key: cord-0954841-8jc885ih authors: Giardini, Valentina; Carrer, Andrea; Casati, Marco; Contro, Ernesto; Vergani, Patrizia; Gambacorti‐Passerini, Carlo title: Increased sFLT1/PlGF ratio in COVID‐19: a novel link to Angiotensin II‐mediated endothelial dysfunction date: 2020-05-30 journal: Am J Hematol DOI: 10.1002/ajh.25882 sha: 67bdcd5b9e75114cf27db920e67a472ce76860eb doc_id: 954841 cord_uid: 8jc885ih nan COVID-19 represents a worldwide emergency. A growing body of evidence indicates the presence of a severe form of coagulopathy 1;2 , which accounts for part of the excess of mortality of the syndrome. The pathogenesis of this coagulopathy is incompletely understood at present. SARS-COV-2 enters lung cells using Angiotensin-Converting-Enzyme 2 (ACE2) 3 , which is expressed on epithelial cells in the lungs, and in the small bowel, and on endothelial cells of virtually every organ. ACE2 is a key regulator of the Renin-Angiotensin-System (RAS) which converts angiotensin-II (AngII) into angiotensin 1-7 (Ang1-7). AngII binds its type 1 and 2 receptors (AT1 and AT2) and exerts proinflammatory, oxidative, vasoconstrictive and pro-fibrotic effects. Ang1-7, by binding the Mas receptor (MasR), mediates vaso-dilatory, anti-inflammatory and anti-oxidants effects 4 . Elevated values of Vascular Growth Factors (VEGFS) and AngII, due to SARS-COV-1 binding to ACE2 and to its downregulation, increase vascular permeability and inflammation and drive acute lung injury (ALI) 5 . AngII also directly mediates endothelial cells activation, perturbation and apoptosis 6 . There is a well-known model of AngII-mediated ED: the preeclampsia syndrome (PE). In a seminal publication by Gant et al. 7 , pregnancy was determined to be a state of relative insensitivity to AngII, a physiological adaptation that contributes to low systemic vascular resistance. Conversely, women who later develop preeclampsia remained sensitive to AngII and exhibit an imbalanced proportion of anti-angiogenic and pro-This article is protected by copyright. All rights reserved. angiogenic soluble plasmatic factors. The most promising markers are PlGF (Placental Growth Factor) and its decoy receptor sFlt-1(soluble fms-like tyrosine kinase 1). PEaffected women display a high sFlt-1/PlGF ratio that is associated with adverse outcome. We speculated that also in COVID-19 patients AngII could mediate an abnormal secretion of sFlt-1 and an ensuing high sFlt-1/PlGf ratio, causing a pathological imbalance between angiogenic and anti-angiogenic factors and subsequent ED. In this report the values of sFlt1 and the related PlGF were measured in COVID-19 patients and in two control groups. We speculate that in response to ACE2 depletion and the consequent imbalance of AngII/Ang1-7 an hypoxia driven secretion of sFlt-1 occurs, leading to a global endothelial damage. Pickkers et al. previously described high values of sFlt1 in septic patients, with VEGFs values rapidly increasing in the first 48 hours from the onset of fever 12 . PlGF was not measured in their work; however the ratio between sFlt1 and VEGFs did not change over time. In COVID-19, the endothelial damage possibly due to direct infection through ACE2, results in increased s-Flt1/PlGF ratio, likely due to a pathological imbalance between AngII and Ang1-7. Our data offer a link between ACE2 downregulation and an AngII/s-Flt-1 mediated ED, a model that strictly resembles preeclampsia. These results could also offer an explanation to the pathogenesis of acute global vascular damage because, as said before, ACE2 is ubiquitarily expressed by endothelial cells . These data also provide a rationale for AngII-targeted therapy, and/or the use of aspirin 13 to decrease sFlt1 production and to counteract the COVID-19-related coagulopathy. S-Flt1 and PlGF tests are already performed in many hospitals for risk stratification among women presenting for hypertensive disorders in pregnancy and reference ranges based on gestational age are readily available. The use of the This article is protected by copyright. All rights reserved. s-Flt1/PlGF ratio in COVID-19 could therefore provide a simple clinical tool to stratify the intensity of ED. Since sFlt-1 is produced only by endothelial cells or monocytes, it remains to be demonstrated if these cells are directly infected by COVID-19 or whether their excessive sFlt-1 production represents a response to increased levels of AngII produced elsewhere or to inflammatory mediators. A recent publication documented the presence of viral particles inside endothelial cells obtained from advanced cases of COVID-19 infection 14 . Prospective serial collection of samples from patients during COVID-19 infection are currently under way and will be needed to confirm these preliminary observations, in addition to the direct study of endothelial cells. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis Severe COVID-19 infection associated with endothelial activation SARS and MERS: recent insights into emerging coronaviruses Renin-angiotensin system at the heart of COVID-19 pandemic Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice This article is protected by copyright. All rights reserved Angiotensin II and the endothelium: diverse signals and effects A study of angiotensin II pressor response throughout primigravid pregnancy Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy Regulation of soluble fms-like tyrosine kinase-1 production in response to placental ischemia/hypoxia: role of angiotensin II Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability Aspirin inhibits expression of sFLT1 from human cytotrophoblasts induced by hypoxia, via cyclooxygenase 1 Endothelial cell infection and endotheliitis in COVID-19 The authors are grateful to all patients who chose to be followed at San Gerardo Hospital and, in particular, to those who accepted to participate in this study.We gratefully acknowledge the help of Federica Poggi, PhD, for data and editorial management. Funded in part from AIRC grant IG 2017 Id.20112. The authors declare no potential conflict of interests. Dr Valentina Giardini wrote the first draft of the paper. This article is protected by copyright. All rights reserved.All authors read the manuscript and approved it.