Format

Send to

Choose Destination
Blood. 2018 Oct 11;132(15):1593-1603. doi: 10.1182/blood-2018-01-828434. Epub 2018 Jul 19.

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

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA.
2
Department of Medicine, University of California San Diego, San Diego, CA.
3
Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium.
4
The Finsen Laboratory, Rigshospitalet/Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
5
Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands; and.
6
Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

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.

PMID:
30026184
PMCID:
PMC6182268
[Available on 2019-10-11]
DOI:
10.1182/blood-2018-01-828434
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center