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

Lina Youssef,Héctor García-Calderó,Jezid Miranda,Sergi Torramade-Moix,Marta Palomo,Olga Tura-Ceide,Miquel Blasco,Eduard Gratacos,Josep Maria Campistol,Pol Herrero,Ana Paula Dantas,Cristina Paules,Fatima Crispi,Francesca Crovetto,Joan Carles Garcia-Pagan,Virginia Hernandez-Gea,Nuria Canela,Maribel Diaz-Ricart

doi:10.1038/s41598-021-82733-z

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.

Highlights

Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality
This study demonstrates the distinct maternal serum proteomic fingerprint in early-onset severe preeclampsia in comparison to uncomplicated pregnancies
This is the first study to show a wide set of circulating proteins and associated pathophysiological pathways which could provide potential therapeutic targets in this specific phenotype of preeclampsia

Summary

Introduction

Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality. Diagnòstic Biomèdic (CDB), Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. Preeclampsia is a pregnancy-specific multisystem disorder, defined as new-onset elevated blood pressure accompanied by proteinuria after 20 weeks of gestation. It complicates 2–5% of p regnancies[1] and is a leading cause of maternal and perinatal morbidity and mortality[2,3]. There is a clinical necessity for a treatment based on understanding the pathophysiology of early-onset preeclampsia to delay its evolution to a severe disease and postpone the need for iatrogenic preterm delivery

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