{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T02:02:37Z","timestamp":1789524157950,"version":"build-2803163510"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences (United States)","doi-asserted-by":"publisher","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bando Ricerca Corrente 2019","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}]},{"name":"Program \u20185Xmille per la Ricerca\u2019 from the Italian Minister of Health","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg\/kg one i.p. dose) or saline in two experimental protocols\u2014placebo (vehicle) and simvastatin (25 mg\/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot\/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p &lt; 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia<\/jats:p>","DOI":"10.3390\/cells11071148","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:40:14Z","timestamp":1648590014000},"page":"1148","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-7184","authenticated-orcid":false,"given":"Vincenzo","family":"La Mura","sequence":"first","affiliation":[{"name":"Fondazione I.R.C.C.S. Ca\u2019 Granda, Ospedale Maggiore Policlinico, U.O.C. Medicina Generale Emostasi e Trombosi, 20122 Milan, Italy"},{"name":"CRC \u201cA.M. e A. Migliavacca\u201d per lo Studio e la Cura delle Malattie del Fegato, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"},{"name":"Dipartimento di Fisiopatologia dei Trapianti, Universit\u00e0 degli Studi di Milano, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3393-3144","authenticated-orcid":false,"given":"Nicoletta","family":"Gagliano","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2041-9928","authenticated-orcid":false,"given":"Francesca","family":"Arnaboldi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4806-2337","authenticated-orcid":false,"given":"Patrizia","family":"Sartori","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4726-2115","authenticated-orcid":false,"given":"Patrizia","family":"Procacci","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Denti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Liguori","sequence":"additional","affiliation":[{"name":"Dipartimento di Fisiopatologia dei Trapianti, Universit\u00e0 degli Studi di Milano, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5667-6857","authenticated-orcid":false,"given":"Niccol\u00f2","family":"Bitto","sequence":"additional","affiliation":[{"name":"Fondazione I.R.C.C.S. Ca\u2019 Granda, Ospedale Maggiore Policlinico, U.O.C. Medicina Generale Emostasi e Trombosi, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ristagno","sequence":"additional","affiliation":[{"name":"Dipartimento di Fisiopatologia dei Trapianti, Universit\u00e0 degli Studi di Milano, 20132 Milan, Italy"},{"name":"Fondazione I.R.C.C.S. Ca\u2019 Granda, Ospedale Maggiore Policlinico, U.O.C. Anestesia e Rianimazione, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Latini","sequence":"additional","affiliation":[{"name":"Dipartimento di Ricerca Cardiovascolare, Istituto di Ricerche Farmacologiche Mario Negri I.R.C.C.S., 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4374-3184","authenticated-orcid":false,"given":"Daniele","family":"Dondossola","sequence":"additional","affiliation":[{"name":"Dipartimento di Fisiopatologia dei Trapianti, Universit\u00e0 degli Studi di Milano, 20132 Milan, Italy"},{"name":"U.O. Chirurgia Generale e dei Trapianti di Fegato, Fondazione IRCCS Ca\u2032 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Salerno","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche per la Salute, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Tripodi","sequence":"additional","affiliation":[{"name":"Fondazione I.R.C.C.S. Ca\u2019 Granda, Ospedale Maggiore Policlinico, U.O.C. 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