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The hyperfibrinolytic state of mice with combined thrombin‐activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor‐1 gene deficiency is critically dependent on TAFI deficiency
Author(s) -
VERCAUTEREN E.,
PEETERS M.,
HOYLAERTS M. F.,
LIJNEN H. R.,
MEIJERS J. C. M.,
DECLERCK P. J.,
GILS A.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12036
Subject(s) - thromboelastometry , fibrinolysis , plasminogen activator , plasminogen activator inhibitor 1 , fibrin , endocrinology , ex vivo , medicine , chemistry , in vivo , knockout mouse , antifibrinolytic , t plasminogen activator , immunology , whole blood , biology , receptor , tranexamic acid , blood loss , microbiology and biotechnology , surgery
Summary. Background : Mice with single gene deficiency of thrombin‐activatable fibrinolysis inhibitor (TAFI) or plasminogen activator inhibitor‐1 (PAI‐1) have an enhanced fibrinolytic capacity. Objectives : To unravel the function and relevance of both antifibrinolytic proteins through the generation and characterization of mice with combined TAFI and PAI‐1 gene deficiency. Results : Mating of TAFI knockout (KO) mice with PAI‐1 KO mice resulted in the production of TAFI/PAI‐1 double‐KO mice that were viable, were fertile, and developed normally. In a tail vein bleeding model, the bleeding time and hemoglobin content of the TAFI/PAI‐1 double‐KO mice did not deviate significantly from those of the single‐KO mice or of the wild‐type (WT) counterparts. Interestingly, in ex vivo rotational thromboelastometry measurements with whole blood samples, TAFI KO mice and TAFI/PAI‐1 double‐KO mice were more sensitive to fibrinolytic activation with tissue‐type plasminogen activator than WT or PAI‐1 KO mice. This enhanced fibrinolytic capacity was confirmed in vivo in a mouse thromboembolism model, as shown by decreased fibrin deposition in the lungs of TAFI KO mice and TAFI/PAI‐1 double‐KO mice as compared with WT or PAI‐1 KO mice. Conclusions : TAFI gene inactivation predominantly contributes to the increased fibrinolytic capacity of TAFI and PAI‐1 double‐gene‐deficient mice, as observed in some basic thrombosis models.