key: cord-1037422-2x36dwyu authors: Nizzoli, Maria Elena; Merati, Gabriele; Tenore, Annamaria; Picone, Cristina; Consensi, Erica; Perotti, Luciano; Ferretti, Virginia Valeria; Sambo, Margherita; Di Sabatino, Antonio; Iotti, Giorgio Antonio; Arcaini, Luca; Bruno, Raffaele; Belliato, Mirko title: Circulating endothelial cells in COVID‐19 date: 2020-06-03 journal: Am J Hematol DOI: 10.1002/ajh.25881 sha: 1d6c12b0254600cebef790f0c6ccee5dd071ca85 doc_id: 1037422 cord_uid: 2x36dwyu nan Since the end of February 2020, Italy is facing an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the clinical picture associated with the infection has been named COVID-19. COVID-19 patients may develop multiple organ dysfunction with signs of endothelial derangement. Vascular damage has been proposed as a relevant mechanism that can perpetuate the activation of complement system and might therefore enhance the inflammatory stimulus. This article is protected by copyright. All rights reserved. Intensive care Unit or in Infectious disease Unit; 6 healthy controls have been analysed. Freshly collected peripheral blood EDTA samples from non-traumatic venipuncture were analysed according to standardized methods by trained operators unaware of patient's clinical conditions. 5 The number of CECs was expressed as cells per milliliter of blood and counts were considered normal when inferior to 30/ml (Supplemental Figure 1) . At the same time peripheral blood smear was evaluated by haematologists to assess schistocyte count; the presence of ≥ 1% schistocytes on peripheral blood smears was considered abnormal. Clinical features of patients, comorbidities and timing of analysis are summarized in Supplemental Table 1 . At the time of CEC evaluation, LDH and D-dimer were elevated in 29/30 (97%) and 22/25 (88%) pts, respectively; schistocytes were detected in 5 patients (range 0 -4.5%). Haemoglobin was less than 13 g/dl in 27 pts (90%) and platelets less than 150 x 10 9 /L in 8 pts (27%). Haptoglobin was normal in all tested pts. In 23 out of 30 patients (76.7%) CECs were > 30/ml while in 1 out of 6 (16.7%) healthy subject (p=0.010). CECs were higher in patients with respect to healthy subjects (46/ml; IQR: 32-89/ml vs 14.5/ml; IQR: 9-20/ml, p=0.002) (Figure 1 ). Supplemental Table 2 reports the comparison of laboratory features according to CECs values. Higher CECs were found in patients at earlier phase of disease (median time between hospitalization and assessment for elevated vs normal CECs: 5 vs 18 days). No differences were found between patients with elevated CECs and those with normal values of haemoglobin, leukocytes, lymphocytes, platelets, LDH, D-dimer (Supplemental Table 2 ). Overall these data add a supplemental element to support the role of endothelial damage in COVID-19. The presence of concomitant comorbidities known to be related to CECs elevation, such as cardiovascular and rheumatic diseases, diabetes and malignancies might exert a confounding effect on CEC assessment. This article is protected by copyright. All rights reserved. On the other hand it has been demonstrated that COVID-19 patients affected by such comorbidities have worse outcome 6 : it can be hypothesized that viral endothelial damage might be enhanced in presence of additional factors that contribute to endothelial impairment. Among possible limitations of the study, the heterogeneous timing of CEC assessment and the lack of sequential analysis have to be acknowledged. Moreover, our assay is not able to identify non vital endothelial cells that already underwent apoptosis after viral injury and, therefore, our analysis might not fully depict the entity of endothelial damage. It would also be of interest to extend our evaluation to the circulating endothelial progenitor cells (CEPs) compartment in order to identify possible correlation between CEC and CEP counts and to investigate angiogenic activity. Finally, from a therapeutic perspective, it will be useful to assess the value of CEC monitoring during treatment with LMWH and other drugs under investigation for COVID-19. Complement inhibitors such as eculizumab and IFX-1 and the endothelial protecting drug defibrotide could limit the extension of endothelial damage and the progression of respiratory failure in COVID-19. Endothelial cell infection and endotheliitis in COVID-19 Circulating endothelial cells as biomarker for cardiovascular diseases Evaluation of endothelial damage in sepsisrelated ARDS using circulating endothelial cells Measurement of circulating endothelial cells to support the diagnosis of veno-occlusive disease after hematopoietic stem cell transplantation A standardized flow cytometry network study for the assessment of circulating endothelial cell physiological ranges Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis The results of clinical trials (NCT04335201; NCT04288713, NCT04333420) investigating these agents are eagerly awaited. This article is protected by copyright. All rights reserved.