{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T19:45:27Z","timestamp":1793303127539,"version":"4.5.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"23","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1999,6,15]]},"abstract":"<jats:p>\n                    <jats:italic>Background<\/jats:italic>\n                    \u2014Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA). Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a murine carotid injury model to test the hypothesis that PAI-1 inhibits thrombolysis mediated by pharmacological concentrations of tPA.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Methods and Results<\/jats:italic>\n                    \u2014Platelet-rich thrombi were induced in wild-type mice (\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+; n=11) and PAI-1\u2013deficient mice (\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212; n=11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ and\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212 mice. Clot lysis was induced by infusion of heparin (200 U\/kg bolus, 70 U \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 h\n                    <jats:sup>\u22121<\/jats:sup>\n                    drip), human plasminogen (50 mg\/kg), and tPA at 20 (n=10) or 100 (n=12) \u03bcg \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 min\n                    <jats:sup>\u22121<\/jats:sup>\n                    . Mean plasma tPA antigens were 2.7 \u03bcg\/mL (tPA infusion, 20 \u03bcg \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 min\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) and 5.5 \u03bcg\/mL (tPA infusion, 100 \u03bcg \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 min\n                    <jats:sup>\u22121<\/jats:sup>\n                    ), with no significant differences between\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ mice and\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212 mice. Reperfusion after tPA 20 \u03bcg \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 min\n                    <jats:sup>\u22121<\/jats:sup>\n                    occurred in 1 of 5\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ mice versus 5 of 5\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212 mice (\n                    <jats:italic>P<\/jats:italic>\n                    =0.0006). Reperfusion occurred in all mice that received tPA 100 \u03bcg \u00b7 kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00b7 min\n                    <jats:sup>\u22121<\/jats:sup>\n                    , but reperfusion times were significantly shorter in\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212 mice (17.8\u00b12.6 minutes, n=6) than in\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ mice (35.7\u00b15.1 minute, n=6;\n                    <jats:italic>P<\/jats:italic>\n                    =0.01). Histological analyses confirmed that carotid thrombi were platelet rich and that PAI-1 was distributed uniformly throughout thrombi from\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ mice. Lysates of\n                    <jats:italic>PAI-1<\/jats:italic>\n                    +\/+ platelets inhibited human tPA, whereas\n                    <jats:italic>PAI-1<\/jats:italic>\n                    \u2212\/\u2212 platelet lysates did not.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>Conclusions<\/jats:italic>\n                    \u2014PAI-1 is a major determinant of the resistance of platelet-rich arterial thrombi to lysis by pharmacological concentrations of tPA. Strategies to inhibit or resist PAI-1 may enhance thrombolysis.\n                  <\/jats:p>","DOI":"10.1161\/01.cir.99.23.3050","type":"journal-article","created":{"date-parts":[[2012,6,11]],"date-time":"2012-06-11T20:42:29Z","timestamp":1339447349000},"page":"3050-3055","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":142,"title":["Plasminogen Activator Inhibitor-1 Is a Major Determinant of Arterial Thrombolysis Resistance"],"prefix":"10.1161","volume":"99","author":[{"given":"Yanhong","family":"Zhu","sequence":"first","affiliation":[{"name":"From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich (Y.Z., W.P.F.), and the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium (P.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich (Y.Z., W.P.F.), and the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium (P.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Fay","sequence":"additional","affiliation":[{"name":"From the Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich (Y.Z., W.P.F.), and the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium (P.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.79.4.2494006"},{"key":"e_1_3_2_2_2","first-page":"87","volume":"9","year":"1989","unstructured":"Loskutoff DJ, Sawdey M, Mimuro J. 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