Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy
Open accessAbstract
Background and aims COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. Methods Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. Results Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. Conclusion IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. Lay summary Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
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In COVID-19 patients, both sgp130Fc and the JAK inhibitor ruxolitinib can block IL-6 trans-signaling, decreasing phosphorylation of JAK1 and STAT1/3, inhibiting proinflammatory factor production, and alleviating liver injury.
“As reported in COVID-19 patients, both sgp130Fc and JAK inhibitors ruxolitinib can block IL-6 trans-signaling with decreased phosphorylation of JAK1 and STAT1/3, resulting in the inhibition of proinflammatory factors production and the alleviation of liver injury [60].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [60]
The Results sections on soluble gp130 and ruxolitinib (page not provided) report that both blocked IL-6 trans-signaling-induced JAK1 and STAT1/3 phosphorylation and proinflammatory-factor expression in liver sinusoidal endothelial cells. The patient data link IL-6 and endotheliopathy with liver injury, but the paper does not show that either treatment alleviated liver injury in COVID-19 patients. (LLM, conf=0.90)
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Cites
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
Ackermann, M., Verleden, S. E., Kuehnel, M., Haverich, A., Welte, T., Laenger, F., Vanstapel, A., Werlein, C., Stark, H., Tzankov, A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2015432 · Cited by 5,613 · see citing works
Tang, N., Li, D., Wang, X., & Sun, Z.-Y. (2020) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14768 · Cited by 5,527 · see citing works
Self-citationPanigada, M., Bottino, N., Tagliabue, P. F., Grasselli, G., Novembrino, C., Chantarangkul, V., Pesenti, A., Peyvandi, F., & Tripodi, A. (2020) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14850 · Cited by 1,315 · see citing works
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
Salama, C., Han, J., Yau, L., Reiss, W. G., Krämer, B., Neidhart, J. D., Criner, G. J., Kaplan‐Lewis, E., Baden, R. P., Pandit, L. M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2030340 · Cited by 1,285 · see citing works
ACG clinical guideline: evaluation of abnormal liver chemistries
Kwo, P. Y., Cohen, S. M., & Lim, J. K. (2017) · American Journal of Gastroenterology · doi:10.1038/ajg.2016.517 · Cited by 1,222 · cited 1× · see citing works
“The upper limit of normal for ALT was defined as 33 IU/L for males and 25 IU/L for females.(24) Within this sample, thromboelastography (TEG) was performed for the 48 patients in the intensive care unit.”
Goshua, G., Pine, A., Meizlish, M. L., Chang, C.-H., Zhang, H.-M., Bahel, P., Baluha, A., Bar, N., Bona, R., Burns, A. J., et al. (2020) · The Lancet Haematology · doi:10.1016/s2352-3026(20)30216-7 · Cited by 918 · cited 4× · see citing works
“Endotheliopathy has been observed not only in the liver but also in the lung,37 and markers of systemic endotheliopathy, such as plasminogen activator inhibitor 1 and soluble thrombomodulin, are elevated in COVID19.”
InfluentialSelf-citationIL-6 pathway in the liver: From physiopathology to therapy
Schmidt-Arras, D., & Rose-John, S. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.004 · Cited by 881 · cited 7× · see citing works
“For further details regarding the materials and methods used, please refer to the CTAT table and supplementary information, which provide further information on: histological examinations, immunofluorescence, human primary LSECs, primary mouse hepatocytes, platelets, chemicals and reagents, western blot analysis, quan…”
InfluentialNishimoto, N., Terao, K., Mima, T., Nakahara, H., Takagi, N., & Kakehi, T. (2008) · Blood · doi:10.1182/blood-2008-05-155846 · Cited by 781 · see citing works
The soluble interleukin 6 receptor: mechanisms of production and implications in disease
Jones, S. A., Horiuchi, S., Topley, N., Yamamoto, N., & Fuller, G. M. (2001) · The FASEB Journal · doi:10.1096/fj.99-1003rev · Cited by 684 · see citing works
Lisman, T., Bongers, T., Adelmeijer, J., Janssen, H., de Maat, M. D., de Groot, P. D., & Leebeek, F. (2006) · Hepatology · doi:10.1002/hep.21231 · Cited by 611 · cited 1× · see citing works
“Third, our demonstration of elevated factor VIII and vWF in patients with liver injury suggests LSEC endotheliopathy in particular, because LSECs are the major producer of factor VIII in the body and vWF upregulation is a well-established phenomenon in liver pathology.(33) On liver histology, steatosis and mild inflam…”
Elevated interleukin‐6 and severe COVID‐19: A meta‐analysis
Aziz, M., Fatima, R., & Assaly, R. (2020) · Journal of Medical Virology · doi:10.1002/jmv.25948 · Cited by 515 · see citing works
Rapkiewicz, A., Mai, X., Carsons, S., Pittaluga, S., Kleiner, D., Berger, J., Thomas, S. V., Adler, N., Charytan, D., Gasmi, B., et al. (2020) · EClinicalMedicine · doi:10.1016/j.eclinm.2020.100434 · Cited by 509 · cited 1× · see citing works
“On liver histology, steatosis and mild inflammatory infiltration in the hepatic lobule and portal tract have been previously observed in patients with COVID-19,(6,34) and several papers have shown sinusoidal thrombosis.(6,35) Our data defines the presence of a procoagulant endotheliopathy in the liver, linking increas…”
Cao, Y., Wei, J., Zou, L., Jiang, T., Wang, G., Chen, L., Huang, L., Meng, F., Huang, L., Wang, N., et al. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.05.019 · Cited by 456 · see citing works
Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation
Gu, S. X., Tyagi, T., Jain, K., Gu, V. W., Lee, S. H., Hwa, J. M., Kwan, J. M., Krause, D. S., Lee, A. I., Halene, S., et al. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00469-1 · Cited by 414 · cited 1× · see citing works
“Discussion Endotheliopathy and a procoagulant state are highly prevalent in COVID-19, and thrombotic complications are a key cause of morbidity and mortality.(26) Our study demonstrates an association between liver injury in COVID-19 and endotheliopathy, and defines a potential thromboinflammatory mechanism likely dri…”
Self-citationPhipps, M. M., Barraza, L. H., LaSota, E. D., Sobieszczyk, M. E., Pereira, M. R., Zheng, E. X., Fox, A. N., Zucker, J. E., & Verna, E. C. (2020) · Hepatology · doi:10.1002/hep.31404 · Cited by 358 · cited 3× · see citing works
“1C) in patients with liver injury, consistent with prior reports.(3) IL-6 additionally exhibited significant positive correlations with levels of vWF antigen (p = 0.”
Zegeye, M. M., Lindkvist, M., Fälker, K., Kumawat, A., Paramel, G., Grenegård, M., Sirsjö, A., & Ljungberg, L. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0268-4 · Cited by 343 · see citing works
Kang, S., Tanaka, T., Inoue, H., Ono, C., Hashimoto, S., Kioi, Y., Matsumoto, H., Matsuura, H., Matsubara, T., Shimizu, K., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2010229117 · Cited by 328 · see citing works
Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations
Sonzogni, A., Previtali, G., Seghezzi, M., Alessio, M. G., Gianatti, A., Licini, L., Morotti, D., Zerbi, P., Carsana, L., Rossi, R., et al. (2020) · Liver International · doi:10.1111/liv.14601 · Cited by 291 · cited 3× · see citing works
“On liver histology, steatosis and mild inflammatory infiltration in the hepatic lobule and portal tract have been previously observed in patients with COVID-19,(6,34) and several papers have shown sinusoidal thrombosis.(6,35) Our data defines the presence of a procoagulant endotheliopathy in the liver, linking increas…”
Self-citationCOVID-19 as the Leading Cause of Death in the United States
Woolf, S., Chapman, D., & Lee, J. H. (2020) · Journal of the American Medical Association (JAMA) · doi:10.1001/jama.2020.24865 · Cited by 281 · cited 2× · see citing works
“COVID-19 has led to a global pandemic and has become the leading cause of death in the United States.1 Liver injury (elevated values of liver biochemical tests) is a common feature of COVID-192 associated with adverse outcomes such as intensive care unit admission/mechanical ventilation and death.3,4 Liver injury in C…”
Hundt, M. A., Deng, Y., Ciarleglio, M. M., Nathanson, M. H., & Lim, J. K. (2020) · Hepatology · doi:10.1002/hep.31487 · Cited by 247 · see citing works
Patra, T., Meyer, K., Geerling, L., Isbell, T. S., Hoft, D. F., Brien, J. D., Pinto, A. K., Ray, R. B., & Ray, R. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1009128 · Cited by 221 · see citing works
Expression of Factor VIII by Murine Liver Sinusoidal Endothelial Cells*
Hung, D., Healey, J., Waller, E., & Lollar, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.28.19587 · Cited by 214 · cited 2× · see citing works
“We next investigated whether knockdown of STAT1/3 affects the protein expression of factor VIII.(30) In LSECs treated with complex, protein expression of factor VIII (0.”
InfluentialMagro, G. (2020) · Cytokine X · doi:10.1016/j.cytox.2020.100029 · Cited by 214 · see citing works
Falasca, L., Nardacci, R., Colombo, D., Lalle, E., Di, A., Nicastri, E., Antinori, A., Petrosillo, N., Marchioni, L., Biava, G., et al. (2020) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiaa578 · Cited by 195 · see citing works
Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII
Shahani, T., Covens, K., Lavend'homme, R., Jazouli, N., Sokal, E., Peerlinck, K., & Jacquemin, M. (2014) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12412 · Cited by 188 · see citing works
IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
Bergmann, J., Müller, M., Baumann, N., Reichert, M., Heneweer, C., Bolik, J., Lücke, K., Gruber, S., Carambia, A., Boretius, S., et al. (2017) · Hepatology · doi:10.1002/hep.28874 · Cited by 152 · see citing works
Fibrinogen Promotes Neutrophil Activation and Delays Apoptosis1
Rubel, C., Fernández, G., Dran, G., Bompadre, M., Isturiz, M., & Palermo, M. (2001) · Journal of Immunology · doi:10.4049/jimmunol.166.3.2002 · Cited by 150 · see citing works
Elevated interleukin‐6 is associated with severity of COVID‐19: A meta‐analysis
Zhu, J.-Y., Pang, J.-L., Ji, P., Zhong, Z., Li, H.-Y., Li, B., & Zhang, J.-F. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26085 · Cited by 117 · see citing works
Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation
Chatterjee, P. K., Al‐Abed, Y., Sherry, B. A., & Metz, C. N. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00160.2009 · Cited by 111 · cited 2× · see citing works
“Transsignaling occurs with IL-6 binding to a soluble form of the receptor alpha subunit (sIL-6R), which is typically increased in inflammatory conditions,(17) to form an IL-6/sIL-6R complex, which then interacts with the beta subunit (gp130) on target cells that may not express IL-6Ra.(18,19) IL-6 trans-signaling is t…”
Systemic inflammation as fuel for acute liver injury in COVID-19
Effenberger, M., Grander, C., Grabherr, F., Griesmacher, A., Ploner, T., Hartig, F., Bellmann-Weiler, R., Joannidis, M., Zoller, H., Weiss, G., et al. (2020) · Digestive and Liver Disease · doi:10.1016/j.dld.2020.08.004 · Cited by 87 · cited 1× · see citing works
“IL-6 is a hallmark cytokine of severe COVID-19(12,13) and is associated with liver injury in the disease.(14) IL-6 induces downstream signaling via Janus kinase (JAK)/signal transducer and activator of transcription (STAT) activation through 2 pathways.”
Liver disease and COVID-19: from Pathogenesis to Clinical Care
Saviano, A., Wrensch, F., Ghany, M., & Baumert, T. (2020) · Hepatology · doi:10.1002/hep.31684 · Cited by 75 · see citing works
Vannucchi, A. M., Sordi, B., Morettini, A., Nozzoli, C., Poggesi, L., Pieralli, F., Bartoloni, A., Atanasio, A., Miselli, F., Paoli, C., et al. (2020) · Leukemia · doi:10.1038/s41375-020-01018-y · Cited by 73 · see citing works
Ward, L. D., Hammacher, A., Howlett, G., Matthews, J., Fabri, L., Moritz, R., Nice, E., Weinstock, J., & Simpson, R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.33.20138 · Cited by 67 · cited 2× · see citing works
“Classical IL-6 signaling is via IL-6 binding to the ligand-binding alpha subunit of its receptor (gp80/IL-6Ra) and subsequently recruiting the signaling beta subunit (glycoprotein 130 [gp130]) to induce downstream signaling.(15,16) Transsignaling occurs with IL-6 binding to a soluble form of the receptor alpha subunit…”
Vermes, C., Jacobs, J., Zhang, J., Firneisz, G., Roebuck, K., & Glant, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200546200 · Cited by 66 · cited 2× · see citing works
“Classical IL-6 signaling is via IL-6 binding to the ligand-binding alpha subunit of its receptor (gp80/IL-6Ra) and subsequently recruiting the signaling beta subunit (glycoprotein 130 [gp130]) to induce downstream signaling.(15,16) Transsignaling occurs with IL-6 binding to a soluble form of the receptor alpha subunit…”
Rubel, C., Fernández, G., Rosa, F., Gomez, S., Bompadre, M., Coso, O., Isturiz, M., & Palermo, M. (2002) · Journal of Immunology · doi:10.4049/jimmunol.168.7.3527 · Cited by 62 · see citing works
Linking inflammation and thrombosis: Role of C-reactive protein.
Fay, W. P. (2010) · World Journal of Cardiology · doi:10.4330/wjc.v2.i11.365 · Cited by 56 · see citing works
Montgomery, A., Tam, F., Gursche, C., Cheneval, C., Besler, K., Enns, W., Manku, S., Rey, K., Hanson, P., Rose-John, S., et al. (2021) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00323.2020 · Cited by 50 · cited 1× · see citing works
“LSECs have been previously shown to react to IL-6 transsignaling with increased angiogenesis,(38) but our data also show that they can adopt a proinflammatory, procoagulant phenotype similar to that of other endothelial cells in response to IL-6 transsignaling.(18,39) Because the global endotheliopathy of COVID-19 has…”
Wang, J., Wang, Q., Han, T., Li, Y., Zhu, S., Ao, F., Feng, J. J., Jing, M.-Z., Wang, L., Ye, L., et al. (2014) · Cellular and Molecular Immunology · doi:10.1038/cmi.2014.80 · Cited by 45 · see citing works
Association of coagulopathy with liver dysfunction in patients with COVID‐19
Tsutsumi, T., Saito, M., Nagai, H., Yamamoto, S., Ikeuchi, K., Lim, L. A., Adachi, E., Koga, M., Okushin, K., Akai, H., et al. (2020) · Hepatology Research · doi:10.1111/hepr.13577 · Cited by 29 · cited 1×
“Liver injury in COVID-19 has been associated with elevated interleukin 6 (IL-6)(3,5) and some hypercoagulable parameters, with evidence of microthrombi on liver histopathology.(3,6,7) These findings suggest a role for vascular pathology in liver injury in COVID-19, but mechanistic details are lacking.”
Ponziani, F., Nesci, A., Zompo, F. D., Santopaolo, F., Pompili, M., & Gasbarrini, A. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.05.103 · Cited by 8
Flagged first, then by citations
7 of the 47 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- [27]Kondo R, Yano H, Nakashima O, Tanikawa K, Nomura Y, Kage M. Accumulation of platelets in the liver may be an important contributory factor to thrombocytopenia and liver fibrosis in chronic hepatitis C. J Gastroenterol 2013; 48: 526– 534. 22911171
- [31]Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res 2007; 100: 1673– 1685. 17585075
Cited by
Sorted by citations
Targeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524 · see citing works
“Such IL-6 trans-signalling-mediated increases in coagulation factors were efficiently inhibited by sgp130Fc in liver sinusoidal endothelial cells 141 .”
Xu, S., Ilyas, I., & Weng, J. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00998-0 · Cited by 444 · see citing works
“A recent study [35] has reported that IL-6 transsignaling in LSECs leads to endotheliopathy and liver injury in COVID19 patients.”
BackgroundThe evolving role of liver sinusoidal endothelial cells in liver health and disease
McConnell, M. J., Kostallari, E., Ibrahim, S. H., & Iwakiri, Y. (2023) · Hepatology · doi:10.1097/hep.0000000000000207 · Cited by 189 · see citing works
“…increased expression of procoagulant Factor VIII along with increased platelet and neutrophil adhesion is associated with acute liver injury and systemic coagulopathy in COVID-19 infection, with IL-6 trans-signaling as a potential mechanism of procoagulant and proinflammatory changes in LSECs(113).”
Self-citationThe double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J. (2024) · Experimental Hematology & Oncology · doi:10.1186/s40164-024-00527-1 · Cited by 84 · see citing works
“These neutralizing antibodies or small molecules against IL-6 signaling have been approved for the clinical treatment of inflammatory diseases, metabolic diseases, and cancers injury [60].”
BackgroundNing, Q., Wu, D., Wang, X., Xi, D., Chen, T., Chen, G., Wang, H., Lü, H., Wang, M., Zhu, L., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00907-1 · Cited by 82 · see citing works
“In the liver sinusoidal endothelial cells (LSEC), IL-6 trans-signaling leads to proinflammatory and procoagulant states endothelial lesions, and liver injury in COVID-19.(124) In addition, macrophage and complement activation(125) play a crucial role in endothelial damage and thrombosis in SARS-CoV-2 infection.”
BackgroundSARS-CoV-2 Spike Protein Induces Paracrine Senescence and Leukocyte Adhesion in Endothelial Cells
Meyer, K., Patra, T., Vijayamahantesh, & Ray, R. (2021) · Journal of Virology · doi:10.1128/jvi.00794-21 · Cited by 71 · see citing works
“expression of adhesion molecules, and leukocyte extravasation (25).”
BackgroundMcConnell, M., Kondo, R., Kawaguchi, N., & Iwakiri, Y. (2021) · Hepatology Communications · doi:10.1002/hep4.1843 · Cited by 60 · see citing works
Self-citationXu, S., Liu, Y.-J., Ding, Y., Luo, S.-H., Zheng, X.-Y., Wu, X., Liu, Z.-H., Ilyas, I., Chen, S., Han, S., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00690-5 · Cited by 56 · see citing works
“COVID-19 is recently reported to be associated with elevated markers of inflammation, coagulation and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, which represents a new mechanism of liver injury caused by SARSCoV-2 infection.(34) However, the precise mechanism underlying these features of…”
BackgroundLi, P.-H., Liu, Y., Cheng, Z.-Q., Yu, X.-R., & Li, Y.-X. (2022) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2022.113568 · Cited by 53 · see citing works
“damaging changes in LSECs and may promote coagulation, leading to liver injury [63].”
Ni, R., Jiang, L., Zhang, C., Liu, M., Luo, Y., Hu, Z., Mou, X., & Zhu, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098358 · Cited by 46 · see citing works
Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis
He, S., Luo, Y., Ma, W., Wang, X. Y., Yan, C., Hao, W., Fang, Y., Su, H., Lai, B., Liu, J., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.02.032 · Cited by 53 · see citing works
Tissue factor in COVID-19-associated coagulopathy
Subramaniam, S., Kothari, H., & Bosmann, M. (2022) · Thrombosis Research · doi:10.1016/j.thromres.2022.09.025 · Cited by 53 · see citing works
Role of SARS-CoV-2 -induced cytokines and growth factors in coagulopathy and thromboembolism
Ahmad, F., Kannan, M., & Ansari, A. W. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.10.007 · Cited by 50 · see citing works
COVID‐19 and the liver: A 2021 update
Spearman, C. W., Aghemo, A., Valenti, L. V. C., & Sonderup, M. W. (2021) · Liver International · doi:10.1111/liv.14984 · Cited by 40 · see citing works
SARS-CoV-2 infection and liver involvement
Luo, M., Ballester, M., Soffientini, U., Jalan, R., & Mehta, G. (2022) · Hepatology International · doi:10.1007/s12072-022-10364-1 · Cited by 39 · see citing works
“demonstrated elevated IL-6 in COVID-19 may lead to hepatic endotheliopathy due to sinusoidal endothelial cell dysfunction, contributing to liver injury [15].”
BackgroundChew, M., Tang, Z.-Y., Radcliffe, C., Caruana, D., Doilicho, N., Ciarleglio, M., Deng, Y., & Garcia-Tsao, G. (2021) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2021.05.022 · Cited by 38
Wilson, A. D., & Forse, L. B. (2023) · Sensors · doi:10.3390/s23062887 · Cited by 42 · see citing works
“High levels of interleukin6 (IL-6) and its circulating receptor, which form a complex to induce the inflammatory signal, have been observed in patients with COVID-19 [76].”
BackgroundZhao, S., Li, Y.-M., Li, Y.-L., & Su, C. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i2.241 · Cited by 30 · see citing works
Kondo, R., Kawaguchi, N., McConnell, M., Sonzogni, A., Licini, L., Valle, C., Bonaffini, P. A., Sironi, S., Alessio, M., Previtali, G., et al. (2021) · Hepatology Research · doi:10.1111/hepr.13696 · Cited by 30
“Platelet microthrombi is also known to exist in other pathological conditions, including thrombotic microangiopathy,8 chronic hepatitis/cirrhosis,9 and SOS.10 Platelet microthrombi formation in SOS depends on unusually large vWF multimer release from injured LSECs.10 von Willebrand factor mediates platelet adhesion to…”
BackgroundInfluentialSelf-citationAngelis, M. D., Della-Morte, D., Buttinelli, G., Martino, A. D., Pacifici, F., Checconi, P., Ambrosio, L., Stefanelli, P., Palamara, A., Garaci, E., et al. (2021) · Biomedicines · doi:10.3390/biomedicines9111721 · Cited by 29
“IL-6 production shows a key role in virus-mediated inflammation and, in particular, on COVID-19 complications [28,29].”
BackgroundIdentification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19
Rodríguez-Hernández, M. A., Carneros, D., Núñez-Núñez, M., Coca, R., Baena, R., López-Ruiz, G. M., Cano-Serrano, M. E., Martínez-Tellería, A., Fuentes-López, A., Praena-Fernández, J., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.891456 · Cited by 28 · see citing works
“It has been implicated in the endotheliopathy in COVID-19 (24, 25), with a central role in the pathogenesis of ARDS and multi-organ failure (23).”
BackgroundEndothelial RUNX3 controls LSEC dysfunction and angiocrine LRG1 signaling to prevent liver fibrosis
Ojha, U., Kim, S., Rhee, C. Y., You, J., Choi, Y. H., Yoon, S.-H., Park, S. Y., Lee, Y. R., Kim, J. K., Bae, S., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000001018 · Cited by 33 · see citing works
“[39] In TMNK-1 cells treated with the IL-6/ sIL-6R complex (trans-signaling), the expression of proinflammatory cytokines was significantly increased compared with that in TMNK-1 cells treated with IL-6 alone, suggesting that IL-6 trans-signaling may be involved in ( 2 P T X - S13A, http://…”
InfluentialLi, Y., Ren, H.-C., & Cao, J.-H. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109005 · Cited by 33 · see citing works
Organokines in COVID-19: A Systematic Review
Barbalho, S., Minniti, G., Miola, V. F. B., Haber, J. F. D. S., Bueno, P. C. D. S., Haber, L. S. D. A., Girio, R. J., Detregiachi, C. R. P., Dall’Antonia, C. T., Rodrigues, V. D., et al. (2023) · Cells · doi:10.3390/cells12101349 · Cited by 22 · see citing works
Rodríguez-Hernández, M. A., Baena-Bustos, M., Carneros, D., Zurita-Palomo, C., Muñoz-Pinillos, P., Millán, J., Padillo, F. J., Smerdou, C., von Kobbe, C., Rose-John, S., et al. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105132 · Cited by 19 · see citing works
“IL-6 trans-signalling underlies various in fl ammatory conditions such as autoimmune disease, sepsis, cytokine release syndrome, 55 SARS-CoV-2 infection, 34,37,56 and other chronic conditions: asthma, 57 rheumatoid arthritis, 58 in fl ammatory bowel disease, 59 neurodegenerative disorders.”
InfluentialNon-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier?
Dietrich, C. G., Geier, A., & Merle, U. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i2.367 · Cited by 22 · see citing works
Ma, X.-Y., Liang, J., Zhu, G.-H., Bhoria, P., Shoara, A. A., MacKeigan, D., Khoury, C. J., Slavkovic, S., Lin, L., Karakas, D., et al. (2023) · Research · doi:10.34133/research.0124 · Cited by 17 · see citing works
“Given the importance of the hepatocytes in the production of coagulation factors, an altered function may contribute to coagulopathy, a common symptom in advanced COVID-19 [78].”
BackgroundMolecular and cellular mechanisms involved in tissue-specific metabolic modulation by SARS-CoV-2
dos Santos, A. A. C., Rodrigues, L. E., Alecrim, A. L., Ferreira, L. D. A., Trettel, C. D. S., Gimenes, G. M., da Silva, A. F., Filho, C. P. B. S., Serdan, T. D. A., Levada‐Pires, A. C., et al. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1037467 · Cited by 13 · see citing works
COVID-19 and hepatic injury: Diversity and risk assessment
Ali, F. E. M., El‐Aziz, M. K. A., Ali, M. M., Ghogar, O. M., & Bakr, A. G. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i3.425 · Cited by 14 · see citing works
Jiang, P., Ye, J., Jia, M.-W., Li, X.-P., Wei, S., & Li, N.-H. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.960267 · Cited by 15 · see citing works
“lymphocytes, thus participating in anti-infective immunity and autoimmunity (Choy et al., 2020; McConnell et al., 2021).”
BackgroundElemam, N., Hammoudeh, S., Salameh, L., Mahboub, B., Alsafar, H. S., Talaat, I., Habib, P. T., Siddiqui, M., Hassan, K., Al-assaf, O., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.865845 · Cited by 15 · see citing works
“org 14 IL-6 trans-signaling drives COVID-19-associated hepatic endotheliopathy, which is suggested as a possible mechanism underlying the liver injury (29).”
BackgroundSevere acute respiratory syndrome coronavirus-2-associated cholangiopathies
Bartoli, A., Cursaro, C., & Andreone, P. (2021) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000808 · Cited by 15
Acute and Chronic Cardiovascular Manifestations of COVID-19: Role for Endotheliopathy
Cooke, J. P., Connor, J. H., & Jain, A. (2021) · Methodist DeBakey Cardiovascular Journal · doi:10.14797/mdcvj.1044 · Cited by 27 · see citing works
Yin, G.-L., Liang, H.-Y., Sun, W.-X., Zhang, S.-Z., Feng, Y.-N., Liang, P., Chen, S.-T., Liu, X., Pan, W., & Zhang, F.-X. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1016745 · Cited by 14 · see citing works
“When liver damage occurs, significant increases in the levels of serum transaminases, including ALT and AST, were found (McConnell et al., 2021).”
BackgroundNicastro, E., Ebel, N., Kehar, M., Czubkowski, P., Ng, V., Michaels, M., Lobritto, S., Martinez, M., & Indolfi, G. (2021) · Journal of Pediatric Gastroenterology and Nutrition - JPGN · doi:10.1097/mpg.0000000000003339 · Cited by 13 · see citing works
“Indirect means of SARS-CoV2-related liver injury are thought to be the systemic inflammatory IL-6 and IL-10 cytokine milieu (21) , hypoxic-ischemic damage, vascular endothelial changes (22) , and drug-induced liver injury from SARS-CoV2 directed therapies (23, 24) .”
BackgroundThe Role of SARS-CoV-2 Nucleocapsid Protein in Host Inflammation
Cao, Y., Wang, Y., Huang, D.-G., & Tan, Y. (2025) · Viruses · doi:10.3390/v17081046 · Cited by 12 · see citing works
“Its signaling has been linked to coagulopathy and hepatic endotheliopathy in COVID-19 pneumonia, contributing to the progression of liver injury [81].”
Ettich, J., Werner, J., Weitz, H. T., Mueller, E.-C., Schwarzer, R., Lang, P. A., Scheller, J., & Moll, J. M. (2021) · Journal of Virology · doi:10.1128/jvi.01622-21 · Cited by 10 · see citing works
“blood clotting and liver injury factors (64).”
BackgroundChen, X., Yang, J., Cao, H.-H., Fang, X., Liu, S.-H., Zou, L.-F., Yu, J.-H., Zuo, J.-P., Zhao, W., Lu, Z.-B., et al. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154977 · Cited by 9
Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury
Akkız, H. (2023) · Viruses · doi:10.3390/v15061287 · Cited by 9 · see citing works
“Baseline levels of sIL-6R are relatively high and were indicated to increase in COVID-19 [69–73].”
BackgroundInfluentialLiver injury in COVID-19: A minireview
Hu, W.-S., Jiang, F.-Y., Shu, W.-T., Zhao, R., Cao, J.-M., & Wang, D.-P. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i47.6716 · Cited by 9 · see citing works
Wang, J., Sun, Q., Wang, G., Wang, H., & Liu, H. (2022) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2022.104372 · Cited by 9 · see citing works
Jiang, S.-T., Liu, Y., Zhang, L., Sang, X., Xu, Y.-Y., & Lu, X. (2022) · European Journal of Medical Research · doi:10.1186/s40001-022-00865-y · Cited by 8 · see citing works
Portal Hypertension in Alcohol-Associated Hepatitis
McConnell, M., & Iwakiri, Y. (2023) · Current Hepatology Reports · doi:10.1007/s11901-023-00601-y · Cited by 7
Self-citationGunji, M., Sawa, C., Akiyama, M., Mukai, S., Takaki, T., Kang, D.-D., & Honda, K. (2023) · Medical Molecular Morphology · doi:10.1007/s00795-022-00347-4 · Cited by 7
“They also revealed the cultured LSECs stimulated by IL-6 produced proinflammatory cytokines through JAK1-STAT1/3 signaling [45].”
BackgroundUnraveling the role of liver sinusoidal endothelial cells in COVID-19 liver injury
Saviano, A., & Baumert, T. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.07.008 · Cited by 7 · see citing works
“ing to McConnell, Kawaguchi et al.(14) SARS-CoV-2 infection induces a systemic IL-6R and gp130.”
InfluentialmTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS
Bar‐Tana, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06220-z · Cited by 10 · see citing works
Host determinants and responses underlying SARS-CoV-2 liver tropism.
Heinen, N., Klöhn, M., Westhoven, S., Brown, R. J. P., & Pfaender, S. (2024) · Current Opinion in Microbiology · doi:10.1016/j.mib.2024.102455 · Cited by 6 · see citing works
Fiel, M., & Schiano, T. (2023) · Surgical Pathology Clinics · doi:10.1016/j.path.2023.04.003 · Cited by 6
COVID-19 and the Liver: A Complex and Evolving Picture
Taylor-Robinson, S., & Morgan, M. Y. (2023) · Hepatic Medicine : Evidence and Research · doi:10.2147/hmer.s384172 · Cited by 5
Non-metabolic causes of steatotic liver disease
Nasr, P., Jönsson, C., Ekstedt, M., & Kechagias, S. (2023) · Metabolism and Target Organ Damage · doi:10.20517/mtod.2023.20 · Cited by 5 · see citing works
SARS-CoV-2: Possible role in children with acute hepatitis of unknown origin
Yu, R., Chen, A.-L., & Zhang, Y.-J. (2023) · hLife · doi:10.1016/j.hlife.2023.10.008 · Cited by 5 · see citing works
Endotheliopathy of liver sinusoidal endothelial cells in liver disease
Kondo, R., Iwakiri, Y., Kage, M., & Yano, H. (2023) · Pathology International · doi:10.1111/pin.13361 · Cited by 5 · see citing works
“We demonstrated that IL‐6 trans‐signaling produces a hypercoagulable and inflammatory LSEC phenotype through JAK/STAT activation, blocked by JAK inhibitors.(22) As shown in Figure 5, neutrophil infiltration and microthrombus formation in liver sinusoids are promoted by the inflammatory endotheliopathy of LSECs via IL‐…”
BackgroundInfluentialSelf-citationCooper, K., Colletta, A., Asirwatham, A. M., Simas, T. M. M., & Devuni, D. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i42.6017 · Cited by 5 · see citing works
Severe acute hepatitis in children with unknown aetiology, etiology analysis and the next action
Gao, Y., Wang, L.-J., Wang, L., & Lu, F.-M. (2022) · Virologica Sinica · doi:10.1016/j.virs.2022.07.004 · Cited by 5
Yan, P., Yu, X.-P., Chen, Z., Lan, L.-J., Kang, J., Zhao, B.-N., & Liu, D.-F. (2025) · BMC Gastroenterology · doi:10.1186/s12876-025-03770-w · Cited by 4 · see citing works
“An early series of autopsy liver biopsies from COVID-19 patients reported that at least 50% of the patients exhibited portal or sinusoidal vascular thrombosis [6], and COVID-19 patients also demonstrated coagulopathy and endotheliopathy [7].”
Sheng, H., Liang, Y., Lauschke, V. M., & Wang, Y. (2025) · Engineering · doi:10.1016/j.eng.2025.01.019 · Cited by 4 · see citing works
Subramaniam, S., Jose, A., Kenney, D., O'Connell, A., Bosmann, M., Douam, F., & Crossland, N. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1443932 · Cited by 4
Bartoli, A., Cursaro, C., Seferi, H., & Andreone, P. (2023) · Hepatic Medicine : Evidence and Research · doi:10.2147/hmer.s384220 · Cited by 4
“Among these cells, liver sinusoidal endothelial cells (LSECs), stimulated by IL-6, determine the production of high amounts of pro-inflammatory mediators (chemokine C-X-C ligand 1–2, IL-6), procoagulant factors (factor VIII and von Willebrand factor), and adhesion molecules (P and E-selectin, intercellular adhesion mo…”
BackgroundInfluentialOrchestrated regulation of immune inflammation with cell therapy in pediatric acute liver injury
Duan, M., Liu, X., Yang, Y., Zhang, Y., Wu, R., Lv, Y., & Lei, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1194588 · Cited by 4 · see citing works
“IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19, which could be a possible mechanism behind liver injury as well (77).”
BackgroundGupta, P., Dev, K., & Kaur, G. (2024) · Phytotherapy Research · doi:10.1002/ptr.8302 · Cited by 3 · see citing works
“Elevated alanine aminotransferase in addition to higher level of pro-inflammatory mediators (IL-6, CXCL1/2, ICAM1, P-selectin, E-selectin), procoagulant factor (factor VIII, vWF), factor II, fibrinogen, platelet marker (CD61) and activation of JAK/STAT 1/3 pathway were seen (McConnell et al., 2021).”
Impact of baseline abnormal liver enzymes in the outcome of COVID-19 infection
Farías, J. P., Codes, L., Vinhaes, D., Amorim, A. P., D'Oliveira, R., Farias, A., & Bittencourt, P. (2021) · Translational Gastroenterology and Hepatology · doi:10.21037/tgh-22-41 · Cited by 3 · see citing works
COVID-19 Infection, Drugs, and Liver Injury
Qiu, D., Cao, W., Zhang, Y., Hao, H., Wei, X. C., Yao, L., Wang, S., Gao, Z., Xie, Y., & Li, M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14207228 · Cited by 3 · see citing works
“Its function is not limited to directly damaging liver sinusoidal endothelial cells leading to liver injury [86], but can also become a key activator of coagulation diseases by inducing tissue factor expression, promoting fibrinogen and platelet production.”
InfluentialLuo, Y.-W., Huang, A.-L., & Tang, K.-F. (2025) · World Journal of Gastroenterology · doi:10.3748/wjg.v31.i6.100864 · Cited by 2
Maimunah, U., Maharani, A. R., Soegiarto, G., Rahniayu, A., Gunawan, V., Wiratama, P. A., Djuanda, S. N., Supriadi, S., Marhana, I. A., Semedi, B., et al. (2023) · Narra J · doi:10.52225/narra.v3i3.463 · Cited by 2 · see citing works
“Several reported investigations focused mainly on serum or systemic IL-6 and other inflammatory markers and their association with liver injury in COVID-19 patients [9-11, 36, 37 ].”
BackgroundGranados, A. A., Bucher, S., Agrawal, A., Song, H., Chen, A. T., Peng, T., Neff, N. F., Pisco, A. O., Huang, F. W., & Wang, B. (2023) · eLife · doi:10.7554/elife.81090 · Cited by 4 · see citing works
“However, we observed an inverse trend for endothelial cells, where approximately 20% of the cells from healthy samples were annotated as endothelial as opposed to less than 10% in COVID-19 donors, which may reflect recently reported endotheliopathy in COVID-19 livers ( McConnell et al., 2021 ).”
ResultKutlutürk, I., Tokuc, E. O., Karabas, L., Rückert, R., Kaya, M., Karagöz, A., & Munk, M. R. (2023) · Immunologic research · doi:10.1007/s12026-023-09412-1 · Cited by 2 · see citing works
“McConnell COVID-19 [44].”
Neymark, M., Epp, D. П., Nikolaeva, M., Momot, A., Proskurin, S. Н., Karkavina, A., Kontseba, V. V., & Mekshun, C. V. (2022) · Messenger of Anesthesiology and Resuscitation · doi:10.21292/2078-5658-2022-19-3-15-24 · Cited by 2
Bustos, M., & Rodríguez-Hernández, M. Á. (2026) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2026.120198 · Cited by 1 · see citing works
Acute Promyelocytic Leukemia Accompanied with Venous Thrombosis Subsequent to Upadacitinib Therapy
Wang, H., Su, Z., Fan, F., Ma, X., Wang, Y.-S., & Wang, W. (2025) · Indian Journal of Hematology and Blood Transfusion · doi:10.1007/s12288-025-02187-5 · Cited by 1
“② Upadaci-tinib may enhance coagulation activity [13].”
Toxicities Associated with Systemic Administration of Interleukin-6 in Wistar Albino Rats
Nabisubi, P., Mugasa, C., Matovu, E., Ssekatawa, K., Uwituze, V., Ssentamu, G., Namayanja, M., & Kato, C. D. (2025) · Journal of Experimental Pharmacology · doi:10.2147/jep.s529995 · Cited by 1
“40 Administration of IFN has been associated with glomerulonephritis, tubulo-interstitial nephritis, systemic lupus erythe-matosus-like syndrome, and in some cases, thrombotic microangiopathy.”
Gázquez-Aguilera, E. M., Parrón-Carreño, T., Cristóbal-Cañadas, D., Nievas-Soriano, B., & Lozano-Paniagua, D. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14093192 · Cited by 1 · see citing works
“Prior research has proposed a thromboinflammatory mechanism connecting liver injury in COVID-19 to endotheliopathy, potentially mediated by IL-6 trans-signaling and subsequent elevation of coagulation factors [31].”
Hosseini, F., Azadmehr, A., Saleki, K., Ahmadifard, M., Oladnabi, M., Shirzad, M., & Javanian, M. (2025) · Health Science Reports · doi:10.1002/hsr2.70630 · Cited by 1 · see citing works
“According to this study, IL ‐ 6 signaling indicates a link between coagulopathy/ epitheliopathy and liver failure associated with COVID ‐ 19 [48].”
Fang, M., Li, J., Zhuang, B., Liang, W., Wang, L., Wang, C., Chen, W., Cai, F., Ruan, J., Huang, Z., et al. (2025) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1155/jcpt/5520102 · Cited by 1 · see citing works
de Souza, A. D., de Souza, A. D., Zimpel, C. K., Ayupe, M., de Araújo, M. V., Machado, R., Salles, É., Salgado, C. L., Tavares, M. S., Silva-Pereira, T. T., et al. (2024) · Revista do Instituto de Medicina Tropical de São Paulo · doi:10.1590/s1678-9946202466044 · Cited by 1
“In turn, this may be associated with sinusoidal endotheliopathy and activation of potential thromboinflammatory mechanisms related to liver injury in COVID-19 12,13 .”
InfluentialDevelopment of Biomarkers and Prognosis Model of Mortality Risk in Patients with COVID-19
Zhang, Z., Tang, L.-J., Guo, Y.-R., Guo, X., Pan, Z., Ji, X., & Gao, C. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s449497 · Cited by 1
“IL-6 29–31 Tocilizumab has been employed in the management of COVID-19 patients by disrupting the interaction between IL-6 to its receptor.”
MethodPepe-Mooney, B. J., Smith, C. J., Sherman, M. S., North, T., Padera, R. F., & Goessling, W. (2023) · Hepatology Communications · doi:10.1097/hc9.0000000000000290 · Cited by 1
“[43] Interestingly, SARS-CoV-2 has also been suggested to lead to platelet activation through the direct association of the virus in the serum with the ACE2 receptor expressed on platelets.”
BackgroundCOVID-19 and Liver Disease: An Evolving Landscape
Zhu, K., Tsai, O., Chahal, D., Hussaini, T., & Yoshida, E. (2023) · Seminars in liver disease (Print) · doi:10.1055/a-2157-3318 · Cited by 1 · see citing works
“These fi ndings have been supported by large studies involving 655 and 3,780 COVID-19 patients, 28,29 which correlated elevated transaminase levels with signi fi cantly higher in fl ammatory markers, including ferritin, LDH, CRP, and cytokines such as tumor necrosis factor-alpha (TNF-α ), interferon…”
BackgroundResultOobo, H., Inada, H., Setoyama, H., Narahara, S., Tanaka, K., Kurano, S., Tokunaga, T., Iio, E., Yoko, Y., Nagaoka, K., et al. (2023) · Kanzo · doi:10.2957/kanzo.64.270 · Cited by 1
Coronavirus disease 2019 in liver transplant patients: Clinical and therapeutic aspects
Loinaz-Segurola, C., Marcacuzco-Quinto, A., & Fernández-Ruiz, M. (2021) · World Journal of Hepatology · doi:10.4254/wjh.v13.i10.1299 · Cited by 1 · see citing works
Potential histopathological and immunological effects of SARS-CoV-2 on the liver
Alnamshan, M. M. (2022) · Brazilian Journal of Biology · doi:10.1590/1519-6984.262008 · Cited by 1 · see citing works
Ngamaleu, M., Tene, H., Djounda, R., Minomo, R., Besong, M., Awanakam, H., Djeukeng, C., Tchamda, K., Seumko'o, R., Feugo, T., et al. (2026) · PLoS ONE · doi:10.1371/journal.pone.0357503
Identification of Prognostic Factors and Regulatory Pathways in Porto‐Sinusoidal Vascular Disorder
Heo, S., Yoon, D., Shin, S., Youn, D., Yoo, Y., Song, I. H., Kang, H., Yoon, Y., Kim, K., Lee, S.-S., et al. (2026) · Liver international (Print) · doi:10.1111/liv.70898
Ueda, Y., Kawaguchi, N., Inomata, Y., Arima, J., Ishida, M., Ito, Y., Lee, S.-W., & Taniguchi, K. (2026) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.70782
Self-citationWhen, Where, and How Much: Toward Smarter Design and Delivery of CAR T‑Cell Therapy
Sathiyamoorthy, E., Poole, N., & Gustafson, H. H. (2026) · ACS Bio & Med Chem Au · doi:10.1021/acsbiomedchemau.6c00127
Hou, X.-F., Wang, Z.-K., Li, J.-H., Li, C.-X., Xu, Z.-H., Lu, Q.-L., Huang, J.-H., & James, T. D. (2026) · Sensors and actuators. B, Chemical · doi:10.1016/j.snb.2026.140851
Sun, C., Zheng, X.-B., Wang, H., & Xu, S.-L. (2026) · Infection and Drug Resistance · doi:10.2147/idr.s618431
“3–5 These pathological alterations may elevate capillary fragility and disrupt coagulation homeostasis in our patient, thereby amplifying the clinical hazards of minor local trauma induced by LMWH injection.”
Identifying MASLD Patients with MASH or Significant Fibrosis: The Role of Lower ALT Thresholds
Ma, Y., Yang, H., Zhao, Y.-Y., Han, P., Jin, Y.-Y., Zhao, L.-L., Liu, J., & Li, J. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15187212
“Notably, a significant proportion of MASLD patients develop MASH and significant fibrosis even in the setting of normal serum alanine aminotransferase (ALT) levels [6,7].”
Platelet-derived S100A9 contributes to endotheliopathy in alcohol-associated hepatitis
Kirlin, F., Fattahi, N., García-Milian, R., Collin, F., Wang, W., Kim, Y., Lucien, F., Sun, Z., Lam, T. T., Hwa, J., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.201114
Self-citationLi, S.-M., Feng, G.-C., Huang, X., Teng, X., Yang, Z.-Y., Liu, Y., Jiang, Y., Zhu, T., Liu, T., Xu, Y.-F., et al. (2026) · Exploration · doi:10.1002/exp2.70210
“In patients with COVID-19, IL6 signaling drives coagulopathy and hepatic endotheliopathy, leading to liver injury [ 42, 43 ].”
The immunopathological spectrum of COVID-19: from cytokine storm to autoimmunity—a systematic review
Dinc, H., Sarıbaş, S., & Kocazeybek, B. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1864452
“Furthermore, endothelial glycocalyx damage and IL-6-mediated signaling have been shown to promote a proinflammatory and procoagulant endothelial phenotype (22, 23).”
Schellens, J., Nagy, M., Hulshof, A., van Rosmalen, F., van Oerle, R., van Herpt, T. V., Alnima, T., Mulder, M., Hellenbrand, D., ten Cate, H., et al. (2026) · Thrombosis Research · doi:10.1016/j.thromres.2026.109723
Ma, W., Soulé, A., Allard, C., Durand, M., Tremblay, K., Rousseau, S., & Emad, A. (2026) · Communications Medicine · doi:10.1038/s43856-026-01520-x
“…cytokine associated with systemic in fl ammatoryresponsesyndrome 27 ,showntobeelevatedinsevereCOVID-19 28 andlinked toendothelialdamageandliverinjury 29 ;(c) ferritin, aniron-storage protein and acute phase reactant, elevated in COVID-19, and like other hyperferritinemic syndromes, associated with…”
Yu, J., Zhang, Y., Ye, Z., Tang, K., Ma, Y., Fu, L., Cui, T., Kang, H., Yuan, Y., & Pan, W. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s472099
A New Approach to Analyze the State of the Complement System in Patients with COVID-19. Pilot Study
Avdonin, P. P., Komleva, L. A., Blinova, M. S., Ivanova, E., Kotenko, O., Frolova, N. F., Stolyarevich, E., Rybakova, E. Y., & Avdonin, P. (2024) · Биологические мембраны Журнал мембранной и клеточной биологии · doi:10.31857/s0233475524020058
Victoria-Castro, A., Arora, T., Simonov, M., Biswas, A., Alausa, J., Subair, L., Gerber, B. A., Nguyen, A. T., Hsiao, A. L., Hintz, R., et al. (2023) · JMIR Formative Research · doi:10.2196/52120
Pathologic Characteristics of Digestive Tract and Liver in Patients with Coronavirus Disease 2019
Yang, C.-X., Cai, L.-J., & Xiao, S. (2022) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2022.09.003
- Authors
- McConnell, M. J., Kawaguchi, N., Kondo, R., Sonzogni, A., Licini, L., Valle, C., Bonaffini, P. A., Sironi, S., Alessio, M. G., Previtali, G., Seghezzi, M., Zhang, X., Lee, A. I., Pine, A. B., Chun, H. J., Zhang, X., Fernandez-Hernando, C., Qing, H., Wang, A., Price, C., Sun, Z., Utsumi, T., Hwa, J., Strazzabosco, M., & Iwakiri, Y.
- Affiliations
- Yale University (US)
- Kurume University (JP)
- Ospedale Papa Giovanni XXIII (IT)
- Johns Hopkins University (US)
- Corresponding author
- Iwakiri, Yasuko
- ORCID
- McConnell, Matthew J.
- Kawaguchi, Nao
- Kondo, Reiichiro
- Sonzogni, Aurelio
- Licini, Lisa
- Valle, Clarissa
- Bonaffini, Pietro A.
- Sironi, Sandro
- Alessio, Maria Grazia
- Previtali, Giulia
- Seghezzi, Michela
- Zhang, Xuchen
- Lee, Alfred I.
- Pine, Alexander B.
- Chun, Hyung J.
- Fernandez-Hernando, Carlos
- Qing, Hua
- Wang, Andrew
- Price, Christina
- Sun, Zhaoli
- Hwa, John
- Strazzabosco, Mario
- Iwakiri, Yasuko
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 75
- Issue
- 3
- Pages
- 647-658
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC8285256
- OpenAlex
- W3163367789
- Cited by
- 111
- References
- 47
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 14 · 2023: 30 · 2022: 25 · 2021: 15
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Heart Lung and Blood Institute
- American Association for the Study of Liver Diseases
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- COVID-19 pandemic, IL-6 trans-signaling, endotheliopathy, liver injury, coagulopathy, liver sinusoidal endothelial cells, von Willebrand factor, factor VIII, D-dimer, fibrinogen, platelet activation, soluble glycoprotein 130, ruxolitinib, STAT1/3 signaling, neutrophils, alanine aminotransferase
- MeSH terms
- COVID-19, SARS-CoV-2, Adult, Blood Coagulation Disorders, Fibrinogen, Humans, Liver Diseases, Nitriles, Pyrazoles, Pyrimidines, Retrospective Studies, von Willebrand Factor, Signal Transduction, Interleukin-6, Endothelial Cells, STAT3 Transcription Factor, Janus Kinase 1
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