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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
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftBlood
Vol/bind132
Udgave nummer15
Sider (fra-til)1593-1603
ISSN0006-4971
DOI
StatusUdgivet - 11 okt. 2018

ID: 54960183