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Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding

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DOI

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  • Tine Wyseure
  • Tingyi Yang
  • Jenny Y Zhou
  • Esther J Cooke
  • Bettina Wanko
  • Merissa Olmer
  • Ruchi Agashe
  • Yosuke Morodomi
  • Niels Behrendt
  • Martin Lotz
  • John Morser
  • Annette von Drygalski
  • Laurent O Mosnier
Vis graf over relationer

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. 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 (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 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's 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 new mechanistic insights allow targeted development of new strategies to normalize vascularity and control re-bleeding in HA.

OriginalsprogEngelsk
TidsskriftJCI Insight
ISSN2379-3708
DOI
StatusUdgivet - 29 aug. 2019

ID: 58014893