6.2 Roflumilast and hypercoagulable states
Neutrophils and platelets have been identified as crucial factors for thrombus initiation and progression. Both animal models and human diseases increased the evidence that neutrophils extracellular traps (NETs) possess a significant role in the pathogenesis of thrombosis. NETs were detected to be released from the activated neutrophils in a process called NETosis, which can be mediated by recruitment of both platelets and PMN into the endothelial wall. Then, NETs could stimulate platelets adhesion, activation and aggregation with subsequent activation of coagulation cascades to trigger thrombosis (Fuchs et al., 2010; Kimball et al., 2016).
Accordingly, inhibiting the prothrombotic function of neutrophils and interfering with NETs formation, by roflumilast, could reduce the risk of thrombosis in COPD as well as in other inflammatory diseases. Moreover, RNO (an active metabolite of roflumilast) was recorded to affect NETs via inhibiting Src family kinases phosphoinositide 3-kinase (SFK–PI3K) pathway in PMNs. In addition, RNO could block the key biochemical mechanisms regulating PMN–platelets adhesion (Totani et al., 2016).