Extended Stability of Activated TAFI Normalizes Vascular Dysfunction in Hemophilic Joint Disease in Mice
ISTH Academy. Wyseure T. Jul 10, 2019; 273940; OC 75.1 Topic: Hemophilia - Basic
Tine Wyseure
Tine Wyseure
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OC 75.1

Extended Stability of Activated TAFI Normalizes Vascular Dysfunction in Hemophilic Joint Disease in Mice

T. Wyseure1, R. Agashe1, A. von Drygalski1,2, S. Henderson1, L.O. Mosnier1
1The Scripps Research Institute, La Jolla, United States, 2University of California San Diego, La Jolla, United States

Main Topic: Hemophilia and Bleeding (including Transfusion)
Category: Hemophilia - Basic

Background: Excessive vascular remodeling is characteristic to hemophilic joint disease and promotes vessel fragility and rebleeding. Low thrombin generation in hemophilia leads to impaired activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI). TAFI deficiency contributes to hemophilic joint bleeding and drives the development of vascular dysfunction in the joints after bleeding in mice.
Aims: To determine the efficacy of induced TAFI expression in preventing joint bleeding and vascular abnormalities in hemophilic (FVIII-/-) mice.
Methods: Human wild type (WT-)TAFI or a stabilized variant, TAFI-CIIYQ, was expressed at normal human plasma levels in FVIII-/- mice by hydrodynamic gene delivery. Bleeding was determined after tail clip or joint injury 2 days after DNA injection. Joint vascularity was evaluated 2 weeks after joint injury by Evans-blue leakage, histology and 2-photon microscopy.
Results: TAFI-CIIYQ, but not WT-TAFI, corrected acute blood loss (within 20 minutes) after tail clip in FVIII-/- mice. However, TAFI-CIIYQ did not correct delayed bleeding after tail clip or joint injury, resulting in low hematocrits similar to untreated, injured FVIII-/- mice. After joint bleeding, TAFI-CIIYQ, but not WT-TAFI, normalized hemophilic vascular dysfunction. Specifically, TAFI-CIIYQ reduced vascular leakage in injured FVIII-/- mice from 1.8 to 1.3-fold (n=8; p< 0.005). Additionally, TAFI-CIIYQ prevented the formation of abnormally enlarged CD31+ vessels (≥ 20µm diameter), typical for vascular dysfunction in hemophilia after joint bleeding (p< 0.001; Figure A). Finally, 3D imaging of isolectin B4-AF568-perfused synovial vessels confirmed normalization of the vasculature by TAFI-CIIYQ with a 30% reduction in vascular volume compared to untreated, injured FVIII-/- mice (Figure B).
Conclusions: Although plasma TAFI-CIIYQ did not prevent hemophilic joint bleeding, it did normalize bleeding-induced vascular defects in hemophilic joints by stabilizing the vascular barrier and preventing aberrant vessel enlargement. These data support further evaluation of TAFI variants with extended enzymatic stability as a potential therapy to correct vascular dysfunction in hemophilic joint disease.


[(A) Large vessel count and (B) 3D imaging of the vasculature in FVIII KO mouse joints.]

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