Thrombin-activatable fibrinolysis inhibitor (TAFI) deficient mice.
In order to examine the physiological role of thrombin-activatable fibrinolysis inhibitor (TAFI), we generated homozygous TAFI deficient mice by targeted gene disruption. Intercrossing of heterozygous TAFI mice showed that TAFI mice were born in the expected Mendelian ratio, indicating that transmission of the mutant TAFI allele did not lead to embryonic lethality. TAFI deficient mice developed normally and reached adulthood. No physical abnormalities were observed. They were fertile and pregnancies were carried to full term. Hematological analysis of TAFI deficient mice did not show any major differences compared with their wild type littermates, including plasma fibrinogen level, PT and aPTT. Prolongation of lysis time upon activation of TAFI was observed only with plasma from wild type and heterozygous mice in an in vitro clot lysis assay. TAFI deficiency did not lead to increased bleeding as determined by blood loss following tail transection. In vivo, TAFI deficiency did not influence occlusion time in either an arterial or a venous thrombosis model. The effects of TAFI deficiency were also investigated in thrombin-induced pulmonary thromboembolism, Factor X coagulant protein-induced thrombosis and endotoxin-induced disseminated intravascular coagulation models. In these models, TAFI deficiency did not improve the morbidity or mortality. Based on the kaolin-induced writhing test, TAFI did not play a major role in bradykinin degradation under normal conditions. These studies demonstrate that TAFI deficiency is compatible with murine life
Nagashima
Mariko
M
Department of Cardiovascular Research, Berlex Biosciences, Richmond, CA 94804, USA. Mariko_Nagashima@berlex.com
Yin
Zheng-Feng
ZF
Broze
George J
GJ
Morser
John
J
D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D025901:Carboxypeptidase B2 / Q000235:genetics* / Q000502:physiology*; D002268:Carboxypeptidases / Q000378:metabolism; D005298:Fertility; D005342:Fibrinolysis; D006801:Humans; D007616:Kaolin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D013927:Thrombosis / Q000209:etiology
D007616:Kaolin; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2; D001920:Bradykinin