{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T23:43:57Z","timestamp":1792539837130,"version":"4.5.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,2,21]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Deep vein thrombosis (DVT) is the primary cause of pulmonary embolism and the third most life\u2010threatening cardiovascular disease in North America. Post\u2010DVT anticoagulants, such as warfarin, heparin, and direct oral anticoagulants, reduce the incidence of subsequent venous thrombi. However, all currently used anticoagulants affect bleeding time at various degrees, and there is therefore a need for improved therapeutic regimens in DVT. It has recently been shown that mast cells play a crucial role in a DVT murine model. The underlying mechanism involved in the prothrombotic properties of mast cells, however, has yet to be identified.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              C57BL\/6 mice and mouse mast cell protease\u20104 (mMCP\u20104) genetically depleted mice (mMCP\u20104 knockout) were used in 2 mouse models of DVT, partial ligation (stenosis) and ferric chloride\u2013endothelial injury model of the inferior vena cava. Thrombus formation and impact of genetically repressed or pharmacologically (specific inhibitor TY\u201051469) inhibited mMCP\u20104 were evaluated by morphometric measurements of thrombi immunochemistry (mouse and human DVT), color Doppler ultrasound, bleeding times, and enzymatic activity assays ex vivo\n              <jats:italic>.<\/jats:italic>\n              Recombinant chymases, mMCP\u20104 (mouse) and CMA\u20101 (human), were used to characterize the interaction with murine and human plasmin, respectively, by mass spectrometry and enzymatic activity assays. Inhibiting mast cell\u2013generated mMCP\u20104, genetically or pharmacologically, resolves and prevents venous thrombus formation in both DVT models. Inferior vena cava blood flow obstruction was observed in the stenosis model after 6\u2009hours of ligation, in control\u2010 but not in TY\u201051469\u2013treated mice. In addition, chymase inhibition had no impact on bleeding times of healthy or DVT mice. Furthermore, endogenous chymase limits plasmin activity in thrombi ex vivo. Recombinant mouse or human chymase degrades\/inactivates purified plasmin in vitro. Finally, mast cell\u2013containing immunoreactive chymase was identified in human DVT.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">This study identified a major role for mMCP\u20104, a granule\u2010localized protease of chymase type, in DVT formation. These findings support a novel pharmacological strategy to resolve or prevent DVT without affecting the coagulation cascade through the inhibition of chymase activity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.028056","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T11:54:01Z","timestamp":1675857241000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Chymase Inhibition Resolves and Prevents Deep Vein Thrombosis Without Increasing Bleeding Time in the Mouse Model"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0636-7781","authenticated-orcid":false,"given":"Catherine","family":"Lapointe","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology and Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9 Universit\u00e9 de Sherbrooke Sherbrooke QC 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