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Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII\u2013deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient  mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI\u2019s protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.<\/jats:p>","DOI":"10.1172\/jci.insight.128379","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T12:04:30Z","timestamp":1567080270000},"source":"Crossref","is-referenced-by-count":17,"title":["TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding"],"prefix":"10.1172","volume":"4","author":[{"given":"Tine","family":"Wyseure","sequence":"first","affiliation":[{"name":"Deptartment of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyi","family":"Yang","sequence":"additional","affiliation":[{"name":"Deptartment of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 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