4.6 Article

Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy

Journal

Publisher

MOSBY-ELSEVIER
DOI: 10.1016/j.ajog.2022.03.048

Keywords

angiogenic factors; angiopoietin; C5b9; COVID-19; endothelial dysfunction; heparan sulfate; hypertensive disorders of pregnancy; neutrophil extracellular traps; placental growth factor; preeclampsia; SARS-CoV-2; soluble fms-like tyrosine kinase-1; soluble tumor necrosis factor-alpha receptor I; von Willebrand factor

Funding

  1. Fundacio Clinic, Barcelona [HCB/2020/0401]
  2. Fundacio La Marato de TV3 [202026-10]
  3. Jazz Pharmaceuticals Plc [IST-16-10355]
  4. German Jose Carreras Leukaemia Foundation [03R/2019]
  5. Instituto de Salud Carlos III from Spanish Government [PI19/00888]
  6. Bristol Myers-Squibb
  7. Pfizer [ERISTA 15]
  8. La Caixa Foundation
  9. Kids Corona Child and Mother COVID-19 Open Data and Biobank Initiative from Hospital Sant Joan de De u (Stavros Niarchos Foundation)
  10. Kids Corona Child and Mother COVID-19 Open Data and Biobank Initiative from Hospital Sant Joan de De u (Santander Foundation)
  11. Fundacio Privada Daniel Bravo Andreu
  12. Generalitat de Catalunya [2017SGR675]
  13. Generalitat de Catalunya (CERCA Programme)
  14. Fundacio Catalana de Trasplantament (FCT 2021)

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This study focused on differentiating between COVID-19 and preeclampsia in pregnant women by examining biomarkers and in vitro alterations in endothelial cells, providing important clues for the differential diagnosis of these conditions.
BACKGROUND: COVID-19 presents a spectrum of signs and symptoms in pregnant women that might resemble preeclampsia. Differentiation between severe COVID-19 and preeclampsia is difficult in some cases. OBJECTIVE: To study biomarkers of endothelial damage, coagulation, innate immune response, and angiogenesis in preeclampsia and COVID-19 in pregnancy in addition to in vitro alterations in endothelial cells exposed to sera from pregnant women with preeclampsia and COVID-19. STUDY DESIGN: Plasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) and from women with normotensive pregnancies as controls (n=10) and patients with preeclampsia (n=13). A panel of plasmatic biomarkers was assessed, including vascular cell adhesion molecule-1, soluble tumor necrosis factor-receptor I, heparan sulfate, von Willebrand factor antigen (activity and multimeric pattern), alpha 2-antiplasmin, C5b9, neutrophil extracellular traps, placental growth factor, soluble fms-like tyrosine kinase-1, and angiopoietin 2. In addition, microvascular endothelial cells were exposed to patients' sera, and changes in the cell expression of intercellular adhesion molecule 1 on cell membranes and von Willebrand factor release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of p38 mitogen-activated protein kinase phosphorylation. Statistical analysis included univariate and multivariate methods. RESULTS: Biomarker profiles of patients with mild COVID-19 were similar to those of controls. Both preeclampsia and severe COVID-19 showed significant alterations in most circulating biomarkers with distinctive profiles. Whereas severe COVID-19 exhibited higher concentrations of vascular cell adhesion molecule-1, soluble tumor necrosis factor-a receptor I, heparan sulfate, von Willebrand factor antigen, and neutrophil extracellular traps, with a significant reduction of placental growth factor compared with controls, preeclampsia presented a marked increase in vascular cell adhesion molecule-1 and soluble tumor necrosis factor-alpha receptor I (significantly increased compared with controls and patients with severe COVID-19), with a striking reduction in von Willebrand factor antigen, von Willebrand factor activity, and alpha 2-antiplasmin. As expected, reduced placental growth factor, increased soluble fms-like tyrosine kinase-1 and angiopoietin 2, and a very high soluble fms-like tyrosine kinase-1 to placental growth factor ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and neutrophil extracellular traps was also detected in preeclampsia compared with controls. Principal component analysis demonstrated a clear separation between patients with preeclampsia and the other groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to von Willebrand factor, soluble tumor necrosis factor-receptor I, heparan sulfate, and soluble fms-like tyrosine kinase-1. Von Willebrand factor multimeric analysis revealed the absence of von Willebrand factor high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A), whereas in healthy pregnancies and COVID-19 patients, von Willebrand factor multimeric pattern was normal. Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of intercellular adhesion molecule 1 and von Willebrand factor in endothelial cells in culture compared with controls. However, the effect of preeclampsia was less pronounced than the that of severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19 and preeclampsia sera showed an increase in p38 mitogen-activated protein kinase phosphorylation. Patients with severe COVID-19 and preeclampsia were statistically different from controls, suggesting that both severe COVID-19 and preeclampsia sera can activate inflammatory signaling pathways. CONCLUSION: Although similar in in vitro endothelial dysfunction, preeclampsia and severe COVID-19 exhibit distinctive profiles of circulating biomarkers related to endothelial damage, coagulopathy, and angiogenic imbalance that could aid in the differential diagnosis of these entities.

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