Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice. / Stagaard, Rikke; Ley, Carsten Dan; Almholt, Kasper; Olsen, Lisbeth Høier; Knudsen, Tom; Flick, Matthew J.

In: Blood advances, Vol. 2, No. 22, 2018, p. 3126-3136.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Stagaard, R, Ley, CD, Almholt, K, Olsen, LH, Knudsen, T & Flick, MJ 2018, 'Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice', Blood advances, vol. 2, no. 22, pp. 3126-3136. https://doi.org/10.1182/bloodadvances.2018024851

APA

Stagaard, R., Ley, C. D., Almholt, K., Olsen, L. H., Knudsen, T., & Flick, M. J. (2018). Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice. Blood advances, 2(22), 3126-3136. https://doi.org/10.1182/bloodadvances.2018024851

Vancouver

Stagaard R, Ley CD, Almholt K, Olsen LH, Knudsen T, Flick MJ. Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice. Blood advances. 2018;2(22):3126-3136. https://doi.org/10.1182/bloodadvances.2018024851

Author

Stagaard, Rikke ; Ley, Carsten Dan ; Almholt, Kasper ; Olsen, Lisbeth Høier ; Knudsen, Tom ; Flick, Matthew J. / Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice. In: Blood advances. 2018 ; Vol. 2, No. 22. pp. 3126-3136.

Bibtex

@article{fd448a795f7a49c4a3397d88a1e6f71d,
title = "Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice",
abstract = "Plasminogen deficiency is associated with severely compromised fibrinolysis and extravascular deposition of fibrin. In contrast, coagulation factor VIII (FVIII) deficiency leads to prolonged and excessive bleeding. Based on opposing biological functions of plasminogen and FVIII deficiencies, we hypothesized that genetic elimination of FVIII would alleviate the systemic formation of fibrin deposits associated with plasminogen deficiency and, in turn, elimination of plasminogen would limit bleeding symptoms associated with FVIII deficiency. Mice with single and combined deficiencies of FVIII (F8-/-) and plasminogen (Plg-/-) were evaluated for phenotypic characteristics of plasminogen deficiency, including wasting disease, shortened lifespan, rectal prolapse, and multiorgan fibrin deposition. Conversely, to specifically examine the role of plasmin-mediated fibrinolysis on bleeding caused by FVIII deficiency, F8-/- and F8-/-/Plg-/- mice were subjected to a bleeding challenge. Mice with a combined deficiency in FVIII and plasminogen displayed no phenotypic differences relative to mice with single FVIII or plasminogen deficiency. Plg-/- and F8-/-/Plg-/- mice exhibited the same penetrance and severity of wasting disease, rectal prolapse, extravascular fibrin deposits, and reduced viability. Furthermore, following a tail vein-bleeding challenge, no significant differences in bleeding times or total blood loss could be detected between F8-/- and F8-/-/Plg-/- mice. Moreover, F8-/- and F8-/-/Plg-/- mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg-/- mice developed independently of FVIII-dependent coagulation, and elimination of plasmin-driven fibrinolysis did not play a significant role in a nonmucosal bleeding model in hemophilia A mice.",
author = "Rikke Stagaard and Ley, {Carsten Dan} and Kasper Almholt and Olsen, {Lisbeth H{\o}ier} and Tom Knudsen and Flick, {Matthew J}",
note = "{\textcopyright} 2018 by The American Society of Hematology.",
year = "2018",
doi = "10.1182/bloodadvances.2018024851",
language = "English",
volume = "2",
pages = "3126--3136",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "22",

}

RIS

TY - JOUR

T1 - Absence of functional compensation between coagulation factor VIII and plasminogen in double-knockout mice

AU - Stagaard, Rikke

AU - Ley, Carsten Dan

AU - Almholt, Kasper

AU - Olsen, Lisbeth Høier

AU - Knudsen, Tom

AU - Flick, Matthew J

N1 - © 2018 by The American Society of Hematology.

PY - 2018

Y1 - 2018

N2 - Plasminogen deficiency is associated with severely compromised fibrinolysis and extravascular deposition of fibrin. In contrast, coagulation factor VIII (FVIII) deficiency leads to prolonged and excessive bleeding. Based on opposing biological functions of plasminogen and FVIII deficiencies, we hypothesized that genetic elimination of FVIII would alleviate the systemic formation of fibrin deposits associated with plasminogen deficiency and, in turn, elimination of plasminogen would limit bleeding symptoms associated with FVIII deficiency. Mice with single and combined deficiencies of FVIII (F8-/-) and plasminogen (Plg-/-) were evaluated for phenotypic characteristics of plasminogen deficiency, including wasting disease, shortened lifespan, rectal prolapse, and multiorgan fibrin deposition. Conversely, to specifically examine the role of plasmin-mediated fibrinolysis on bleeding caused by FVIII deficiency, F8-/- and F8-/-/Plg-/- mice were subjected to a bleeding challenge. Mice with a combined deficiency in FVIII and plasminogen displayed no phenotypic differences relative to mice with single FVIII or plasminogen deficiency. Plg-/- and F8-/-/Plg-/- mice exhibited the same penetrance and severity of wasting disease, rectal prolapse, extravascular fibrin deposits, and reduced viability. Furthermore, following a tail vein-bleeding challenge, no significant differences in bleeding times or total blood loss could be detected between F8-/- and F8-/-/Plg-/- mice. Moreover, F8-/- and F8-/-/Plg-/- mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg-/- mice developed independently of FVIII-dependent coagulation, and elimination of plasmin-driven fibrinolysis did not play a significant role in a nonmucosal bleeding model in hemophilia A mice.

AB - Plasminogen deficiency is associated with severely compromised fibrinolysis and extravascular deposition of fibrin. In contrast, coagulation factor VIII (FVIII) deficiency leads to prolonged and excessive bleeding. Based on opposing biological functions of plasminogen and FVIII deficiencies, we hypothesized that genetic elimination of FVIII would alleviate the systemic formation of fibrin deposits associated with plasminogen deficiency and, in turn, elimination of plasminogen would limit bleeding symptoms associated with FVIII deficiency. Mice with single and combined deficiencies of FVIII (F8-/-) and plasminogen (Plg-/-) were evaluated for phenotypic characteristics of plasminogen deficiency, including wasting disease, shortened lifespan, rectal prolapse, and multiorgan fibrin deposition. Conversely, to specifically examine the role of plasmin-mediated fibrinolysis on bleeding caused by FVIII deficiency, F8-/- and F8-/-/Plg-/- mice were subjected to a bleeding challenge. Mice with a combined deficiency in FVIII and plasminogen displayed no phenotypic differences relative to mice with single FVIII or plasminogen deficiency. Plg-/- and F8-/-/Plg-/- mice exhibited the same penetrance and severity of wasting disease, rectal prolapse, extravascular fibrin deposits, and reduced viability. Furthermore, following a tail vein-bleeding challenge, no significant differences in bleeding times or total blood loss could be detected between F8-/- and F8-/-/Plg-/- mice. Moreover, F8-/- and F8-/-/Plg-/- mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg-/- mice developed independently of FVIII-dependent coagulation, and elimination of plasmin-driven fibrinolysis did not play a significant role in a nonmucosal bleeding model in hemophilia A mice.

U2 - 10.1182/bloodadvances.2018024851

DO - 10.1182/bloodadvances.2018024851

M3 - Journal article

C2 - 30459211

VL - 2

SP - 3126

EP - 3136

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 22

ER -

ID: 222164262