key: cord-1033556-bojb29cg authors: Falcinelli, Emanuela; Petito, Eleonora; Becattini, Cecilia; De Robertis, Edoardo; Paliani, Ugo; Sebastiano, Manuela; Vaudo, Gaetano; Guglielmini, Giuseppe; Paciullo, Francesco; Cerotto, Vittorio; Malvestiti, Marco; Gori, Fabio; Bury, Loredana; Lazzarini, Teseo; Gresele, Paolo title: Role of endothelial dysfunction in the thrombotic complications of COVID-19 patients date: 2020-12-02 journal: J Infect DOI: 10.1016/j.jinf.2020.11.041 sha: 86225f24baa610a7cc6fddbfac59547a86e14eaa doc_id: 1033556 cord_uid: bojb29cg nan We note with interest the review of Kunutsor SK. et al (1) on cardiovascular implications of coronavirus disease 2019 . Indeed, Sars-Cov-2 infection begins in lungs but moves rapidly to the vascular system with platelet alterations and blood clotting abnormalities, and associates with a high incidence of cardiovascular events and venous thromboembolism (VTE), especially in critically ill patients (10-34%) (2) . Based on autopsy findings, endothelial injury has been hypothesized to play a crucial role in the Sars-Cov-2 associated pro-coagulant condition (3) . Very few studies, however, have assessed circulating biomarkers of endothelial damage in COVID-19 patients. Among these particularly interesting are circulating endothelial cells (CECs), circulating endothelial progenitor cells (EPCs), endothelial extracellular vesicles (EEVs) and soluble forms of endothelial adhesive proteins (CAM) which are known to be altered in conditions associated with enhanced cardiovascular risk and to be predictive of vascular complications in various conditions, including infectious diseases (4) . For these parameters no data are available, to our knowledge, in Sars-Cov-2 infection. Aim of our study was to assess the role of cellular and soluble circulating endothelial derangement parameters as markers of endothelial damage in COVID-19 patients and to unravel if they may identify patients developing VTE or adverse outcome. Fifty-six COVID-19 patients and 36 healthy, age-and sex-matched controls were enrolled in a multicenter study in the Umbria Region, Italy. Peripheral blood was collected for EEVs, CECs and EPCs by flow cytometry and for sVCAM and sICAM by ELISA (5 CD45 positive high (CD45 +high ) was observed, suggesting that these EPCs with high phagocytic capability may represent a reactive mechanism to limit viral proliferation (6). COVID-19 patients also had higher plasma levels of soluble markers of EC disturbance, sVCAM-1 (3122±324 vs 1135±82 ng/ml, p<0.001) and sICAM-1 ( Figure 1C) and VWF:Ag and VWF:RCo (Table 1) , as compared with controls. Notably, sICAM-1 was significantly more elevated in COVID-19 patients admitted into ICU compared to those not in ICU ( Figure 1D ) and in patients with reduced PaO 2 /FiO 2 ratio compared to those with normal PaO 2 /FiO 2 (Figure 1E) , suggesting that severe respiratory syndrome and hypoxemia are associated with endothelial damage. A significant correlation was also found between sICAM-1 and the SOFA score (r=0.65, p<0.01), suggesting that elevated sICAM-1 may represent a marker of severe disease evolution in Sars-Cov-2 infection. D-dimer, VWF:Ag (not shown) and sICAM-1 ( Figure 1F) were significantly higher in patients who developed VTE than in patients who did not. ROC curve analysis showed that sICAM-1 >519.06 ng/ml discriminates COVID-19 patients with VTE from those without with moderate accuracy (AUC= 0.83, p<0.01) (Suppl. Fig. 1 ). Most patients were under standard-(n=32) or incremented-dose (n=8) prophylactic LMWH (40/56, 71%) but no differences between treated and untreated patients were found for any of the circulating endothelial dysfunction markers assessed. In patients who had recovered from COVID-19, CECs, EMPs, EPCs, VWF:Ag, VWF:RCo, sICAM-1 and sVCAM-1 returned to levels close to those of healthy controls, suggesting that endothelial damage is strictly dependent on active COVID-19 infection (Suppl. Fig. 2 ). Our results show that COVID-19 patients have increased circulating CECs, EMPs and phagocytic EPCs and increased plasma levels of sICAM-1, sVCAM-1, VWF:Ag and VWF:RCo, with concomitant decrease of angiogenic EPCs, proving that circulating parameters of endothelial derangement are strongly altered in COVID-19 patients. In particular, plasma levels of sICAM-1 and of sVCAM-1 were more than threefold increased probably reflecting the enhanced adhesiveness of microvascular endothelium mediating the strong leukocyte extravasation in tissue, in particular in lungs. Moreover, the endothelial activation triggered by SARS-CoV-2 probably contributes to the strong in vivo platelet activation found in COVID-19 patients and to platelet adhesion to lung endothelium leading to lung injury. Elevated sICAM-1 predicts cardiovascular events in apparently healthy men and in patients with cardiovascular disease and is associated with recurrent VTE (7) , and in our study strongly associated with VTE incidence and disease severity, therefore this marker warrants more extensive investigation for prognostic prediction in COVID-19 patients. In our study prophylactic-dose LMWH did not affect biomarkers of endothelial dysfunction, in agreement with low clinical efficacy in preventing VTE in COVID-19 patients (8) . A recent study evaluated the impact of therapeutic-dose anticoagulation given to COVID-19 patients prior to hospitalization on endothelial damage, measured by CECs, suggesting that early treatment may prevent COVID-19-associated endothelial lesion (9) . Thus sICAM-1 might be used as an indicator to switch to therapeutic dose heparin in high-risk patients. Finally, our data, strongly confirming that COVID-19 is an endothelial disease, provide the rationale for the search of novel therapeutic strategies targeting inflammatory mediators and/or promoting endothelial protection/repair to prevent the thrombotic and systemic complications of COVID-19. Laura Franco 1 , Luca Saccarelli 2 , Maria Lapenna 3 , Marco D'Abbondanza 4 , Stefano Cristallini 6 . The authors declare no conflict of interest This work was supported by a fellowship from Fondazione Umberto Veronesi to L. Bury and E. Falcinelli. Cardiovascular complications in COVID-19: A systematic review and meta-analysis Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis COVID-19 and thrombosis: beyond a casual association Biomarkers of endothelial activation/dysfunction in infectious diseases Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication An in vitro study of differentiation of hematopoietic cells to endothelial cells E-selectin and sICAM-1, biomarkers of endothelial function, predict recurrence of venous thromboembolism Thrombosis risk associated with COVID-19 infection. A scoping review Curative anticoagulation prevents endothelial lesion in COVID-19 patients Results are reported as mean±SEM if not differently indicated A) and hematopoietic EPCs CD45 +int (B) in COVID-19 patients and in healthy controls. Results are expressed as absolute number/l. *=p<0.05 vs healthy controls. sICAM-1 (C) levels are increased in COVID-19 patients compared to healthy controls (p<0.05) and in plasma of COVID-19 patients admitted into intensive care unit (ICU) or in non-ICU COVID-19 wards (p<0.05) (D), with normal or abnormal PaO 2 /FIO 2 ratio (p<0.05) (E) and patients with or without thromboembolic event Supplementary materials associated with this article can be found in the online version.