Why was this study conducted?
What does this add to what is known?
Materials and Methods
Study populations and design
Maternal blood sample collection
Assessment of circulating biomarkers
In vitro studies
Baseline and perinatal characteristics of the study populations
|Controls n=10||Mild COVID-19 n=9||Severe COVID-19 n=8||Preeclampsia n=13|
|Age (y)||36.9 (31.6–38.7)||36 (30.6–37.7)||35.2 (24.7–39.1)||29 (26–35.9)|
|White||8 (80)||5 (55.6)||4 (50)||4 (30.8)|
|African||0 (0)||0 (0)||1 (12.5)||2 (15.4)|
|Latin||2 (20)||3 (33.3)||2 (25)||2 (15.4)|
|Asian||0 (0)||1 (11.1)||1 (12.5)||5 (38.5)|
|Pregestational body mass index (kg/m2)||22.4 (21.1–25.6)||22.7 (20.3–28.7)||21.8 (21–23.9)||25.9 (21.9–28.4)|
|Nulliparity||7 (70)||5 (55.6)||2 (25)||7 (53.8)|
|Use of assisted reproductive technologies||2 (20)||0 (0)||0 (0)||0 (0)|
|Smoking during pregnancy||0 (0)||0 (0)||1 (12.5)||0 (0)|
|Gestational age at delivery (weeks)||40.2 (38.9–41)||39.1 (38.7–39.6)||39.2 (38.3–41.1)||39.1 (35.1–39.6)|
|1 (10)||1 (11.1)||2 (25)||4 (30.8)|
|Cesarean delivery||1 (10)||3 (33.3)||2 (25)||5 (38.5)|
|Female gender||4 (40)||4 (44.4)||5 (62.5)||6 (46.1)|
|Birthweight (g)||2975 (2780–3220)||3280 (2940–3335)||3290 (2780–3670)||2558 (2010–3268)|
|3 (30)||0 (0)||0 (0)||7 (53.8)|
|APGAR score at 5 min <7||0 (0)||0 (0)||1 (12.5)||1 (7.7)|
|Umbilical artery pH||7.21 (7.15–7.23)||7.18 (7.12–7.21)||7.17 (7.12–7.2)||7.22 (7.17–7.24)|
|Admission to neonatal intensive care unit||1 (10)||0 (0)||1 (12.5)||5 (38.5)|
Endothelial and angiogenic circulating biomarkers are differentially altered in COVID-19 vs preeclampsia
Severe COVID-19 and preeclampsia sera induce similar endothelial damage and inflammation in vitro
Preeclampsia vs COVID-19: a distinct profile of circulating endothelial damage biomarkers
Preeclampsia is associated with remarkable alterations in von Willebrand factor antigen and functionality
Innate immune dysregulation in preeclampsia vs COVID-19 in pregnancy
Preferential angiogenic imbalance in preeclampsia vs COVID-19
Similar in vitro-induced endotheliopathy in preeclampsia and SARS-CoV-2 infection
Strengths and limitations
Conclusion, clinical and research implications
- •A disintegrin and metalloproteinase with thrombospondin type 1 motif, 13 (ADAMTS-13): is primarily synthesized in the liver, and its main function is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury.
- •Angiopoetin 2 (Ang2): is produced by endothelial cells and acts as an autocrine regulator mediating vascular destabilization and regulating vascular homeostasis.
- •α2-antiplasmin (α2AP): is a serine protease inhibitor (serpin) responsible for inactivating plasmin.
- •Endothelium: composed by endothelial cells, it plays an important role in inflammation by regulating vascular permeability for macromolecules and leukocytes, vascular tone, and hemostasis, and by binding and producing inflammatory mediators such as cytokines.
- •Ex vivo approach: to quantify the degree of endothelial activation is of interest when evaluating inflammation. Because of the localization of this type of cells, this evaluation cannot be carried out directly, and a number of indirect measures such as the measurement of soluble molecules released by the endothelium has been employed instead.
- •Soluble fms-like tyrosine kinase-1 (sFlt-1): is a circulating antiangiogenic protein synthesized by the placenta, which acts as an antagonist of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and is up-regulated in preeclampsia.
- •sFlt-1/PIGF ratio: an imbalance in the levels of these 2 biomarkers has been reported to be involved in preeclampsia pathogenesis. An elevated sFlt-1/PIGF seems to be highly predictive of preeclampsia.
- •Heparan sulfate (HS): is the glycosaminoglycan from endothelial glycocalyx used by viral pathogens such as SARS-CoV-2 for the initial interaction with host cells.
- •In vitro approach: consists in a well-characterized in vitro model of endothelial dysfunction, in which endothelial cells in culture are exposed to patients’ sera to assess its capacity to modulate the endothelial phenotype. This analysis is performed through the quantification of changes in inflammatory and thrombogenicity markers together with the activation of certain intracellular signaling pathways.
- •Intercellular adhesion molecule-1 (ICAM-1): adhesion molecule that is up-regulated during endothelial activation and mediates lymphocyte binding. This molecule is not only released from the endothelium, but also from lymphocytes, monocytes, and eosinophils. Elevated levels of soluble ICAM-1 have been reported in preeclampsia.
- •Neutrophil extracellular traps (NETs): are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to fight against infections and that, in elevated concentrations, have the potential to propagate inflammation and microvascular thrombosis.
- •Placental growth factor (PlGF): is a member of the vascular endothelial growth factor (VEGF) family and is predominantly expressed in the placenta. The circulating levels of this molecule have been postulated as a useful screening tool in the prediction of preeclampsia.
- •Plasminogen activator inhibitor (PAI): is a member of the serine protease inhibitor (serpin) superfamily and constitutes a central molecule linking pathogenesis and progression of thrombotic vascular events.
- •Principal component analysis: is a statistical method that aims to reduce the dimensionality of large data sets by transforming them into smaller ones. This method preserves as much information as possible, and the resulting data set becomes easier to explore and visualize than the original one.
- •P38 mitogen-activated protein kinase (P38 MAPK): plays a pivotal role in mediating cellular responses to injurious stress and immune signaling partly through the activation of gene expression.
- •Soluble complement 5b-9 (C5b9): is also known as soluble membrane attack complex and constitutes a marker of complement activation. This molecule creates a transmembrane channel on the surface of targeted cells that leads to cell lysis and death.
- •Soluble tumor necrosis factor-α receptor I (sTNFRI): is 1 of the 2 soluble receptors of TNF-alpha (TNFα), a proinflammatory cytokine that plays a central role in inflammation, which act as physiological attenuator of TNFα activity.
- •Thrombomodulin (TM): is a thrombin receptor on endothelial cells that is involved in promoting activation of the anticoagulant protein C pathway during blood coagulation.
- •Vascular cell adhesion molecule-1 (VCAM-1): adhesion molecule that is up-regulated during endothelial activation and mediates lymphocyte binding. Elevated levels of soluble VCAM-1 have been reported in preeclampsia.
- •Von Willebrand factor (VWF): a multimeric blood protein primarily synthesized, stored, and secreted by endothelial cells. It constitutes a marker of acute and chronic inflammation. The analysis of this protein implies both antigen concentration (VWF:Ag) and functionality (VWF:GPIbM).
- •Von Willebrand factor multimeric analysis: is a method carried out by electrophoresis of plasma samples using nonreducing agarose gels in the presence of different concentrations of sodium dodecyl sulfate. This analysis aims to identify qualitative defects of this protein and is usually performed after functional and immunologic VWF assays to indicate a potential abnormality.
- Video 1
Palomo et al. Endothelial dysfunction in preeclampsia vs COVID-19 in pregnancy. Am J Obstet Gynecol 2022.
Laboratory tests for SARS-CoV-2 infection
Multimeric profile of circulating von Willebrand factor
Human endothelial cell culture
Immunofluorescence detection of intercellular adhesion molecule 1 and van Willebrand factor
Activation of inflammation cell signaling pathways in endothelial cells
|Circulating biomarkers||Controls n=10||Mild COVID-19 n=9||Severe COVID-19 n=8||Preeclampsia n=13|
|Biomarkers of endothelial damage|
|VCAM-1 (ng/mL)||158.7 (129.2–179)||162.9 (129.2–248.3)||273.9 (200–350.4)a||369.5 (304.6–610)b,d,e|
|sTNFRI (pg/mL)||1215.3 (910.5–1648.6)||1360.5 (1248.6–1610.5)||1772.4 (1417.6–2022.4)a||2639 (2091.4–3234.3)b,d,e|
|HS (ng/mL)||2524.8 (1647.3–3330.6)||3401.7 (2285.4–4034.6)||4021.7 (2505.8–5718.2)a||1799 (1414–2589.4)e|
|Biomarkers of coagulopathy/fibrinolysis|
|VWF:Ag (%)||297.4 (237.2–375.4)||406.6 (364.3–428.5)a||432.7 (365.9–470.7)a||89.6 (84.5–135.3)b,d,f|
|VWF:GPIbM (%)||280.9 (250–337)||295.3 (228.4–324.3)||376.6 (285.5–429.5)||44.6 (20–54.5)b,c,f|
|VWF:Ag / VWF:GPIbM||0.99 (0.83–1.1)||0.76 (0.73–0.78)||0.9 (0.85–0.94)c||0.33 (0.28–0.5)b,d,f|
|α2AP (%)||107 (87–118)||98 (95–106)||92.5 (81.5–99)||70 (67–74)b,d,f|
|ADAMTS-13 activity (%)||100||100||100||100|
|PAI (ng/mL)||70.1 (66.7–85.3)||79.3 (64–106.2)||71.5 (59.1–89)||80.7 (68.7–136.4)|
|TM (ng/mL)||9.9 (9.5–10.1)||9.7 (9.6–10)||10.1 (9.6–10.4)||9.7 (9.5–10)|
|Immune response markers|
|C5b9 (ng/mL)||31 (22–36.6)||29.1 (26.7–31.8)||38.1 (31.4–50)||51.1 (46.1–66.6)b,d|
|NETs (ugr/mL)||17.7 (15.2–19.9)||14 (11.5–17.3)||35.7 (20.7–52)a,c||28 (16.5–38)a,c|
|Biomarkers of angiogenesis|
|sFlt-1 (pg/mL)||18,390.1 (12,014.2–23,187.4)||35,588.1 (19,006–46,271.4)||27,302.5 (8033.2–38,236.8)||161,368.9 (56,737.2–216,405.5)a,c,e|
|PlGF (pg/mL)||247.5 (181.7–325.6)||130.5 (122.6–152)a||118.4 (70.2–142.4)a||55.1 (43.6–79.7)a|
|sFlt-1 / PIGF||62.5 (44.3–150.8)||225 (135.2–372.9)a||202.5 (102.4 – 334)||2024.7 (850.3 – 3927.5)a,c,e|
|Ang2 (ng/mL)||6952.5 (4746–9996)||6078.1 (4496.3–10,396.3)||6552.5 (4365–15,690)||13,671.3 (6996.3–21,996.3)a|
|Circulating biomarkers||Early-onset preeclampsia n=4||Late-onset preeclampsia|
|Biomarkers of endothelial damage|
|VCAM-1 (ng/mL)||666.2 (612.8–738.2)a||321.8 (291.4–369.5)b|
|sTNFRI (pg/mL)||3498.6 (2489.1–4331.9)a||2343.8 (2091.4–2762.9)b|
|HS (ng/mL)||1859.1 (977.7–3194.2)||1799 (1414–2589.4)|
|Biomarkers of coagulopathy/fibrinolysis|
|VWF:Ag (%)||82.8 (60.6–88.7)a||130.8 (86.8–138)a|
|VWF:GPIbM (%)||8.8 (5–16.3)a||45.9 (44.6–78.9)a|
|VWF:Ag / VWF:GPIbM||0.15 (0.05–0.27)a||0.48 (0.33–0.58)a|
|α2AP (%)||73.5 (36–79)b||69 (67–71)b|
|ADAMTS-13 activity (%)||100||100|
|PAI (ng/mL)||152.2 (108.7–169.1)b||78.3 (52.3–83.2)|
|TM (ng/mL)||9.5 (9.2–10)||9.8 (9.7–10)|
|Immune response markers|
|C5b9 (ng/mL)||41.9 (29.4–59.6)||60.5 (60.5–66.6)a|
|NETS (ugr/mL)||33 (25.5–50.5)||21 (13.9–34.6)b|
|Biomarkers of angiogenesis|
|sFlt-1 (pg/mL)||316,461.5 (125,464.1–567,831.6)a||132,000.9 (56,737.2–166,513.1)|
|PlGF (pg/mL)||47.9 (38.8–64.8)b||71.2 (53.1–147.4)b|
|sFlt-1 / PIGF||6911 (2388.9–10,575.9)a||866.1 (823.9–3135.8)|
|Ang2 (ng/mL)||24,052.5 (15,233.8–42,840)b||11,721.3 (6546.3–14,058.8)|
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Publication stageIn Press Journal Pre-Proof
M.P. and L.Y. contributed equally as first authors.
F.C. and M.D.R. contributed equally as last authors.
The authors report no conflict of interest.
The authors acknowledge support from Fundació Clínic, Barcelona (HCB/2020/0401), Fundació La Marató de TV3 (202026-10), Jazz Pharmaceuticals Plc (IST-16-10355), German José Carreras Leukaemia Foundation (03R/ 2019), Instituto de Salud Carlos III from Spanish Government (PI19/00888), Bristol Myers-Squibb & Pfizer (ERISTA 15), La Caixa Foundation , the Kids Corona Child and Mother COVID-19 Open Data and Biobank Initiative from Hospital Sant Joan de Déu (Stavros Niarchos Foundation, Santander Foundation, and others), Fundació Privada Daniel Bravo Andreu, Generalitat de Catalunya (2017-SGR675 and CERCA Programme), Fundació Catalana de Trasplantament (FCT 2021), and ad hoc patronage funds for research on COVID-19 from donations from citizens and organizations to the Hospital Clínic de Barcelona-Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain. All funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.
Cite this article as: Palomo M, Youssef L, Ramos A, et al. Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy. Am J Obstet Gynecol 2022;XX:x.ex–x.ex.
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