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 - 2018/11/27
Y1 - 2018/11/27
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 (F82/2) and plasminogen (Plg2/2) 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, F82/2 and F82/2/Plg2/2 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. Plg2/2 and F82/2/Plg2/2 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 F82/2 and F82/2/Plg2/2 mice. Moreover, F82/2 and F82/2/Plg2/2 mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg2/2 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 (F82/2) and plasminogen (Plg2/2) 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, F82/2 and F82/2/Plg2/2 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. Plg2/2 and F82/2/Plg2/2 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 F82/2 and F82/2/Plg2/2 mice. Moreover, F82/2 and F82/2/Plg2/2 mice responded similarly to recombinant FVIII (rFVIII) therapy. In summary, the pathological phenotype of Plg2/2 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
SN - 2473-9529
VL - 2
SP - 3126
EP - 3136
JO - Blood advances
JF - Blood advances
IS - 22
ER -