Mechanisms of Complement Activation and NETosis Interplay in Early Pregnancy Loss: From Autoimmunity to...

Early Pregnancy Loss (EPL) represents a formidable challenge in reproductive medicine. Its complex pathophysiology is primarily characterized by dysregulation of both the immune and coagulation systems. In recent years, abnormal activation of the complement system and neutrophil extracellular trap formation (NETosis) have received increasing scientific attention as key molecular events underlying EPL. This interest is fueled significantly by compelling evidence from non-pregnant models, such as antiphospholipid syndrome (APS) and severe infections (e.g., COVID-19), which demonstrate a pathogenic synergy between complement and NETosis in thrombo-inflammatory pathways. Dysregulation of the complement system can trigger strong inflammatory responses and promote a prothrombotic state. Similarly, excessive NETosis acts as a significant driver of tissue damage and thrombosis. This review aims to systematically delineate the complex crosstalk between complement activation and NETosis in EPL, with particular emphasis on their bidirectional regulatory relationship within autoimmune and thrombo-inflammatory pathways. By thoroughly analyzing the critical pathological role of this "complement-NETosis axis" in disrupting uteroplacental interface homeostasis and ultimately causing pregnancy failure, this review not only presents an integrative conceptual framework for comprehensively understanding the molecular mechanisms of EPL, but, more importantly, proposes a novel hypothesis, based on mechanistic insights derived from non-pregnant models, that this axis may play acentral role in EPL. This perspective provides a framework for future research, encompassing the validation of associated potential biomarkers and the exploration of targeted intervention strategies, thereby holding promise for advancing precise clinical intervention paradigms for specific EPL subtypes.