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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2455-2458
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Impact of antithrombin deficiency in thrombogenesis:
lipopolysaccharide and stress-induced thrombus formation in
heterozygous antithrombin-deficient mice
Masamitsu Yanada,
Tetsuhito Kojima,
Kazuhiro Ishiguro,
Yukiko Nakayama,
Koji Yamamoto,
Tadashi Matsushita,
Kenji Kadomatsu,
Masahiko Nishimura,
Takashi Muramatsu, and
Hidehiko Saito
From the First Department of Internal Medicine,
Department of Biochemistry, and Institute for Laboratory Animal
Research, Nagoya University School of Medicine, and the Department of
Medical Technology, Nagoya University School of Health Sciences, Nagoya
National Hospital, Japan.
Antithrombin (AT) deficiency is an autosomal disorder associated
with venous thromboembolism. However, a diagnosis of homozygous AT
deficiency is seldom made. Most patients are heterozygous and have
approximately 50% AT activities, and they are at higher risk for the
development of thromboembolism. Through gene targeting we generated
AT-deficient mice and previously reported that completely AT-deficient
mice could not survive the prenatal period because of extensive
thrombosis in the myocardium and liver sinusoids. In contrast,
heterozygous AT-deficient mice with 50% AT activities have not shown
spontaneous thromboembolic episodes. To demonstrate a thrombotic
tendency in heterozygous AT deficiency, we challenged heterozygous
AT-deficient mice (AT+/ mice) with the administration of
lipopolysaccharide (LPS) or with restraint stress by immobilization. LPS injection markedly induced fibrin deposition in the kidney glomeruli, myocardium, and liver sinusoids in AT+/ mice
compared with wild-type mice (AT+/+ mice). Restraint stress
tests were performed by placing mice in 50-mL conical centrifuge tubes
for 20 hours. Fibrin deposition was observed in the kidney of
AT+/+ and AT+/ mice, but AT+/
mice exhibited more extensive fibrin deposition than
AT+/+ mice. After prophylactic administration of human AT
concentrates to increase plasma AT activities of AT+/ mice, LPS-induced fibrin deposition was effectively prevented. These results suggest that heterozygous AT deficiency is significantly associated with a tendency toward thrombosis formation in the kidney.
The AT+/ mouse thus is a useful model for studying the effect of environmental or genetic risk factors on thrombogenesis.
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