycin pulmonary fibrosis model (5). Importantly, the antifibrotic effects of dabigatran etexilate were achieved without inhibition of the coagulation cascade. Thrombin activity in BALF was significantly reduced in bleomycin-treated mice receiving dabigatran etexilate as compared with bleomycin-treated mice receiving placebo, but not significantly different compared with saline-treated control mice receiving placebo. We have not observed any hemorrhagic side effects during our studies of dabigatran etexilate in this rodent model of ILD, suggesting that levels of dabigatran in mouse plasma are not sufficient to perturb the normal hemostatic process, yet were sufficient to ameliorate thrombin-induced and protease-activated receptor 1–mediated lung inflammation and fibrosis.

The study published by Noth and coworkers was not designed to address the molecular mechanisms involved in the respiratory worsening (exacerbation or progression) associated with warfarin treatment (1). One obvious explanation for the respiratory worsening and higher mortality rate of warfarin-treated patients with IPF is inhibition of vitamin K–dependent synthesis of protein C, known to already be at a very low level in patients with IPF. Activated protein C plays a protective role in lung tissue repair and remodeling. Yasui and colleagues demonstrated that intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis (6). In contrast to warfarin, dabigatran etexilate does not interfere with protein C synthesis; therefore, the protective effect of protein C on lung tissue should remain intact even when dabigatran etexilate is administered. We suggest that thrombin inhibition as a strategy to treat fibrosing lung diseases needs to be explored and not abandoned based on studies employing warfarin as an anticoagulant, particularly since lung fibrosis may be ameliorated with doses of a thrombin inhibitor not sufficient to cause significant perturbation of hemostasis.