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

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  • Tine Wyseure
  • Esther J Cooke
  • Paul J Declerck
  • Niels Behrendt
  • Joost C M Meijers
  • Annette von Drygalski
  • Laurent O Mosnier
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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 mice (receiving an anti-FVIII antibody), and congenital hemophilia A (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 to 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 to wild-type 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 analysis 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 Plasminogen Activator (uPA)-induced fibrinolysis drove joint bleeding, whereas tissue-type Plasminogen Activator (tPA)-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 due to severely defective TAFI activation, underscoring the importance of clot protection in addition to clot formation when considering prohemostatic strategies for hemophilic joint bleeding.

Original languageEnglish
JournalBlood
Volume132
Issue number15
Pages (from-to)1593-1603
ISSN0006-4971
DOIs
Publication statusPublished - 11 Oct 2018

ID: 54960183