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Palomo M, Youssef L, Ramos A, Torramade-Moix S, Belen Moreno-Castaño A, Martinez-Sanchez J, Bonastre L, Pino M, Gomez-Ramirez P, Martin L, Mateos EG, Sanchez P, Fernandez S, Crovetto F, Escolar G, Carreras E, Castro P, Gratacos E, Crispi F, Diaz-Ricart M

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

Am J Obstet Gynecol 26 Mar 2022, . Epub 26 Mar 2022
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. Methods: Plasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) in addition to 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 (VCAM-1), soluble TNF-receptor I (sTNFRI), heparan sulfate (HS), von Willebrand factor (VWF) antigen, activity and multimeric pattern, α2-antiplasmin (α2AP), C5b9, neutrophil extracellular traps (NETS), placental growth factor (PlGF), fms-like tyrosine kinase-1 (sFlt-1) and angiopoietin 2 (Ang2). Additionally, microvascular endothelial cells were exposed patient's serum, and changes in the cell expression of intercellular adhesion molecule 1 (ICAM-1) on cell membrane and VWF release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of P38MAPK phosphorylation. Statistical analysis included univariate and multivariate methods. Results: Biomarker profiles in mild COVID-19 were similar to controls. Both preeclampsia and severe COVID-19 showed significant alterations in the majority of circulating biomarkers with distinctive profiles. While severe COVID-19 exhibited higher concentrations of VCAM-1, sTNFR-I, HS, VWF antigen and NETS with a significant reduction of PlGF as compared to controls; preeclampsia presented a marked increase in VCAM-1, sTNFR-I (significantly increased compared to controls and to severe COVID-19) with a striking reduction in VWF antigen, VWF activity and α2AP. As expected, reduced PlGF, increased sFlt-1 and Ang2 and a very high sFlt-1/PlGF ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and NETS was also detected in preeclampsia compared to controls. The principal component analysis demonstrated a clear separation between preeclampsia and the rest of groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to VWF, sTNFRI, HS and sFlt-1. VWF multimeric analysis revealed the absence of VWF high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A) whereas in healthy pregnancies and COVID-19 patients, VWF multimeric pattern was normal. Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of ICAM-1 and VWF in endothelial cells in culture compared to controls. However, the effect of preeclampsia was less pronounced than the one triggered by severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19, and preeclampsia sera showed an increase in p38MAPK phosphorylation. 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: While similar 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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