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

Affiliation

Youssef L(1), Miranda J(1), Blasco M(2), Paules C(1), Crovetto F(1), Palomo M(3)(4)(5), Torramade-Moix S(4), García-Calderó H(6)(7), Tura-Ceide O(8)(9)(10), Dantas AP(11), Hernandez-Gea V(6)(7), Herrero P(12), Canela N(12), Campistol JM(2)(13), Garcia-Pagan JC(6)(7), Diaz-Ricart M(4)(5), Gratacos E(14)(15)(16), Crispi F(1)(13).
Author information:
(1)BCNatal | Fetal Medicine Research Center
(Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain.
(2)Nephrology and Renal Transplantation Department, Hospital Clínic, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud
(CSUR), University of Barcelona, Barcelona, Spain.
(3)Josep Carreras Leukaemia Research Institute, Hospital Clinic, University of Barcelona Campus, Barcelona, Spain.
(4)Hematopathology, Centre Diagnòstic Biomèdic
(CDB), Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain.
(5)Barcelona Endothelium Team
(BET), Barcelona, Spain.
(6)Barcelona Hepatic Hemodynamics Laboratory, Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain.
(7)Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas
(CIBEREHD), Health Care Provider of the European Reference Network on Rare Liver Disorders
(ERN-Liver), Barcelona, Spain.
(8)Department of Pulmonary Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain.
(9)Biomedical Research Networking Center on Respiratory Diseases
(CIBERES), Madrid, Spain.
(10)Girona Biomedical Research Institute - IDIBGI, Girona, Spain.
(11)Cardiovascular Institute, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain.
(12)Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences
(COS), Joint Unit Universitat Rovira i Virgili-EURECAT, Unique Scientific and Technical Infrastructures
(ICTS), 43204, Reus, Spain.
(13)Centre for Biomedical Research on Rare Diseases
(CIBER-ER), Madrid, Spain.
(14)BCNatal | Fetal Medicine Research Center
(Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), University of Barcelona, Barcelona, Spain. [Email]
(15)Centre for Biomedical Research on Rare Diseases
(CIBER-ER), Madrid, Spain. [Email]
(16)Department of Maternal-Fetal Medicine
(ICGON), Hospital Clínic, Sabino de Arana 1, 08028, Barcelona, Spain. [Email]

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.