{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:49:15Z","timestamp":1792464555298,"version":"4.5.0"},"reference-count":118,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,5,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Plasminogen is an abundant plasma protein that exists in various zymogenic forms. Plasmin, the proteolytically active form of plasminogen, is known for its essential role in fibrinolysis. To date, therapeutic targeting of the fibrinolytic system has been for 2 purposes: to promote plasmin generation for thromboembolic conditions or to stop plasmin to reduce bleeding. However, plasmin and plasminogen serve other important functions, some of which are unrelated to fibrin removal. Indeed, for &amp;gt;40 years, the antifibrinolytic agent tranexamic acid has been administered for its serendipitously discovered skin-whitening properties. Plasmin also plays an important role in the removal of misfolded\/aggregated proteins and can trigger other enzymatic cascades, including complement. In addition, plasminogen, via binding to one of its dozen cell surface receptors, can modulate cell behavior and further influence immune and inflammatory processes. Plasminogen administration itself has been reported to improve thrombolysis and to accelerate wound repair. Although many of these more recent findings have been derived from in vitro or animal studies, the use of antifibrinolytic agents to reduce bleeding in humans has revealed additional clinically relevant consequences, particularly in relation to reducing infection risk that is independent of its hemostatic effects. The finding that many viruses harness the host plasminogen to aid infectivity has suggested that antifibrinolytic agents may have antiviral benefits. Here, we review the broadening role of the plasminogen-activating system in physiology and pathophysiology and how manipulation of this system may be harnessed for benefits unrelated to its conventional application in thrombosis and hemostasis.<\/jats:p>","DOI":"10.1182\/blood.2020008951","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T22:17:00Z","timestamp":1616105820000},"page":"2881-2889","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":174,"title":["Plasminogen: an enigmatic zymogen"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4265-4291","authenticated-orcid":false,"given":"Charithani B.","family":"Keragala","sequence":"first","affiliation":[{"name":"Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6885-3892","authenticated-orcid":false,"given":"Robert L.","family":"Medcalf","sequence":"additional","affiliation":[{"name":"Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University, Melbourne VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2021052715230733100_B1","first-page":"661","article-title":"Fibrinolyse dans le sang","volume":"5","author":"Dastre","year":"1893","journal-title":"Arch Physiol"},{"issue":"4","key":"2021052715230733100_B2","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1084\/jem.58.4.485","article-title":"The fibrinolytic activity of hemolytic streptococci","volume":"58","author":"Tillett","year":"1933","journal-title":"J Exp Med"},{"key":"2021052715230733100_B3","first-page":"171","article-title":"On the fibrolysis of the staphylococcus","volume":"9","author":"Aoi","year":"1932","journal-title":"Kitasato Arch Exp Med"},{"key":"2021052715230733100_B4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4049\/jimmunol.42.2.109","article-title":"A factor in normal human blood which participates in streptococcal fibrinolysis","volume":"42","author":"Milstone","year":"1941","journal-title":"J Immunol"},{"issue":"4","key":"2021052715230733100_B5","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1085\/jgp.28.4.363","article-title":"Streptococcal fibrinolysis: a proteolytic reaction due to a serum enzyme activated by streptococcal fibrinolysin","volume":"28","author":"Christensen","year":"1945","journal-title":"J Gen Physiol"},{"issue":"2","key":"2021052715230733100_B6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1084\/jem.60.2.239","article-title":"Biochemical studies on the fibrinolytic activity of hemolytic streptococci: I. 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Med"},{"issue":"3","key":"2021052715230733100_B52","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/SHK.0b013e318264b95d","article-title":"The fibrinopeptide b\u03b215-42 reduces inflammation in mice subjected to polymicrobial sepsis","volume":"38","author":"Jennewein","year":"2012","journal-title":"Shock"},{"issue":"11","key":"2021052715230733100_B53","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/s41590-018-0232-x","article-title":"Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration","volume":"19","author":"Ryu","year":"2018","journal-title":"Nat Immunol"},{"issue":"6","key":"2021052715230733100_B54","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.neuron.2019.01.014","article-title":"Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer\u2019s disease 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