Fatal thrombosis of antithrombin-deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice.
BACKGROUND
We previously reported that the targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5 gestational days (gd) because of severe cardiac and hepatic thrombosis.


OBJECTIVE
To investigate the influences of lowered tissue factor (TF) activity upon hypercoagulation of AT-/- embryos, we crossed AT+/- with low TF (mTF-/- hTF+) mice to yield homozygous AT-deficient mice with the extremely low TF activity, that is expressed from the inserted human TF mini gene.


RESULTS
AT-/- embryos either with 50% TF (AT-/- mTF+/- hTF+) or with low (approximately 1% TF, AT-/- mTF-/- hTF+) were not born, although the survival was prolonged until 18.5 gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that the thrombogenesis caused loss of hepatic blood flow. As in original AT-/-, AT-/- mTF+/- hTF+ showed subcutaneous (s.c.) bleeding and also suffered from the myocardial degeneration apparently because of coronary thrombus formation. However, AT-/- mTF-/- hTF+ had no skin hemorrhage and the thrombosis and degeneration were completely abolished in the heart. Myocardium of adult low TF mice had exhibited fibrosis secondary to hemorrhage; however, it was significantly decreased in low TF mice with AT+/-.


CONCLUSIONS
Our current model suggests that, in the heart, TF plays an important role in the thrombogenesis and it counterbalances AT-dependent anticoagulation. AT may be a potent anticoagulant during mice development and the activation and subsequent regulation of TF-procoagulant activity take place differently between the liver and the heart. These differences appear to point to local regulatory mechanisms in murine hemostasis.
Hayashi
M
M
Department of Cardiology, Nagoya University Graduate School of Medicine, Japan.
Matsushita
T
T
Mackman
N
N
Ito
M
M
Adachi
T
T
Katsumi
A
A
Yamamoto
K
K
Takeshita
K
K
Kojima
T
T
Saito
H
H
Murohara
T
T
Naoe
T
T
D000818:Animals; D000990:Antithrombin III / Q000235:genetics / Q000502:physiology*; D006502:Budd-Chiari Syndrome / Q000097:blood / Q000209:etiology; D003328:Coronary Thrombosis / Q000097:blood / Q000209:etiology; D004622:Embryo, Mammalian; D006470:Hemorrhage / Q000209:etiology; D006487:Hemostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D013925:Thromboplastin / Q000172:deficiency / Q000502:physiology*; D013927:Thrombosis / Q000097:blood / Q000209:etiology* / Q000401:mortality
D000990:Antithrombin III; D013925:Thromboplastin