Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics

Abstract

Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality. The exact pathogenesis of this multifactorial disease remains poorly defined. We applied proteomics analysis on maternal blood samples collected from 14 singleton pregnancies with early-onset severe preeclampsia and 6 uncomplicated pregnancies to investigate the pathophysiological pathways involved in this specific subgroup of preeclampsia. Maternal blood was drawn at diagnosis for cases and at matched gestational age for controls. LC–MS/MS proteomics analysis was conducted, and data were analyzed by multivariate and univariate statistical approaches with the identification of differential pathways by exploring the global human protein–protein interaction network. The unsupervised multivariate analysis (the principal component analysis) showed a clear difference between preeclamptic and uncomplicated pregnancies. The supervised multivariate analysis using orthogonal partial least square discriminant analysis resulted in a model with goodness of fit (R2X = 0.99, p < 0.001) and a strong predictive ability (Q2Y = 0.8, p < 0.001). By univariate analysis, we found 17 proteins statistically different after 5% FDR correction (q-value < 0.05). Pathway enrichment analysis revealed 5 significantly enriched pathways whereby the activation of the complement and coagulation cascades was on top (p = 3.17e−07). To validate these results, we assessed the deposits of C5b-9 complement complex and on endothelial cells that were exposed to activated plasma from an independent set of 4 cases of early-onset severe preeclampsia and 4 uncomplicated pregnancies. C5b-9 and Von Willbrand factor deposits were significantly higher in early-onset severe preeclampsia. Future studies are warranted to investigate potential therapeutic targets for early-onset severe preeclampsia within the complement and coagulation pathway.

The Interplay between Pathophysiological Pathways in Early-Onset Severe Preeclampsia Unveiled by Metabolomics

“…On the other hand, lipid data seem to be highly disturbed in early-onset severe preeclampsia. It is well established that preeclampsia is a disease characterized by inflammation, complement activation, altered lipid metabolism and related oxidative stress [16,[32][33][34]. Lipid classes are linked tightly during their synthesis, which may explain the similarity of observed alterations in most of them.…”

Proteome-defined changes in cellular pathways for decidua and trophoblast tissues associated with location and viability of early-stage pregnancy

“…Moreover, a balanced complement and coagulation system is recognized as being an essential immune response factor in normal placental and fetal development [28,32,33]. Dysregulation of the complement system has been implicated in adverse pregnancy outcomes such as recurrent miscarriage and pre-ecclampsia [33][34][35][36]; however, the role of the complement cascade in EP is less established.…”

Vascular Dysfunction in Preeclampsia

“…During pregnancy, there is a natural decline in platelet count throughout gestation [ 236 ], part of which may be attributed to sequestration of blood cells in the intervillous space [ 237 ], increases in plasma volume [ 238 ], and heightened aggregation from thromboxane A2 [ 239 ]. Thrombocytopenia beyond normal pregnancy-induced platelet decreases is commonly seen in preeclampsia and may specifically be accompanied by reduced platelet numbers [ 239 , 240 , 241 ] and activated coagulation [ 240 , 242 ]. Together, these hemostatic effects contribute to bleeding and microthrombi risk in preeclamptic mothers [ 239 , 243 ].…”