{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:34:26Z","timestamp":1792978466345,"version":"4.5.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RA 799\/5-1"],"award-info":[{"award-number":["RA 799\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cardiovasc Drugs Ther"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to assess the effect of metformin on TF activity and markers of vascular inflammation in poorly controlled type 2 diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>In a cohort of patients with uncontrolled type 2 diabetes (glycosylated hemoglobin 8.39\u00a0<jats:italic>\u00b1<\/jats:italic>\u00a00.24%, 68.1\u00a0<jats:italic>\u00b1<\/jats:italic>\u00a02.6\u00a0mmol\/mol, <jats:italic>n<\/jats:italic>\u2009=\u200946) of whom half of the individuals were treated with metformin and the other half did not receive metformin as part of an anti-diabetic combination therapy, we assessed TF activity and markers of vascular inflammation. In vitro, human monocytic cells (THP-1) were exposed to metformin and TF expression measured in the presence and absence of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the AMPK inhibitor compound C.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In the patients, metformin treatment was associated with lower levels of TF protein (241.5\u2009\u00b1\u200919 vs. 315.4\u2009\u00b1\u200925\u00a0pg\/mL, <jats:italic>p<\/jats:italic>\u2009=\u20090.03) and reduced TF activity (408.9\u2009\u00b1\u200949 vs. 643.8\u2009\u00b1\u200947\u00a0U\/mL, <jats:italic>p<\/jats:italic>\u2009=\u20090.001) compared with controls. Moreover, the patients on metformin showed lower levels of vascular cell adhesion molecule (VCAM)1 (26.6\u2009\u00b1\u20091.4 vs. 35.03\u2009\u00b1\u20093.1\u00a0ng\/mL, <jats:italic>p<\/jats:italic>\u2009=\u20090.014) and higher expression of miR-126-3p\/U6sno (11.39\u2009\u00b1\u20092.8 vs. 4.26\u2009\u00b1\u20090.9, <jats:italic>p<\/jats:italic>\u2009=\u20090.006), a known post-transcriptional down regulator of TF and VCAM1. In vitro, metformin dose-dependently reduced lipopolysaccharide (LPS)-induced TF expression in THP-1 cells. The AMPK activator AICAR alone lowered TF expression in THP-1, while the AMPK inhibitor compound C abrogated the metformin-dependent reduction in TF expression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our data are the first to report that metformin is associated with reduced plasma TF procoagulant activity possibly explaining\u2014at least in part\u2014the vasculoprotective properties of metformin.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10557-020-07040-7","type":"journal-article","created":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T14:06:27Z","timestamp":1600351587000},"page":"809-813","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes"],"prefix":"10.1007","volume":"35","author":[{"given":"Marco","family":"Witkowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Friebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Termeh","family":"Tabaraie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinah","family":"Grabitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"D\u00f6rner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Taghipour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Jakobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Stratmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diethelm","family":"Tschoepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Landmesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1544-7644","authenticated-orcid":false,"given":"Ursula","family":"Rauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"issue":"4","key":"7040_CR1","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.cmet.2016.09.003","volume":"24","author":"CS Zhang","year":"2016","unstructured":"Zhang CS, Li M, Ma T, Zong Y, Cui J, Feng JW, et al. Metformin activates AMPK through the lysosomal pathway. Cell Metab. 2016;24(4):521\u20132.","journal-title":"Cell Metab"},{"issue":"5","key":"7040_CR2","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1111\/dom.13642","volume":"21","author":"DM Charytan","year":"2019","unstructured":"Charytan DM, Solomon SD, Ivanovich P, Remuzzi G, Cooper ME, McGill JB, et al. Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2019;21(5):1199\u2013208.","journal-title":"Diabetes Obes Metab"},{"issue":"3","key":"7040_CR3","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1161\/01.ATV.0000201938.78044.75","volume":"26","author":"K Isoda","year":"2006","unstructured":"Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26(3):611\u20137.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"3","key":"7040_CR4","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1111\/acel.12469","volume":"15","author":"N Noren Hooten","year":"2016","unstructured":"Noren Hooten N, Martin-Montalvo A, Dluzen DF, Zhang Y, Bernier M, Zonderman AB, et al. Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell. 2016;15(3):572\u201381.","journal-title":"Aging Cell"},{"issue":"4","key":"7040_CR5","doi-asserted-by":"publisher","first-page":"499","DOI":"10.2478\/jomb-2018-0009","volume":"37","author":"\u0130H Demirsoy","year":"2018","unstructured":"Demirsoy \u0130H, Ertural DY, Balci \u015e, \u00c7\u0131nk\u0131r \u00dc, Sezer K, Tamer L, et al. Profiles of circulating MiRNAs following metformin treatment in patients with type 2 diabetes. J Med Biochem. 2018;37(4):499\u2013506.","journal-title":"J Med Biochem"},{"issue":"4","key":"7040_CR6","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.tcm.2015.12.001","volume":"26","author":"M Witkowski","year":"2016","unstructured":"Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation. Trends Cardiovasc Med. 2016;26(4):297\u2013303.","journal-title":"Trends Cardiovasc Med"},{"issue":"4","key":"7040_CR7","doi-asserted-by":"publisher","first-page":"472","DOI":"10.2174\/1381612822666151222160933","volume":"22","author":"A Weithauser","year":"2016","unstructured":"Weithauser A, Witkowski M, Rauch U. The role of protease-activated receptors for the development of myocarditis: possible therapeutic implications. Curr Pharm Des. 2016;22(4):472\u201384.","journal-title":"Curr Pharm Des"},{"issue":"40","key":"7040_CR8","doi-asserted-by":"publisher","first-page":"3318","DOI":"10.1093\/eurheartj\/ehz117","volume":"40","author":"J Friebel","year":"2019","unstructured":"Friebel J, Weithauser A, Witkowski M, Rauch BH, Savvatis K, Dorner A, et al. Protease-activated receptor 2 deficiency mediates cardiac fibrosis and diastolic dysfunction. Eur Heart J. 2019;40(40):3318\u201332.","journal-title":"Eur Heart J"},{"issue":"2","key":"7040_CR9","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.thromres.2009.06.033","volume":"125","author":"VY Bogdanov","year":"2010","unstructured":"Bogdanov VY, Osterud B. Cardiovascular complications of diabetes mellitus: the tissue factor perspective. Thromb Res. 2010;125(2):112\u20138.","journal-title":"Thromb Res"},{"issue":"1","key":"7040_CR10","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12933-020-0993-z","volume":"19","author":"M Witkowski","year":"2020","unstructured":"Witkowski M, Witkowski M, Saffarzadeh M, Friebel J, Tabaraie T, Ta Bao L, et al. Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes. Cardiovasc Diabetol. 2020;19(1):20.","journal-title":"Cardiovasc Diabetol"},{"issue":"12","key":"7040_CR11","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1161\/01.RES.0000171805.24799.fa","volume":"96","author":"B Szotowski","year":"2005","unstructured":"Szotowski B, Antoniak S, Poller W, Schultheiss HP, Rauch U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ Res. 2005;96(12):1233\u20139.","journal-title":"Circ Res"},{"issue":"6","key":"7040_CR12","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1161\/ATVBAHA.115.306094","volume":"36","author":"M Witkowski","year":"2016","unstructured":"Witkowski M, Weithauser A, Tabaraie T, Steffens D, Krankel N, Witkowski M, et al. Micro-RNA-126 reduces the blood Thrombogenicity in diabetes mellitus via targeting of tissue factor. Arterioscler Thromb Vasc Biol. 2016;36(6):1263\u201371.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"7040_CR13","doi-asserted-by":"publisher","first-page":"291209","DOI":"10.1155\/2015\/291209","volume":"2015","author":"J Wang","year":"2015","unstructured":"Wang J, Ciaraldi TP, Samad F. Tissue factor expression in obese type 2 diabetic subjects and its regulation by antidiabetic agents. J Obes. 2015;2015:291209.","journal-title":"J Obes"},{"issue":"4","key":"7040_CR14","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1007\/s00404-017-4471-0","volume":"296","author":"LML Carvalho","year":"2017","unstructured":"Carvalho LML, Ferreira CN, Candido AL, Reis FM, S\u00f3ter MO, Sales MF, et al. Metformin reduces total microparticles and microparticles-expressing tissue factor in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2017;296(4):617\u201321.","journal-title":"Arch Gynecol Obstet"},{"issue":"1","key":"7040_CR15","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.metabol.2012.06.009","volume":"62","author":"R Krysiak","year":"2013","unstructured":"Krysiak R, Okopien B. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metab Clin Exp. 2013;62(1):39\u201343.","journal-title":"Metab Clin Exp"},{"key":"7040_CR16","doi-asserted-by":"publisher","first-page":"697972","DOI":"10.1155\/2013\/697972","volume":"2013","author":"A Schildberger","year":"2013","unstructured":"Schildberger A, Rossmanith E, Eichhorn T, Strassl K, Weber V. Monocytes, peripheral blood mononuclear cells, and THP-1 cells exhibit different cytokine expression patterns following stimulation with lipopolysaccharide. Mediat Inflamm. 2013;2013:697972.","journal-title":"Mediat Inflamm"},{"issue":"7","key":"7040_CR17","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1161\/01.ATV.0000131784.50633.4f","volume":"24","author":"S Sugiyama","year":"2004","unstructured":"Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler Thromb Vasc Biol. 2004;24(7):1309\u201314.","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"7040_CR18","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s12933-018-0678-z","volume":"17","author":"M Witkowski","year":"2018","unstructured":"Witkowski M, Tabaraie T, Steffens D, Friebel J, Dorner A, Skurk C, et al. MicroRNA-19a contributes to the epigenetic regulation of tissue factor in diabetes. Cardiovasc Diabetol. 2018;17(1):34.","journal-title":"Cardiovasc Diabetol"},{"issue":"1","key":"7040_CR19","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/jdi.13074","volume":"11","author":"X Luo","year":"2020","unstructured":"Luo X, Hu R, Zheng Y, Liu S, Zhou Z. Metformin shows anti-inflammatory effects in murine macrophages through Dicer\/microribonucleic acid-34a-5p and microribonucleic acid-125b-5p. J Diabetes Inv. 2020;11(1):101\u20139.","journal-title":"J Diabetes Inv"}],"container-title":["Cardiovascular Drugs and Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10557-020-07040-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10557-020-07040-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10557-020-07040-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:59:15Z","timestamp":1631840355000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10557-020-07040-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,17]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["7040"],"URL":"https:\/\/doi.org\/10.1007\/s10557-020-07040-7","relation":{},"ISSN":["0920-3206","1573-7241"],"issn-type":[{"value":"0920-3206","type":"print"},{"value":"1573-7241","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,17]]},"assertion":[{"value":"15 July 2020","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2020","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed Consent"}}]}}