Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice.
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.
Yanada
Masamitsu
M
First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Kojima
Tetsuhito
T
Ishiguro
Kazuhiro
K
Nakayama
Yukiko
Y
Yamamoto
Koji
K
Matsushita
Tadashi
T
Kadomatsu
Kenji
K
Nishimura
Masahiko
M
Muramatsu
Takashi
T
Saito
Hidehiko
H
D000818:Animals; D000991:Antithrombins / Q000172:deficiency* / Q000235:genetics; D004167:Diphtheria Toxin / Q000235:genetics; D005337:Fibrin / Q000032:analysis / Q000096:biosynthesis*; D005340:Fibrinogen / Q000032:analysis; D006580:Genetic Carrier Screening; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics; D013312:Stress, Physiological / Q000503:physiopathology; D013917:Thrombin / Q000096:biosynthesis*
D000991:Antithrombins; D004167:Diphtheria Toxin; D008070:Lipopolysaccharides; D010446:Peptide Fragments; C029795:diphtheria toxin fragment A; D005337:Fibrin; D005340:Fibrinogen; D013917:Thrombin