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Objective: This study aims to determine whether C5a activation in the inflammatory environment of thrombotic antiphospholipid syndrome (APS) drives polymorphonuclear neutrophils (PMNs) to release neutrophil extracellular traps (NETs), and whether interferon-λ1/interleukin 29 (IFN-λ1/IL-29) has a function of inhibiting thrombotic inflammation. Methods: The expression of NETs and autophagosome markers were assessed by confocal microscopy. Western blotting was performed to investigate the autophagy-related proteins. Flow cytometry was performed to detect the expression of NET-related markers on PMNs. The thrombin-antithrombin (TAT) complex level was determined by enzyme-linked immunosorbent assay (ELISA). Results: Serum-derived C5a activation in APS patients induced the expression of NETs in PMNs. C5a promoted autophagy and NET-dependent thrombin generation in PMNs. IL-29 reduced the production of NETs and NET-associated thrombin by inhibiting autophagy. Conclusion: IL-29 has an effect of inhibiting NET-associated thrombotic APS induced by C5a activation.