Defective TAFI activation in hemophilia a mice is a major contributor to joint bleeding
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- Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding
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Joint bleeds are common in congenital hemophilia but rare in acquired hemophilia A (aHA) for reasons unknown. To identify key mechanisms responsible for joint-specific bleeding in congenital hemophilia, bleeding phenotypes after joint injury and tail transection were compared in aHA wild-type (WT) mice (receiving an anti–factor VIII [FVIII] antibody) and congenital HA (FVIII2/2) mice. Both aHA and FVIII2/2 mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII2/2 mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI2/2 mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII2/2 mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII2/2 mice in vivo, consistent with previous in vitro analyses in FVIII-deficient plasma. In contrast, notable TAFI activation was observed in aHA mice, suggesting that TAFI protected aHA joints against bleeding. Pharmacological inhibitors of fibrinolysis revealed that urokinase-type plasminogen activator (uPA)–induced fibrinolysis drove joint bleeding, whereas tissue-type plasminogen activator–mediated fibrinolysis contributed to tail bleeding. These data identify TAFI as an important modifier of hemophilic joint bleeding in aHA by inhibiting uPA-mediated fibrinolysis. Moreover, our data suggest that bleed protection by TAFI was absent in congenital FVIII2/2 mice because of severely defective TAFI activation, underscoring the importance of clot protection in addition to clot formation when considering prohemostatic strategies for hemophilic joint bleeding. (Blood. 2018;132(15):1593-1603)
Original language | English |
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Journal | Blood |
Volume | 132 |
Issue number | 15 |
Pages (from-to) | 1593-1603 |
Number of pages | 11 |
ISSN | 0006-4971 |
DOIs | |
Publication status | Published - 2018 |
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