Aberrant neutrophil and complement activation in thrombotic microangiopathies in pregnancy - Is there a missing link?

Pregnancy-related acute kidney injury is a major global health burden associated with increased maternal and fetal morbidity and mortality. Thrombotic microangiopathies (TMA) occurring in pregnancy or postpartum include severe preeclampsia/Hemolysis Elevated Liver Enzymes Low Platelets (HELLP) syndrome, atypical Hemolytic Uremic Syndrome (aHUS) and Thrombotic Thrombocytopenic Purpura (TTP). Severe acute kidney injury and progression to chronic kidney disease are particularly associated with complement-mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome and may also complicate severe preeclampsia/HELLP syndrome, while renal involvement is usually less prominent in TTP. Interestingly, preeclampsia, HELLP syndrome, aHUS, TTP, lupus nephritis and antiphospholipid syndrome share common autoimmune pathogenic mechanisms, as both are characterized by exaggerated neutrophil activation and increased neutrophil extracellular traps (NETs) release, as well as complement activation. In an era of targeted therapies, the lack of treatment of preeclampsia and HELLP results from the limited understanding of the underlying pathogenetic mechanisms. Eculizumab, a C5 inhibitor that targets the complement, significantly reduced the risk of ESKD in women with pregnancy-associated aHUS, supporting the therapeutic relevance of complement modulation. In this review, we performed a narrative synthesis of established and emerging experimental, translational and clinical data on pregnancy-associated TMAs, summarizing current evidence on the interaction between neutrophil dysregulation, NET formation, complement activation and endothelial injury in pregnancy-associated thrombotic microangiopathies. A better understanding of the neutrophil-NET-complement axis may help refine diagnostic distinctions among overlapping pregnancy-associated thrombotic microangiopathies and facilitate the development of more targeted therapeutic strategies.