{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T09:48:06Z","timestamp":1762508886727,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T00:00:00Z","timestamp":1667347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u2018Dr. Siegried Stettendorf\u2019 Foundation","award":["Stv\/2009-0286\/SA","1369-401"],"award-info":[{"award-number":["Stv\/2009-0286\/SA","1369-401"]}]},{"name":"German Federal Ministry of Health to the German National Reference Center for Papilloma and Polyomaviruses","award":["Stv\/2009-0286\/SA","1369-401"],"award-info":[{"award-number":["Stv\/2009-0286\/SA","1369-401"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8\/IL-8 expression in HPV-E6\/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.<\/jats:p>","DOI":"10.3390\/ijms232113377","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T03:11:21Z","timestamp":1667445081000},"page":"13377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-0195","authenticated-orcid":false,"given":"Stephan A.","family":"Braun","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany"},{"name":"Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander T.","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Csongor","family":"N\u00e9meth","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, University of P\u00e9cs, Medical Center, 7632 P\u00e9cs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annam\u00e1ria","family":"R\u00f3zsa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, University of P\u00e9cs, Medical Center, 7632 P\u00e9cs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louisa","family":"Rusch","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luise","family":"Erpenbeck","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Schloer","sequence":"additional","affiliation":[{"name":"Center for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany"},{"name":"Leibniz Institute of Virology, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9555-3876","authenticated-orcid":false,"given":"Steffi","family":"Silling","sequence":"additional","affiliation":[{"name":"Institute of Virology, National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine and University Hospital Cologne, 50935 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Metze","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A.","family":"Gerber","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan W.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3286-8846","authenticated-orcid":false,"given":"Rolland","family":"Gyulai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Oncodermatology, University of P\u00e9cs, Medical Center, 7632 P\u00e9cs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Homey","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1056\/NEJMoa1811850","article-title":"Randomized Trial of Four Treatment Approaches for Actinic Keratosis","volume":"380","author":"Jansen","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1056\/NEJMoa1111170","article-title":"Ingenol mebutate gel for actinic keratosis","volume":"366","author":"Lebwohl","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"156","DOI":"10.36849\/JDD.2020.4731","article-title":"Ingenol Mebutate: Expanded Utility","volume":"19","author":"Khalfe","year":"2020","journal-title":"J. Drugs Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.3390\/v7072802","article-title":"Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia","volume":"7","author":"Egawa","year":"2015","journal-title":"Viruses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00105-015-3593-1","article-title":"Successful therapy of condylomata acuminata with ingenol mebutate","volume":"66","author":"Braun","year":"2015","journal-title":"Hautarzt"},{"key":"ref_6","first-page":"616","article-title":"Successful treatment of perianal condylomata acuminata with ingenol mebutate gel","volume":"14","author":"Braun","year":"2016","journal-title":"J. Dtschl. Dermatol. Ges."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1111\/jdv.13097","article-title":"Ingenol mebutate gel is effective against anogenital warts\u2014A case series in 17 patients","volume":"30","author":"Schopf","year":"2015","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1016\/j.jaad.2017.01.034","article-title":"Ingenol mebutate for the management of genital warts in sensitive anatomic locations","volume":"77","author":"Braun","year":"2017","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1097\/OLQ.0000000000000867","article-title":"Fast Ablation of Anogenital Warts of the Urinary Meatus by Low-dose Ingenol Mebutate Gel","volume":"45","author":"Braun","year":"2018","journal-title":"Sex Transm Dis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1111\/jdv.14625","article-title":"An exploratory, prospective, open-label trial of ingenol mebutate gel 0.05% for the treatment of external anogenital warts","volume":"32","author":"Larsen","year":"2018","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/ced.13840","article-title":"Ingenol mebutate for the treatment of anogenital condylomata acuminata","volume":"44","year":"2019","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1177\/0956462418824453","article-title":"Successful treatment of condylomata acuminata at the urethral meatus with high-dose ingenol mebutate gel: Report of two cases","volume":"30","year":"2019","journal-title":"Int. J. STD AIDS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1097\/OLQ.0000000000001165","article-title":"Ingenol Mebutate Gel 0.05% in the Treatment of Anogenital Warts: A Prospective Controlled Trial Comparing It With Topical Podophyllin Solution 25","volume":"47","author":"Bizaval","year":"2020","journal-title":"Sex. Transm. Dis."},{"key":"ref_14","first-page":"e13937","article-title":"Ingenol mebutate for the management of cryotherapy-resistant anogenital warts","volume":"33","author":"Hoormand","year":"2020","journal-title":"Dermatol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/j.jaad.2010.12.038","article-title":"Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response","volume":"66","author":"Rosen","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Emmert, S., Haenssle, H.A., Zibert, J.R., Schon, M., Hald, A., Hansen, M.H., Litman, T., and Schon, M.P. (2016). Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160096"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1158\/1535-7163.1651.3.12","article-title":"Ingenol 3-angelate induces dual modes of cell death and differentially regulates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in melanoma cells","volume":"3","author":"Gillespie","year":"2004","journal-title":"Mol. Cancer Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1158\/0008-5472.CAN-03-2837","article-title":"Antitumor activity of 3-ingenyl angelate: Plasma membrane and mitochondrial disruption and necrotic cell death","volume":"64","author":"Ogbourne","year":"2004","journal-title":"Cancer Res."},{"key":"ref_19","first-page":"1181","article-title":"Ingenol mebutate: Induced cell death patterns in normal and cancer epithelial cells","volume":"11","author":"Stahlhut","year":"2012","journal-title":"J. Drugs Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/imm.12510","article-title":"Protein kinase C in the immune system: From signalling to chromatin regulation","volume":"146","author":"Lim","year":"2015","journal-title":"Immunology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/cvr\/cvm085","article-title":"Protein kinase C alpha promotes angiogenic activity of human endothelial cells via induction of vascular endothelial growth factor","volume":"78","author":"Xu","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1158\/0008-5472.CAN-03-3403","article-title":"Characterization of the interaction of ingenol 3-angelate with protein kinase C","volume":"64","author":"Kedei","year":"2004","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1182\/blood-2004-10-4117","article-title":"PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC","volume":"106","author":"Hampson","year":"2005","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8123","DOI":"10.4049\/jimmunol.177.11.8123","article-title":"Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3-angelate","volume":"177","author":"Challacombe","year":"2006","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1007\/s00262-008-0458-9","article-title":"The anti-tumor agent, ingenol-3-angelate (PEP005), promotes the recruitment of cytotoxic neutrophils by activation of vascular endothelial cells in a PKC-delta dependent manner","volume":"57","author":"Hampson","year":"2008","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40001-018-0343-8","article-title":"Ingenol mebutate induces a tumor cell-directed inflammatory response and antimicrobial peptides thereby promoting rapid tumor destruction and wound healing","volume":"23","author":"Braun","year":"2018","journal-title":"Eur. J. Med. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/exd.13516","article-title":"Time-lapse imaging points towards a non-toxic, mainly immune-driven mode of action of ingenol mebutate in the treatment of anogenital warts","volume":"27","author":"Braun","year":"2018","journal-title":"Exp. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7899","DOI":"10.1073\/pnas.0608422104","article-title":"Shear-induced unfolding triggers adhesion of von Willebrand factor fibers","volume":"104","author":"Schneider","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3746","DOI":"10.1182\/blood-2006-03-010322","article-title":"P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor","volume":"108","author":"Pendu","year":"2006","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4712","DOI":"10.1182\/blood-2010-03-276311","article-title":"von Willebrand factor promotes leukocyte extravasation","volume":"116","author":"Petri","year":"2010","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15880","DOI":"10.1073\/pnas.1005743107","article-title":"Extracellular DNA traps promote thrombosis","volume":"107","author":"Fuchs","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1182\/blood-2014-08-595686","article-title":"von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans","volume":"125","author":"Bauer","year":"2015","journal-title":"Blood"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1056\/NEJM199802123380706","article-title":"Chemokines--chemotactic cytokines that mediate inflammation","volume":"338","author":"Luster","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3399","DOI":"10.1161\/01.ATV.17.12.3399","article-title":"Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity","volume":"17","author":"Neumann","year":"1997","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1046\/j.1365-2141.2002.03245.x","article-title":"Interleukin 8 and venous thrombosis: Evidence for a role of inflammation in thrombosis","volume":"116","author":"Reitsma","year":"2002","journal-title":"Br. J. Haematol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4509","DOI":"10.1158\/0008-5472.CAN-09-4303","article-title":"The skin cancer chemotherapeutic agent ingenol-3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature","volume":"70","author":"Li","year":"2010","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"155828","DOI":"10.1016\/j.cyto.2022.155828","article-title":"Interleukin-8: An evolving chemokine","volume":"153","author":"Matsushima","year":"2022","journal-title":"Cytokine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1182\/blood-2013-10-463646","article-title":"Thrombosis: Tangled up in NETs","volume":"123","author":"Martinod","year":"2014","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.ajpath.2012.04.012","article-title":"Highly invasive melanoma cells activate the vascular endothelium via an MMP-2\/integrin alphavbeta5-induced secretion of VEGF-A","volume":"181","author":"Desch","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nri3345","article-title":"Thrombosis as an intravascular effector of innate immunity","volume":"13","author":"Engelmann","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"68527","DOI":"10.18632\/oncotarget.11832","article-title":"Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis","volume":"7","author":"Goertz","year":"2016","journal-title":"Oncotarget"},{"key":"ref_42","first-page":"s3","article-title":"Role of von Willebrand factor in the haemostasis","volume":"9","author":"Peyvandi","year":"2011","journal-title":"Blood Transfus."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1111\/j.1538-7836.2008.03138.x","article-title":"Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine","volume":"6","author":"Lorenzi","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e150862","DOI":"10.1172\/jci.insight.150862","article-title":"Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19","volume":"6","author":"Kaiser","year":"2021","journal-title":"JCI Insight"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.chom.2014.04.011","article-title":"The balancing act of neutrophils","volume":"15","author":"Bardoel","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1182\/blood.2020007008","article-title":"Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome","volume":"136","author":"Middleton","year":"2020","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1161\/CIRCULATIONAHA.120.048488","article-title":"Immunothrombotic Dysregulation in COVID-19 Pneumonia Is Associated with Respiratory Failure and Coagulopathy","volume":"142","author":"Nicolai","year":"2020","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1172\/JCI141374","article-title":"Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis","volume":"130","author":"Skendros","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_49","first-page":"e138999","article-title":"Neutrophil extracellular traps in COVID-19","volume":"5","author":"Zuo","year":"2020","journal-title":"JCI Insight"},{"key":"ref_50","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":"Klok","year":"2020","journal-title":"Thromb. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1161\/CIRCULATIONAHA.120.051828","article-title":"Microthrombi as a Major Cause of Cardiac Injury in COVID-19: A Pathologic Study","volume":"143","author":"Pellegrini","year":"2021","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Al-Eitan, L.N., Tarkhan, A.H., Alghamdi, M.A., Al-Qarqaz, F.A., and Al-Kofahi, H.S. (2020). Transcriptome analysis of HPV-induced warts and healthy skin in humans. BMC Med. Genom., 13.","DOI":"10.1186\/s12920-020-0700-7"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.canlet.2018.04.036","article-title":"Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway","volume":"428","author":"Rigalli","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Alkharsah, K.R. (2018). VEGF Upregulation in Viral Infections and Its Possible Therapeutic Implications. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061642"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1111\/jdv.17114","article-title":"Human Papillomavirus-type distribution in anogenital lesions of prepubertal children","volume":"35","author":"Braun","year":"2021","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1038\/jid.2010.136","article-title":"The mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cells","volume":"130","author":"Kerk","year":"2010","journal-title":"J. Investig. Dermatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13377\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:09:12Z","timestamp":1760144952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":56,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113377"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113377","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,11,2]]}}}