{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:53:06Z","timestamp":1780361586060,"version":"3.54.1"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sao Paulo Research Foundation","award":["2020\/04558-0"],"award-info":[{"award-number":["2020\/04558-0"]}]},{"name":"Sao Paulo Research Foundation","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Sao Paulo Research Foundation","award":["2013\/07607-8"],"award-info":[{"award-number":["2013\/07607-8"]}]},{"name":"Sao Paulo Research Foundation","award":["309971\/2023-3"],"award-info":[{"award-number":["309971\/2023-3"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["2020\/04558-0"],"award-info":[{"award-number":["2020\/04558-0"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["2013\/07607-8"],"award-info":[{"award-number":["2013\/07607-8"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["309971\/2023-3"],"award-info":[{"award-number":["309971\/2023-3"]}]},{"name":"CEPID\u2014FAPESP\u2014OCRC\u2014Obesity and Comorbidities Research Center, Brazil","award":["2020\/04558-0"],"award-info":[{"award-number":["2020\/04558-0"]}]},{"name":"CEPID\u2014FAPESP\u2014OCRC\u2014Obesity and Comorbidities Research Center, Brazil","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"CEPID\u2014FAPESP\u2014OCRC\u2014Obesity and Comorbidities Research Center, Brazil","award":["2013\/07607-8"],"award-info":[{"award-number":["2013\/07607-8"]}]},{"name":"CEPID\u2014FAPESP\u2014OCRC\u2014Obesity and Comorbidities Research Center, Brazil","award":["309971\/2023-3"],"award-info":[{"award-number":["309971\/2023-3"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["2020\/04558-0"],"award-info":[{"award-number":["2020\/04558-0"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["2013\/07607-8"],"award-info":[{"award-number":["2013\/07607-8"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","award":["309971\/2023-3"],"award-info":[{"award-number":["309971\/2023-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to investigate the role of PC in vascular and thrombotic events in COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the publicly available Gene Expression Omnibus (GEO) repository. In addition, HUVECs were treated with inactive protein C before exposure to SARS-CoV-2 infection or a severe COVID-19 serum. An RT-qPCR array containing 84 related genes was used, and the candidate genes obtained were evaluated. Activated protein C levels were measured using an ELISA kit. We identified at the single-cell level the expression of several pro-inflammatory and pro-coagulation genes in endothelial cells from the patients with COVID-19. Furthermore, we demonstrated that exposure to SARS-CoV-2 promoted transcriptional changes in HUVECs that were partly reversed by the activated protein C pretreatment. We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus.<\/jats:p>","DOI":"10.3390\/v16071049","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T03:38:27Z","timestamp":1719805107000},"page":"1049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1555-7648","authenticated-orcid":false,"given":"Bruna Rafaela dos Santos","family":"Silva","sequence":"first","affiliation":[{"name":"School of Nursing, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"Laboratory of Cell Signalling, Obesity and Comorbidities Center (OCRC), Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davi","family":"Sidarta-Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signalling, Obesity and Comorbidities Center (OCRC), Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"School of Medical Sciences, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseane","family":"Morari","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signalling, Obesity and Comorbidities Center (OCRC), Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"School of Medical Sciences, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Bombassaro","sequence":"additional","affiliation":[{"name":"School of Nursing, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"Laboratory of Cell Signalling, Obesity and Comorbidities Center (OCRC), Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Poblete","family":"Jara","sequence":"additional","affiliation":[{"name":"Surgery Department, Omaha VA Medical Center, Omaha, NE 68105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2288-5500","authenticated-orcid":false,"given":"Camila Lopes","family":"Simeoni","sequence":"additional","affiliation":[{"name":"Laboratory of Emerging Viruses, Institute of Biology, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2818-1301","authenticated-orcid":false,"given":"Pierina Lorencini","family":"Parise","sequence":"additional","affiliation":[{"name":"Laboratory of Emerging Viruses, Institute of Biology, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4996-3153","authenticated-orcid":false,"given":"Jos\u00e9 Luiz","family":"Proenca-Modena","sequence":"additional","affiliation":[{"name":"Laboratory of Emerging Viruses, Institute of Biology, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licio A.","family":"Velloso","sequence":"additional","affiliation":[{"name":"Laboratory of Cell Signalling, Obesity and Comorbidities Center (OCRC), Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"School of Medical Sciences, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-5174","authenticated-orcid":false,"given":"William H.","family":"Velander","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana P.","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"School of Nursing, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"},{"name":"School of Medical Sciences, Universidade Estadual de Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID-19 associated with acute respiratory distress syndrome","volume":"8","author":"Xu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S2213-2600(20)30079-5","article-title":"Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study","volume":"8","author":"Yang","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Charfeddine, S., Ibn Hadj Amor, H., Jdidi, J., Torjmen, S., Kraiem, S., Hammami, R., Bahloul, A., Kallel, N., Moussa, N., and Touil, I. (2021). Long COVID-19 syndrome: Is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV study. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.745758"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"\u00d8stergaard, L. (2021). SARS-CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiol. Rep., 9.","DOI":"10.14814\/phy2.14726"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1161\/ATVBAHA.118.310367","article-title":"Thrombotic regulation from the endothelial cell perspectives","volume":"38","author":"Wang","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1089\/ars.2005.7.1744","article-title":"The role of endothelial cells in the resolution of acute inflammation","volume":"7","author":"Kadl","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_7","first-page":"148","article-title":"Exploring traditional and nontraditional roles for thrombomodulin","volume":"132","author":"Loghmani","year":"2018","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7944","DOI":"10.1016\/S0021-9258(18)34276-5","article-title":"Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation","volume":"257","author":"Esmon","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"van Hinsbergh, V.W. (2012). Endothelium\u2014role in regulation of coagulation and inflammation. Seminars in Immunopathology, Springer.","DOI":"10.1007\/s00281-011-0285-5"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1161\/CIRCULATIONAHA.120.052318","article-title":"Integrated single-cell atlas of endothelial cells of the human lung","volume":"144","author":"Schupp","year":"2021","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1164\/rccm.202003-0576UP","article-title":"Update in pulmonary vascular diseases and right ventricular dysfunction 2019","volume":"202","author":"Goncharova","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/bjh.17240","article-title":"COVID-19-induced endotheliitis: Emerging evidence and possible therapeutic strategies","volume":"193","author":"Calabretta","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/ajcp\/aqaa062","article-title":"COVID-19 autopsies, oklahoma, usa","volume":"153","author":"Barton","year":"2020","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1111\/jth.14844","article-title":"Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19","volume":"18","author":"Dolhnikoff","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/S2213-2600(20)30243-5","article-title":"Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series from New Orleans","volume":"8","author":"Fox","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1111\/bjh.16749","article-title":"COVID-19 coagulopathy in Caucasian patients","volume":"189","author":"Fogarty","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Schimmel, L., Chew, K.Y., Stocks, C.J., Yordanov, T.E., Essebier, P., Kulasinghe, A., Monkman, J., dos Santos Miggiolaro, A.F.R., Cooper, C., and de Noronha, L. (2021). Endothelial cells are not productively infected by SARS-CoV-2. Clin. Transl. Immunol., 10.","DOI":"10.1002\/cti2.1350"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Won, T., Wood, M.K., Hughes, D.M., Talor, M.V., Ma, Z., Schneider, J., Skinner, J.T., Asady, B., Goerlich, E., and Halushka, M.K. (2022). Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs. eBioMedicine, 75.","DOI":"10.1016\/j.ebiom.2022.103812"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJM200103083441001","article-title":"Efficacy and safety of recombinant human activated protein C for severe sepsis","volume":"344","author":"Bernard","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1056\/NEJMoa1202290","article-title":"Drotrecogin alfa (activated) in adults with septic shock","volume":"366","author":"Ranieri","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1001\/jama.2019.5358","article-title":"Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: The SCARLET randomized clinical trial","volume":"321","author":"Vincent","year":"2019","journal-title":"JAMA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1213\/ANE.0000000000005059","article-title":"Revisiting the protein C pathway: An opportunity for adjunctive intervention in COVID-19?","volume":"131","author":"Mazzeffi","year":"2020","journal-title":"Anesth. Analg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1182\/blood-2004-03-1203","article-title":"Patients with severe sepsis vary markedly in their ability to generate activated protein C","volume":"104","author":"Liaw","year":"2004","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/S1473-3099(12)70157-3","article-title":"Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: A meta-analysis and metaregression","volume":"12","author":"Kalil","year":"2012","journal-title":"Lancet Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Griffin, J.H., and Lyden, P. (2020). COVID-19 hypothesis: Activated protein C for therapy of virus-induced pathologic thromboinflammation. Res. Pract. Thromb. Haemost., 4.","DOI":"10.1002\/rth2.12362"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1055\/s-0040-1716544","article-title":"Derivation and validation of a predictive score for disease worsening in patients with COVID-19","volume":"120","author":"Gerotziafas","year":"2020","journal-title":"Thromb. Haemost."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1182\/blood.V79.9.2340.2340","article-title":"Direct detection of activated protein C in blood from human subjects","volume":"79","author":"Gruber","year":"1992","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Silva, B.R.S., Jara, C.P., Sidarta-Oliveira, D., Velloso, L.A., Velander, W.H., and Ara\u00fajo, E.P. (2022). Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability\u2014A Single-Cell Transcriptomics Analysis. Viruses, 14.","DOI":"10.3390\/v14122753"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_30","unstructured":"Debmalya Barh, V.A. (2019). Data Analysis in Single-Cell RNA-Seq. Single-Cell Omics, Elsevier."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41392-020-00454-7","article-title":"Endothelial activation and dysfunction in COVID-19: From basic mechanisms to potential therapeutic approaches","volume":"5","author":"Jin","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Ionescu, M., Stoian, A.P., Rizzo, M., Serban, D., Nuzzo, D., Mazilu, L., Suceveanu, A.I., Dascalu, A.M., and Parepa, I.R. (2021). The role of endothelium in COVID-19. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111920"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bernard, I., Limonta, D., Mahal, L.K., and Hobman, T.C. (2020). Endothelium infection and dysregulation by SARS-CoV-2: Evidence and caveats in COVID-19. Viruses, 13.","DOI":"10.3390\/v13010029"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hatch, C.J., Piombo, S.D., Fang, J.S., Gach, J.S., Ewald, M.L., Van Trigt, W.K., Coon, B.G., Tong, J.M., Forthal, D.N., and Hughes, C.C. (2024). SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1360364"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/art.42094","article-title":"Endothelial cell\u2013activating antibodies in COVID-19","volume":"74","author":"Shi","year":"2022","journal-title":"Arthritis Rheumatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e132","DOI":"10.1093\/cvr\/cvaa140","article-title":"COVID-19 as a cardiovascular disease: The potential role of chronic endothelial dysfunction","volume":"116","author":"Almansa","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41577-020-0343-0","article-title":"COVID-19: The vasculature unleashed","volume":"20","author":"Teuwen","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"11855","DOI":"10.1038\/s41598-022-15976-z","article-title":"Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction","volume":"12","author":"Urata","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.niox.2021.08.001","article-title":"Lifestyle-mediated nitric oxide boost to prevent SARS-CoV-2 infection: A perspective","volume":"115","author":"Kobayashi","year":"2021","journal-title":"Nitric Oxide"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"26S","DOI":"10.1378\/chest.124.3_suppl.26S","article-title":"The protein C pathway","volume":"124","author":"Esmon","year":"2003","journal-title":"Chest"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11199","DOI":"10.1074\/jbc.C100017200","article-title":"Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis","volume":"276","author":"Joyce","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/j.1365-2141.2006.06059.x","article-title":"Recombinant human activated protein C upregulates the release of soluble fractalkine from human endothelial cells","volume":"133","author":"Brueckmann","year":"2006","journal-title":"Br. J. Haematol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1161\/01.CIR.0000146344.49689.BB","article-title":"Gene expression profiling of inflamed human endothelial cells and influence of activated protein C","volume":"110","author":"Franscini","year":"2004","journal-title":"Circulation"},{"key":"ref_44","unstructured":"Horby, P.W., Pessoa-Amorim, G., Peto, L., Brightling, C.E., Sarkar, R., Thomas, K., Jeebun, V., Ashish, A., Tully, R., and Chadwick, D. (2021). Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): Preliminary results of a randomised, controlled, open-label, platform trial. Medrxiv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e373","DOI":"10.1093\/cid\/ciaa1177","article-title":"Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): A randomized, double-blind, phase IIb, placebo-controlled trial","volume":"72","author":"Jeronimo","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1007\/s00134-021-06507-x","article-title":"Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: A randomized clinical trial","volume":"47","author":"Rosas","year":"2021","journal-title":"Intensive Care Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"048","DOI":"10.1055\/s-0038-1645685","article-title":"Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects","volume":"63","author":"Okajima","year":"1990","journal-title":"Thromb. Haemost."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13122","DOI":"10.1074\/jbc.M410381200","article-title":"PAR1 cleavage and signaling in response to activated protein C and thrombin","volume":"280","author":"Ludeman","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.maturitas.2008.11.008","article-title":"Reprint of Crosstalk between inflammation and thrombosis","volume":"61","author":"Esmon","year":"2008","journal-title":"Maturitas"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1172\/JCI111626","article-title":"Detection of protein C activation in humans","volume":"74","author":"Bauer","year":"1984","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"056","DOI":"10.1055\/s-0038-1650221","article-title":"Quantification of circulating activated protein C in human plasma by immunoassays-enzyme levels are proportional to total protein C levels","volume":"75","author":"Zuazu","year":"1996","journal-title":"Thromb. Haemost."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1182\/blood.V87.9.3531.bloodjournal8793531","article-title":"Inherited thrombophilia: Pathogenesis, clinical syndromes, and management","volume":"87","author":"Finazzi","year":"1996","journal-title":"Blood"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1161\/01.ATV.18.9.1371","article-title":"Plasma levels of activated protein C in healthy subjects and patients with previous venous thromboembolism: Relationships with plasma homocysteine levels","volume":"18","author":"Cattaneo","year":"1998","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1182\/blood-2003-02-0416","article-title":"Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia","volume":"102","author":"Derhaschnig","year":"2003","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1097\/01.CCM.0000072121.61120.D8","article-title":"Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: A randomized, double-blinded, placebo-controlled, dose-finding study","volume":"31","author":"Hack","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/01.TP.0000046529.83650.8A","article-title":"Activation of protein C during reperfusion in clinical liver transplantation","volume":"75","author":"Ilmakunnas","year":"2003","journal-title":"Transplantation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.thromres.2021.05.016","article-title":"Low admission protein C levels are a risk factor for disease worsening and mortality in hospitalized patients with COVID-19","volume":"204","author":"Stanne","year":"2021","journal-title":"Thromb. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1111\/j.1476-5381.2009.00251.x","article-title":"Protective mechanisms of activated protein C in severe inflammatory disorders","volume":"158","author":"Neyrinck","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Flaskamp, L., Roubal, C., Uddin, S., Sotzny, F., Kedor, C., Bauer, S., Scheibenbogen, C., and Seifert, M. (2022). Serum of post-COVID-19 syndrome patients with or without ME\/CFS differentially affects endothelial cell function in vitro. Cells, 11.","DOI":"10.3390\/cells11152376"},{"key":"ref_60","first-page":"117","article-title":"Serum from COVID-19 patients promotes endothelial cell dysfunction through protease-activated receptor 2","volume":"73","author":"Fortini","year":"2023","journal-title":"Inflamm. Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/7\/1049\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:07:22Z","timestamp":1760108842000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/7\/1049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,28]]},"references-count":60,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["v16071049"],"URL":"https:\/\/doi.org\/10.3390\/v16071049","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,28]]}}}