Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19
The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failu...
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| Veröffentlicht in: | Journal of hepatology 2024-11, Vol.81 (5), p.872-885 |
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| creator | Cadamuro, Massimiliano Lasagni, Alberto Radu, Claudia Maria Calistri, Arianna Pilan, Matteo Valle, Clarissa Bonaffini, Pietro Andrea Vitiello, Adriana Toffanin, Serena Venturin, Camilla Friòn-Herrera, Yahima Sironi, Sandro Alessio, Maria Grazia Previtali, Giulia Seghezzi, Michela Gianatti, Andrea Strazzabosco, Mario Strain, Alastair J. Campello, Elena Spiezia, Luca Palù, Giorgio Frigo, Anna Chiara Tosoni, Antonella Nebuloni, Manuela Parolin, Cristina Sonzogni, Aurelio Simioni, Paolo Fabris, Luca |
| description | The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19.
Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment.
IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules.
SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19.
Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotyp |
| doi_str_mv | 10.1016/j.jhep.2024.06.014 |
| format | Article |
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Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment.
IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules.
SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19.
Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.
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•Portal vein microthrombosis is associated with IPVD in fatal COVID-19-related hypoxia.•In thrombosed portal venules, pericytes are preponderantly infected by SARS-CoV-2.•Pericytes embedding the thrombosed portal vein radicles overexpress tissue factor.•SARS-CoV-2 induces infected pericytes to overexpress tissue factor.•Infected pericytes kindle endothelial cells to overexpress von Willebrand factor.</description><identifier>ISSN: 0168-8278</identifier><identifier>ISSN: 1600-0641</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2024.06.014</identifier><identifier>PMID: 38908437</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Aged ; Betacoronavirus ; COVID-19 - complications ; COVID-19 - mortality ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Endothelial Cells - virology ; Female ; Humans ; Hypoxia ; Lung - pathology ; Male ; Middle Aged ; Pericytes - metabolism ; Pericytes - pathology ; Pericytes - virology ; Phenotype ; Pneumonia, Viral - complications ; Pneumonia, Viral - mortality ; Pneumonia, Viral - pathology ; Pneumonia, Viral - virology ; portal fibrosis ; Portal Vein - pathology ; SARS-CoV-2 ; Thromboplastin - analysis ; Thromboplastin - metabolism ; tissue factor ; vascular liver disease ; Venous Thrombosis - etiology ; Venous Thrombosis - pathology ; Venous Thrombosis - virology ; von Willebrand factor</subject><ispartof>Journal of hepatology, 2024-11, Vol.81 (5), p.872-885</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c281t-38101e8999f08714d37f079853a6d894a2e81722ded21033bb1c4372ecaa535e3</cites><orcidid>0000-0001-5001-9533 ; 0000-0002-0899-7613 ; 0000-0003-2478-8878 ; 0000-0001-8538-6317 ; 0000-0003-2303-7394 ; 0000-0003-3837-6890 ; 0000-0002-3567-7332 ; 0000-0002-6642-8937 ; 0000-0003-4339-8525 ; 0000-0003-4233-6541 ; 0009-0004-5740-7669 ; 0000-0002-1995-6331 ; 0000-0001-5335-9429 ; 0000-0002-7977-7909</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jhep.2024.06.014$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38908437$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cadamuro, Massimiliano</creatorcontrib><creatorcontrib>Lasagni, Alberto</creatorcontrib><creatorcontrib>Radu, Claudia Maria</creatorcontrib><creatorcontrib>Calistri, Arianna</creatorcontrib><creatorcontrib>Pilan, Matteo</creatorcontrib><creatorcontrib>Valle, Clarissa</creatorcontrib><creatorcontrib>Bonaffini, Pietro Andrea</creatorcontrib><creatorcontrib>Vitiello, Adriana</creatorcontrib><creatorcontrib>Toffanin, Serena</creatorcontrib><creatorcontrib>Venturin, Camilla</creatorcontrib><creatorcontrib>Friòn-Herrera, Yahima</creatorcontrib><creatorcontrib>Sironi, Sandro</creatorcontrib><creatorcontrib>Alessio, Maria Grazia</creatorcontrib><creatorcontrib>Previtali, Giulia</creatorcontrib><creatorcontrib>Seghezzi, Michela</creatorcontrib><creatorcontrib>Gianatti, Andrea</creatorcontrib><creatorcontrib>Strazzabosco, Mario</creatorcontrib><creatorcontrib>Strain, Alastair J.</creatorcontrib><creatorcontrib>Campello, Elena</creatorcontrib><creatorcontrib>Spiezia, Luca</creatorcontrib><creatorcontrib>Palù, Giorgio</creatorcontrib><creatorcontrib>Frigo, Anna Chiara</creatorcontrib><creatorcontrib>Tosoni, Antonella</creatorcontrib><creatorcontrib>Nebuloni, Manuela</creatorcontrib><creatorcontrib>Parolin, Cristina</creatorcontrib><creatorcontrib>Sonzogni, Aurelio</creatorcontrib><creatorcontrib>Simioni, Paolo</creatorcontrib><creatorcontrib>Fabris, Luca</creatorcontrib><title>Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19.
Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment.
IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules.
SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19.
Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.
[Display omitted]
•Portal vein microthrombosis is associated with IPVD in fatal COVID-19-related hypoxia.•In thrombosed portal venules, pericytes are preponderantly infected by SARS-CoV-2.•Pericytes embedding the thrombosed portal vein radicles overexpress tissue factor.•SARS-CoV-2 induces infected pericytes to overexpress tissue factor.•Infected pericytes kindle endothelial cells to overexpress von Willebrand factor.</description><subject>Aged</subject><subject>Betacoronavirus</subject><subject>COVID-19 - complications</subject><subject>COVID-19 - mortality</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Endothelial Cells - virology</subject><subject>Female</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Lung - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pericytes - metabolism</subject><subject>Pericytes - pathology</subject><subject>Pericytes - virology</subject><subject>Phenotype</subject><subject>Pneumonia, Viral - complications</subject><subject>Pneumonia, Viral - mortality</subject><subject>Pneumonia, Viral - pathology</subject><subject>Pneumonia, Viral - virology</subject><subject>portal fibrosis</subject><subject>Portal Vein - pathology</subject><subject>SARS-CoV-2</subject><subject>Thromboplastin - analysis</subject><subject>Thromboplastin - metabolism</subject><subject>tissue factor</subject><subject>vascular liver disease</subject><subject>Venous Thrombosis - etiology</subject><subject>Venous Thrombosis - pathology</subject><subject>Venous Thrombosis - virology</subject><subject>von Willebrand factor</subject><issn>0168-8278</issn><issn>1600-0641</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc2O0zAUhS0EYsrAC7BAXrJJuLbTxJbYoPIzI400LICt5do31FUSB9sp6lPwyjjqMEtWlq6-c6xzDiGvGdQMWPvuWB8PONcceFNDWwNrnpANawEqaBv2lGwKJCvJO3lFXqR0BAABqnlOroRUIBvRbcifrzHYYH4ug5kynQ84hXyekYaennxcUuWnHm1GR2eM3p4zJuoTNSkF6816_-3zgc4hZjPQfIhh3Ie0EpOjfsrRzMswhsnEMz2ZZMs_kTo_mOzDVKwm2ptVubv_cfuxYuoledabIeGrh_eafP_86dvuprq7_3K7-3BXWS5ZroQsDaBUSvUgO9Y40fXQKbkVpnVSNYajZB3nDh1nIMR-z2zJy9EasxVbFNfk7cV3juHXginr0SeLQ6kBw5K0gI5xKUCqgvILamNIKWKv5-jHEkgz0OsQ-qjXIfQ6hIZWlyGK6M2D_7If0T1K_jVfgPcXAEvKk8eok_U4WXQ-lsK1C_5__n8BPLmcAQ</recordid><startdate>202411</startdate><enddate>202411</enddate><creator>Cadamuro, Massimiliano</creator><creator>Lasagni, Alberto</creator><creator>Radu, Claudia Maria</creator><creator>Calistri, Arianna</creator><creator>Pilan, Matteo</creator><creator>Valle, Clarissa</creator><creator>Bonaffini, Pietro Andrea</creator><creator>Vitiello, Adriana</creator><creator>Toffanin, Serena</creator><creator>Venturin, Camilla</creator><creator>Friòn-Herrera, Yahima</creator><creator>Sironi, Sandro</creator><creator>Alessio, Maria Grazia</creator><creator>Previtali, Giulia</creator><creator>Seghezzi, Michela</creator><creator>Gianatti, Andrea</creator><creator>Strazzabosco, Mario</creator><creator>Strain, Alastair J.</creator><creator>Campello, Elena</creator><creator>Spiezia, Luca</creator><creator>Palù, Giorgio</creator><creator>Frigo, Anna Chiara</creator><creator>Tosoni, Antonella</creator><creator>Nebuloni, Manuela</creator><creator>Parolin, Cristina</creator><creator>Sonzogni, Aurelio</creator><creator>Simioni, Paolo</creator><creator>Fabris, Luca</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5001-9533</orcidid><orcidid>https://orcid.org/0000-0002-0899-7613</orcidid><orcidid>https://orcid.org/0000-0003-2478-8878</orcidid><orcidid>https://orcid.org/0000-0001-8538-6317</orcidid><orcidid>https://orcid.org/0000-0003-2303-7394</orcidid><orcidid>https://orcid.org/0000-0003-3837-6890</orcidid><orcidid>https://orcid.org/0000-0002-3567-7332</orcidid><orcidid>https://orcid.org/0000-0002-6642-8937</orcidid><orcidid>https://orcid.org/0000-0003-4339-8525</orcidid><orcidid>https://orcid.org/0000-0003-4233-6541</orcidid><orcidid>https://orcid.org/0009-0004-5740-7669</orcidid><orcidid>https://orcid.org/0000-0002-1995-6331</orcidid><orcidid>https://orcid.org/0000-0001-5335-9429</orcidid><orcidid>https://orcid.org/0000-0002-7977-7909</orcidid></search><sort><creationdate>202411</creationdate><title>Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19</title><author>Cadamuro, Massimiliano ; Lasagni, Alberto ; Radu, Claudia Maria ; Calistri, Arianna ; Pilan, Matteo ; Valle, Clarissa ; Bonaffini, Pietro Andrea ; Vitiello, Adriana ; Toffanin, Serena ; Venturin, Camilla ; Friòn-Herrera, Yahima ; Sironi, Sandro ; Alessio, Maria Grazia ; Previtali, Giulia ; Seghezzi, Michela ; Gianatti, Andrea ; Strazzabosco, Mario ; Strain, Alastair J. ; Campello, Elena ; Spiezia, Luca ; Palù, Giorgio ; Frigo, Anna Chiara ; Tosoni, Antonella ; Nebuloni, Manuela ; Parolin, Cristina ; Sonzogni, Aurelio ; Simioni, Paolo ; Fabris, Luca</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c281t-38101e8999f08714d37f079853a6d894a2e81722ded21033bb1c4372ecaa535e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Aged</topic><topic>Betacoronavirus</topic><topic>COVID-19 - complications</topic><topic>COVID-19 - mortality</topic><topic>Endothelial Cells - metabolism</topic><topic>Endothelial Cells - pathology</topic><topic>Endothelial Cells - virology</topic><topic>Female</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Lung - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pericytes - metabolism</topic><topic>Pericytes - pathology</topic><topic>Pericytes - virology</topic><topic>Phenotype</topic><topic>Pneumonia, Viral - complications</topic><topic>Pneumonia, Viral - mortality</topic><topic>Pneumonia, Viral - pathology</topic><topic>Pneumonia, Viral - virology</topic><topic>portal fibrosis</topic><topic>Portal Vein - pathology</topic><topic>SARS-CoV-2</topic><topic>Thromboplastin - analysis</topic><topic>Thromboplastin - metabolism</topic><topic>tissue factor</topic><topic>vascular liver disease</topic><topic>Venous Thrombosis - etiology</topic><topic>Venous Thrombosis - pathology</topic><topic>Venous Thrombosis - virology</topic><topic>von Willebrand factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cadamuro, Massimiliano</creatorcontrib><creatorcontrib>Lasagni, Alberto</creatorcontrib><creatorcontrib>Radu, Claudia Maria</creatorcontrib><creatorcontrib>Calistri, Arianna</creatorcontrib><creatorcontrib>Pilan, Matteo</creatorcontrib><creatorcontrib>Valle, Clarissa</creatorcontrib><creatorcontrib>Bonaffini, Pietro Andrea</creatorcontrib><creatorcontrib>Vitiello, Adriana</creatorcontrib><creatorcontrib>Toffanin, Serena</creatorcontrib><creatorcontrib>Venturin, Camilla</creatorcontrib><creatorcontrib>Friòn-Herrera, Yahima</creatorcontrib><creatorcontrib>Sironi, Sandro</creatorcontrib><creatorcontrib>Alessio, Maria Grazia</creatorcontrib><creatorcontrib>Previtali, Giulia</creatorcontrib><creatorcontrib>Seghezzi, Michela</creatorcontrib><creatorcontrib>Gianatti, Andrea</creatorcontrib><creatorcontrib>Strazzabosco, Mario</creatorcontrib><creatorcontrib>Strain, Alastair J.</creatorcontrib><creatorcontrib>Campello, Elena</creatorcontrib><creatorcontrib>Spiezia, Luca</creatorcontrib><creatorcontrib>Palù, Giorgio</creatorcontrib><creatorcontrib>Frigo, Anna Chiara</creatorcontrib><creatorcontrib>Tosoni, Antonella</creatorcontrib><creatorcontrib>Nebuloni, Manuela</creatorcontrib><creatorcontrib>Parolin, Cristina</creatorcontrib><creatorcontrib>Sonzogni, Aurelio</creatorcontrib><creatorcontrib>Simioni, Paolo</creatorcontrib><creatorcontrib>Fabris, Luca</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cadamuro, Massimiliano</au><au>Lasagni, Alberto</au><au>Radu, Claudia Maria</au><au>Calistri, Arianna</au><au>Pilan, Matteo</au><au>Valle, Clarissa</au><au>Bonaffini, Pietro Andrea</au><au>Vitiello, Adriana</au><au>Toffanin, Serena</au><au>Venturin, Camilla</au><au>Friòn-Herrera, Yahima</au><au>Sironi, Sandro</au><au>Alessio, Maria Grazia</au><au>Previtali, Giulia</au><au>Seghezzi, Michela</au><au>Gianatti, Andrea</au><au>Strazzabosco, Mario</au><au>Strain, Alastair J.</au><au>Campello, Elena</au><au>Spiezia, Luca</au><au>Palù, Giorgio</au><au>Frigo, Anna Chiara</au><au>Tosoni, Antonella</au><au>Nebuloni, Manuela</au><au>Parolin, Cristina</au><au>Sonzogni, Aurelio</au><au>Simioni, Paolo</au><au>Fabris, Luca</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2024-11</date><risdate>2024</risdate><volume>81</volume><issue>5</issue><spage>872</spage><epage>885</epage><pages>872-885</pages><issn>0168-8278</issn><issn>1600-0641</issn><eissn>1600-0641</eissn><abstract>The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19.
Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-β) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment.
IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-β+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules.
SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19.
Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.
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•Portal vein microthrombosis is associated with IPVD in fatal COVID-19-related hypoxia.•In thrombosed portal venules, pericytes are preponderantly infected by SARS-CoV-2.•Pericytes embedding the thrombosed portal vein radicles overexpress tissue factor.•SARS-CoV-2 induces infected pericytes to overexpress tissue factor.•Infected pericytes kindle endothelial cells to overexpress von Willebrand factor.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>38908437</pmid><doi>10.1016/j.jhep.2024.06.014</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-5001-9533</orcidid><orcidid>https://orcid.org/0000-0002-0899-7613</orcidid><orcidid>https://orcid.org/0000-0003-2478-8878</orcidid><orcidid>https://orcid.org/0000-0001-8538-6317</orcidid><orcidid>https://orcid.org/0000-0003-2303-7394</orcidid><orcidid>https://orcid.org/0000-0003-3837-6890</orcidid><orcidid>https://orcid.org/0000-0002-3567-7332</orcidid><orcidid>https://orcid.org/0000-0002-6642-8937</orcidid><orcidid>https://orcid.org/0000-0003-4339-8525</orcidid><orcidid>https://orcid.org/0000-0003-4233-6541</orcidid><orcidid>https://orcid.org/0009-0004-5740-7669</orcidid><orcidid>https://orcid.org/0000-0002-1995-6331</orcidid><orcidid>https://orcid.org/0000-0001-5335-9429</orcidid><orcidid>https://orcid.org/0000-0002-7977-7909</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0168-8278 |
| ispartof | Journal of hepatology, 2024-11, Vol.81 (5), p.872-885 |
| issn | 0168-8278 1600-0641 1600-0641 |
| language | eng |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Aged Betacoronavirus COVID-19 - complications COVID-19 - mortality Endothelial Cells - metabolism Endothelial Cells - pathology Endothelial Cells - virology Female Humans Hypoxia Lung - pathology Male Middle Aged Pericytes - metabolism Pericytes - pathology Pericytes - virology Phenotype Pneumonia, Viral - complications Pneumonia, Viral - mortality Pneumonia, Viral - pathology Pneumonia, Viral - virology portal fibrosis Portal Vein - pathology SARS-CoV-2 Thromboplastin - analysis Thromboplastin - metabolism tissue factor vascular liver disease Venous Thrombosis - etiology Venous Thrombosis - pathology Venous Thrombosis - virology von Willebrand factor |
| title | Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19 |
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