{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:20:03Z","timestamp":1775607603884,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011777","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:00:00Z","timestamp":1720137600000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["HHSN272201700040I"],"award-info":[{"award-number":["HHSN272201700040I"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jecho Laboratories","award":["P74365"],"award-info":[{"award-number":["P74365"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    COVID-associated coagulopathy seemly plays a key role in post-acute sequelae of SARS- CoV-2 infection. However, the underlying pathophysiological mechanisms are poorly understood, largely due to the lack of suitable animal models that recapitulate key clinical and pathological symptoms. Here, we fully characterized AC70 line of human ACE2 transgenic (AC70 hACE2 Tg) mice for SARS-CoV-2 infection. We noted that this model is highly permissive to SARS-CoV-2 with values of 50% lethal dose and infectious dose as ~ 3 and ~ 0.5 TCID\n                    <jats:sub>50<\/jats:sub>\n                    of SARS-CoV-2, respectively. Mice infected with 10\n                    <jats:sup>5<\/jats:sup>\n                    TCID\n                    <jats:sub>50<\/jats:sub>\n                    of SARS-CoV-2 rapidly succumbed to infection with 100% mortality within 5 days. Lung and brain were the prime tissues harboring high viral titers, accompanied by histopathology. However, viral RNA and inflammatory mediators could be detectable in other organs, suggesting the nature of a systemic infection. Lethal challenge of AC70 hACE2 Tg mice caused acute onset of leukopenia, lymphopenia, along with an increased neutrophil-to-lymphocyte ratio (NLR). Importantly, infected animals recapitulated key features of COVID-19-associated coagulopathy. SARS-CoV-2 could induce the release of circulating neutrophil extracellular traps (NETs), along with activated platelet\/endothelium marker. Immunohistochemical staining with anti-platelet factor-4 (PF4) antibody revealed profound platelet aggregates especially within blocked veins of the lungs. We showed that acute SARS-CoV-2 infection triggered a hypercoagulable state coexisting with ill-regulated fibrinolysis. Finally, we highlighted the potential role of Annexin A2 (ANXA2) in fibrinolytic failure. ANXA2 is a calcium-dependent phospholipid-binding protein that forms a heterotertrameric complexes localized at the extracellular membranes with two S100A10 small molecules acting as a co-receptor for tissue-plasminogen activator (t-PA), tightly involved in cell surface fibrinolysis. Thus, our results revealing elevated IgG type anti-ANXA2 antibody production, downregulated\n                    <jats:italic>de novo<\/jats:italic>\n                    ANXA2\/S100A10 synthesis, and reduced ANXA2\/S100A10 association in infected mice, this protein might serve as druggable targets for development of antithrombotic and\/or anti-fibrinolytic agents to attenuate pathogenesis of COVID-19.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011777","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T15:39:03Z","timestamp":1719243543000},"page":"e1011777","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Characterization of Unique Pathological Features of COVID-Associated Coagulopathy: Studies with AC70 hACE2 Transgenic Mice Highly Permissive to SARS-CoV-2 Infection"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0201-5017","authenticated-orcid":true,"given":"Aleksandra K.","family":"Drelich","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kempaiah","family":"Rayavara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panatda","family":"Saenkham-Huntsinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara M.","family":"Judy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Tat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas G.","family":"Ksiazek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bi-Hung","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Te K.","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"ppat.1011777.ref001","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1007\/s11606-022-07523-3","article-title":"Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort.","volume":"37","author":"SM Yoo","year":"2022","journal-title":"J Gen Intern Med"},{"issue":"12","key":"ppat.1011777.ref002","doi-asserted-by":"crossref","first-page":"1 176","DOI":"10.1161\/CIRCULATIONAHA.120.048488","article-title":"Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated With Respiratory Failure and Coagulopathy","volume":"142","author":"L Nicolai","year":"2020","journal-title":"Circulation"},{"key":"ppat.1011777.ref003","doi-asserted-by":"crossref","first-page":"5417","DOI":"10.1038\/s41467-021-25509-3","article-title":"New-onset IgG autoantibodies in hospitalized patients with COVID-19.","volume":"12","author":"SE Chang","year":"2021","journal-title":"Nat Commun."},{"issue":"5","key":"ppat.1011777.ref004","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.3390\/jcm12051915","article-title":"The Very Long COVID: Persistence of Symptoms after 12\u201318 Months from the Onset of Infection and Hospitalization.","volume":"12","author":"M Ranucci","year":"2023","journal-title":"J Clin Med."},{"key":"ppat.1011777.ref005","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.thromres.2020.07.047","article-title":"D-dimer level is associated with the severity of COVID-19","volume":"195","author":"HH Yu","year":"2020","journal-title":"Thromb Res"},{"issue":"2","key":"ppat.1011777.ref006","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1002\/jha2.654","article-title":"SARS-CoV-2 infection results in upregulation of Plasminogen Activator Inhibitor-1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity","volume":"4","author":"KH Toomer","year":"2023","journal-title":"EJHaem"},{"issue":"7","key":"ppat.1011777.ref007","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":"SE Fox","year":"2020","journal-title":"Lancet Respir Med"},{"key":"ppat.1011777.ref008","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.thromres.2020.04.013","article-title":"Incidence of thrombotic complications in critically ill ICU patients with COVID-19","volume":"191","author":"FA Klok","year":"2020","journal-title":"Thromb Res"},{"issue":"7","key":"ppat.1011777.ref009","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1111\/jth.14869","article-title":"High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients","volume":"18","author":"JF Llitjos","year":"2020","journal-title":"J Thromb Haemost"},{"issue":"570","key":"ppat.1011777.ref010","doi-asserted-by":"crossref","first-page":"eabd3876","DOI":"10.1126\/scitranslmed.abd3876","article-title":"Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.","volume":"12","author":"Y Zuo","year":"2020","journal-title":"Sci Transl Med."},{"issue":"4","key":"ppat.1011777.ref011","doi-asserted-by":"crossref","first-page":"2100918","DOI":"10.1183\/13993003.00918-2021","article-title":"Autoimmunity to annexin A2 predicts mortality among hospitalised COVID-19 patients","volume":"58","author":"M Zuniga","year":"2021","journal-title":"Eur Respir J"},{"key":"ppat.1011777.ref012","first-page":"144","article-title":"The Biology of Annexin A2: From Vascular Fibrinolysis to Innate Immunity.","volume":"126","author":"KA Hajjar","year":"2015","journal-title":"Trans Am Clin Climatol Assoc."},{"key":"ppat.1011777.ref013","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.molimm.2009.11.019","article-title":"Annexin A2 on lung epithelial cell surface is recognized by severe acute respiratory syndrome-associated coronavirus spike domain 2 antibodies","volume":"47","author":"YT Fang","year":"2010","journal-title":"Mol. Immunol"},{"key":"ppat.1011777.ref014","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"M Hoffmann","year":"2020","journal-title":"Cell"},{"issue":"3","key":"ppat.1011777.ref015","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1128\/JVI.01702-06","article-title":"Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor","volume":"81","author":"CT Tseng","year":"2007","journal-title":"J Virol"},{"issue":"7","key":"ppat.1011777.ref016","doi-asserted-by":"crossref","first-page":"3039","DOI":"10.1128\/JVI.01792-08","article-title":"Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells.","volume":"83","author":"T Yoshikawa","year":"2009","journal-title":"J Virol"},{"issue":"1","key":"ppat.1011777.ref017","doi-asserted-by":"crossref","first-page":"5 7","DOI":"10.1128\/JVI.02009-15","article-title":"Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease","volume":"90","author":"X Tao","year":"2015","journal-title":"J Virol"},{"issue":"5","key":"ppat.1011777.ref018","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1007\/s00134-020-05991-x","article-title":"Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.","volume":"46","author":"Q Ruan","year":"2020","journal-title":"Intensive Care Med."},{"issue":"1","key":"ppat.1011777.ref019","first-page":"206","article-title":"Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage.","volume":"18","author":"J Liu","journal-title":"J Transl Med. 2020 May 20"},{"key":"ppat.1011777.ref020","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s40560-020-00466-z","article-title":"D-dimer as a biomarker for disease severity and mortality in COVID-19 patients: a case control study.","volume":"8","author":"Y Yao","year":"2020","journal-title":"J Intensive Care"},{"issue":"6","key":"ppat.1011777.ref021","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.jamcollsurg.2021.02.019","article-title":"Fibrinolysis Shutdown in COVID-19: Clinical Manifestations, Molecular Mechanisms, and Therapeutic Implications.","volume":"232","author":"JP Meizoso","year":"2021","journal-title":"J Am Coll Surg."},{"key":"ppat.1011777.ref022","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1111\/jth.15534","article-title":"Platelets contribute to disease severity in COVID-19","volume":"19","author":"TJ Barrett","year":"2021","journal-title":"J Thromb 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Commun"},{"issue":"3","key":"ppat.1011777.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nsr\/nwaa291","article-title":"Replication, pathogenicity, and transmission of SARS-CoV-2 in minks.","volume":"8","author":"L Shuai","year":"2020","journal-title":"Natl Sci Rev"},{"issue":"7818","key":"ppat.1011777.ref030","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/s41586-020-2342-5","article-title":"Pathogenesis and transmission of SARS-CoV-2 in golden hamsters","volume":"583","author":"SF Sia","year":"2020","journal-title":"Nature"},{"issue":"28","key":"ppat.1011777.ref031","doi-asserted-by":"crossref","first-page":"16587","DOI":"10.1073\/pnas.2009799117","article-title":"Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development","volume":"117","author":"M Imai","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7830","key":"ppat.1011777.ref032","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/s41586-020-2708-8","article-title":"A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures","volume":"586","author":"KH 3rd Dinnon","year":"2020","journal-title":"Nature"},{"issue":"3","key":"ppat.1011777.ref033","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.cell.2020.06.011","article-title":"A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies","volume":"182","author":"AO Hassan","year":"2020","journal-title":"Cell"},{"issue":"3","key":"ppat.1011777.ref034","first-page":"734","article-title":"Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and","volume":"182","author":"J Sun","year":"2020","journal-title":"Treatment. Cell"},{"issue":"3","key":"ppat.1011777.ref035","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.4269\/ajtmh.20-0762","article-title":"Evaluation of K18-hACE2 Mice as a Model of SARS-CoV-2 Infection","volume":"103","author":"GB Moreau","year":"2020","journal-title":"Am J Trop Med Hyg"},{"issue":"11","key":"ppat.1011777.ref036","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/s41590-020-0778-2","article-title":"SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function","volume":"21","author":"ES Winkler","year":"2020","journal-title":"Nat Immunol"},{"issue":"12","key":"ppat.1011777.ref037","doi-asserted-by":"crossref","first-page":"1 230","DOI":"10.1038\/s41422-021-00578-7","article-title":"SARS-CoV-2 promotes RIPK1 activation to facilitate viral propagation","volume":"31","author":"G Xu","year":"2021","journal-title":"Cell Res"},{"key":"ppat.1011777.ref038","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s12985-020-01396-w","article-title":"Intranasal exposure of African green monkeys to SARS-CoV-2 results in acute phase pneumonia with shedding and lung injury still present in the early convalescence phase","volume":"17","author":"RW Cross","year":"2020","journal-title":"Virol J"},{"issue":"12","key":"ppat.1011777.ref039","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.3390\/v13122506","article-title":"High-fat high-sugar diet-induced changes in the lipid metabolism are associated with mildly increased COVID-19 severity and delayed recovery in the Syrian hamster.","volume":"13","author":"JR Port","year":"2021","journal-title":"Viruses."},{"issue":"1","key":"ppat.1011777.ref040","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41421-022-00381-7","article-title":"Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD","volume":"8","author":"H Ma","year":"2022","journal-title":"Cell Discov"},{"issue":"15","key":"ppat.1011777.ref041","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China.","volume":"71","author":"C Qin","year":"2020","journal-title":"Clin Infect Dis"},{"key":"ppat.1011777.ref042","doi-asserted-by":"crossref","first-page":"106504","DOI":"10.1016\/j.intimp.2020.106504","article-title":"The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients","volume":"84","author":"AP Yang","year":"2020","journal-title":"Int Immunopharmacol"},{"issue":"2","key":"ppat.1011777.ref043","first-page":"311","article-title":"Hematological findings in SARS patients and possible mechanisms (review).","volume":"14","author":"M Yang","year":"2004","journal-title":"Int J Mol Med"},{"key":"ppat.1011777.ref044","doi-asserted-by":"crossref","first-page":"25359","DOI":"10.1038\/srep25359","article-title":"Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity.","volume":"6","author":"CK Min","year":"2016","journal-title":"Sci Rep."},{"issue":"1","key":"ppat.1011777.ref045","doi-asserted-by":"crossref","first-page":"e5","DOI":"10.1371\/journal.ppat.0030005","article-title":"A mouse-adapted SARS-coronavirus causes disease and mortality in BALB\/c mice.","volume":"3","author":"A Roberts","year":"2007","journal-title":"PLoS Pathog."},{"issue":"7","key":"ppat.1011777.ref046","doi-asserted-by":"crossref","first-page":"e0220126","DOI":"10.1371\/journal.pone.0220126","article-title":"Increasing the translation of mouse models of MERS coronavirus pathogenesis through kinetic hematological analysis.","volume":"14","author":"SR Leist","year":"2019","journal-title":"PLoS One."},{"issue":"11","key":"ppat.1011777.ref047","doi-asserted-by":"crossref","first-page":"dmm049632","DOI":"10.1242\/dmm.049632","article-title":"Comparison of the pathogenesis of SARS-CoV-2 infection in K18-hACE2 mouse and Syrian golden hamster models.","volume":"15","author":"H Jeong","year":"2022","journal-title":"Dis Model Mech."},{"key":"ppat.1011777.ref048","doi-asserted-by":"crossref","first-page":"108486","DOI":"10.1016\/j.clim.2020.108486","article-title":"Selective CD8 cell reduction by SARS-CoV-2 is associated with a worse prognosis and systemic inflammation in COVID-19 patients","volume":"217","author":"JM Urra","year":"2020","journal-title":"Clin Immunol"},{"key":"ppat.1011777.ref049","doi-asserted-by":"crossref","first-page":"198","DOI":"10.28932\/jmh.v3i2.3097","article-title":"Common Change of Complete Blood Count Parameters in COVID-19: A Literature Review","volume":"3","author":"K. Dhinata","year":"2021","journal-title":"J. Med. 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Med."},{"issue":"10223","key":"ppat.1011777.ref053","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.","volume":"395","author":"N Chen","year":"2020","journal-title":"Lancet"},{"key":"ppat.1011777.ref054","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1056\/NEJMoa2002032","article-title":"Clinical characteristics of coronavirus disease 2019 in China.","volume":"382","author":"W Guan","year":"2020","journal-title":"N Engl J Med"},{"issue":"11","key":"ppat.1011777.ref055","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1161\/CIRCRESAHA.120.317703","article-title":"Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19","volume":"127","author":"Y Zaid","year":"2020","journal-title":"Circ 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