Reply: Is Warfarin the Right Anticoagulant in Idiopathic Pulmonary Fibrosis?

Abstract

From the Authors: We thank Drs. Bendstrup and Hilberg for their comments regarding the IPFnet ACE trial examining the use of warfarin in idiopathic pulmonary fibrosis (IPF), and agree with their premise for the need for further investigation of anticoagulant therapy in IPF (1). We agree that the ACE study addresses the use of only warfarin in IPF. Importantly, there are several differences between ACE and the previous study examining the utility of anticoagulation in IPF by Kubo and coworkers (2). In the prior study, much less physiologically impaired patients with IPF were enrolled at hospitalization and placed on warfarin and prednisolone in combination, as opposed to warfarin alone. In fact, the number of subjects on both agents in ACE was very small. Furthermore, dalteparin, a low-molecular-weight heparin, was added during subsequent hospitalizations for acute exacerbation events. By allowing sicker patients in ACE, we both enhanced event rates, which was the objective, but may not have allowed sufficient time for a treatment effect to occur in altering the course of fibrosis. There is a plethora of evidence demonstrating antifibrotic effects of anticoagulants, both dependent and independent of their anticoagulant actions (3). Factor VII activity has been demonstrated to be elevated in patients with interstitial lung disease, and specifically in IPF (3). Also recently demonstrated, factor VIIa stimulates proliferation of human lung fibroblasts and extracellular matrix in a PAR-2–dependent manner. This effect is factor Xa and thrombin independent (4). Additionally shown after ACE’s inception is that increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury (5). Furthermore, evidence supports a protective role for protein C, a vitamin K–dependent anticoagulant protein, on the endothelial cell barrier function in acute lung injury (6). This growing body of evidence supports the concept that anticoagulants targeting specific coagulation factors or their “fibrosis-signaling” receptors may exert antifibrotic effects independent of their anticoagulant activities. Heparin shares anticoagulant action with warfarin, but its coagulation factor targets only partially overlap with that of warfarin. Furthermore, different heparin size fractions, and biochemical modifications, differ in their potencies, anticoagulant targets (such as thrombin or Factor X), and in their antiinflammatory and antiproliferative capacities (7–9). There is much evidence in vitro and in vivo to suggest that all anticoagulants are not equal with respect to their antifibrotic therapeutic potential. Thus, we agree that the compelling basic science and animal model observations would provide a solid foundation upon which to implement additional trials of “anti-coagulants” in IPF. In conclusion, we have answered the question of the utility of warfarin in progressive IPF, but many questions remain.