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Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding

Tine Wyseure, Esther J. Cooke, Paul J. Declerck, Niels Behrendt, Joost C. M. Meijers, Annette von Drygalski and Laurent O. Mosnier

Key Points

  • Degree of TAFI activation in HA is a modifier of hemophilic joint bleeding that inversely affects bleeding severity.

  • Defective TAFI activation in severe congenital HA impairs protection against uPA-mediated fibrinolysis in bleeding joints.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

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 (FVIII−/−) mice. Both aHA and FVIII−/− mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII−/− mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI−/− mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII−/− mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII−/− 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 FVIII−/− 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.

  • Submitted January 19, 2018.
  • Accepted July 11, 2018.
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