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

Tine Wyseure; Esther J. Cooke; Paul J. Declerck; Niels Behrendt; Joost C.M. Meijers; Annette Von Drygalski; Laurent O. Mosnier

doi:10.1182/blood-2018-01-828434

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

Tine Wyseure, Esther J. Cooke, Paul J. Declerck, Niels Behrendt, Joost C.M. Meijers, Annette Von Drygalski, Laurent O. Mosnier^*

^*Corresponding author for this work

14 Citations (Scopus)

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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 (FVIII²/²) mice. Both aHA and FVIII2/2 mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII2/2 mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI2/2 mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII2/2 mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII2/2 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 FVIII2/2 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. (Blood. 2018;132(15):1593-1603)

Original language	English
Journal	Blood
Volume	132
Issue number	15
Pages (from-to)	1593-1603
Number of pages	11
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2018-01-828434
Publication status	Published - 2018

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@article{dce9968dcdf549289cb38cb9ab550c27,

title = "Defective TAFI activation in hemophilia a mice is a major contributor to joint bleeding",

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 (FVIII2/2) mice. Both aHA and FVIII2/2 mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII2/2 mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI2/2 mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII2/2 mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII2/2 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 FVIII2/2 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. (Blood. 2018;132(15):1593-1603)",

author = "Tine Wyseure and Cooke, {Esther J.} and Declerck, {Paul J.} and Niels Behrendt and Meijers, {Joost C.M.} and {Von Drygalski}, Annette and Mosnier, {Laurent O.}",

year = "2018",

doi = "10.1182/blood-2018-01-828434",

language = "English",

volume = "132",

pages = "1593--1603",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "15",

}

TY - JOUR

T1 - Defective TAFI activation in hemophilia a mice is a major contributor to joint bleeding

AU - Wyseure, Tine

AU - Cooke, Esther J.

AU - Declerck, Paul J.

AU - Behrendt, Niels

AU - Meijers, Joost C.M.

AU - Von Drygalski, Annette

AU - Mosnier, Laurent O.

PY - 2018

Y1 - 2018

N2 - 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 (FVIII2/2) mice. Both aHA and FVIII2/2 mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII2/2 mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI2/2 mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII2/2 mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII2/2 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 FVIII2/2 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. (Blood. 2018;132(15):1593-1603)

AB - 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 (FVIII2/2) mice. Both aHA and FVIII2/2 mice bled severely after tail transection, but consistent with clinical findings, joint bleeding was notably milder in aHA compared with FVIII2/2 mice. Focus was directed to thrombin-activatable fibrinolysis inhibitor (TAFI) to determine its potentially protective effect on joint bleeding in aHA. Joint bleeding in TAFI2/2 mice with anti-FVIII antibody was increased, compared with WT aHA mice, and became indistinguishable from joint bleeding in FVIII2/2 mice. Measurements of circulating TAFI zymogen consumption after joint injury indicated severely defective TAFI activation in FVIII2/2 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 FVIII2/2 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. (Blood. 2018;132(15):1593-1603)

U2 - 10.1182/blood-2018-01-828434

DO - 10.1182/blood-2018-01-828434

M3 - Journal article

C2 - 30026184

AN - SCOPUS:85054758413

SN - 0006-4971

VL - 132

SP - 1593

EP - 1603

JO - Blood

JF - Blood

IS - 15

ER -

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

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