title: Acquired coagulant factor VIII deficiency induced by Bacillus anthracis lethal toxin in mice.
abstract: Mice treated with anthrax lethal toxin (LT) exhibit hemorrhage caused by unknown mechanisms. Moreover, LT treatment in mice induced liver damage. In this study, we hypothesized that a suppressed coagulation function may be associated with liver damage, because the liver is the major producing source of coagulation factors. The hepatic expression of coagulant factors and the survival rates were analyzed after cultured cells or mice were exposed to LT. In agreement with our hypothesis, LT induces cytotoxicity against hepatic cells in vitro. In addition, suppressed expression of coagulation factor VIII (FVIII) in the liver is associated with a prolonged plasma clotting time in LT-treated mice, suggesting a suppressive role of LT in coagulation. Accordingly, we further hypothesized that a loss-of-function approach involving treatments of an anticoagulant should exacerbate LT-induced abnormalities, whereas a gain-of-function approach involving injections of recombinant FVIII to complement the coagulation deficiency should ameliorate the pathogenesis. As expected, a sublethal dose of LT caused mortality in the mice that were non-lethally pretreated with an anticoagulant (warfarin). By contrast, treatments of recombinant FVIII reduced the mortality from a lethal dose of LT in mice. Our results indicated that LT-induced deficiency of FVIII is involved in LT-mediated pathogenesis. Using recombinant FVIII to correct the coagulant defect may enable developing a new strategy to treat anthrax.
authors.affiliation: a Department of Molecular Biology and Human Genetics; Tzu-Chi University ; Hualien , Taiwan.
authors.forename: Der-Shan
authors.initials: DS
authors.lastname: Sun
authors.forename: Po-Chien
authors.initials: PC
authors.lastname: Lee
authors.forename: Jyh-Hwa
authors.initials: JH
authors.lastname: Kau
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Shih
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Huang
authors.forename: Chen-Ru
authors.initials: CR
authors.lastname: Li
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Lee
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Kuo-Ching
authors.initials: KC
authors.lastname: Chen
authors.forename: Hsin-Hou
authors.initials: HH
authors.lastname: Chang
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000633:toxicity*; D001408:Bacillus anthracis / Q000472:pathogenicity; D001427:Bacterial Toxins / Q000633:toxicity*; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005169:Factor VIII / Q000008:administration & dosage / Q000378:metabolism; D006467:Hemophilia A / Q000139:chemically induced* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D011994:Recombinant Proteins / Q000008:administration & dosage; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C030325:anthrax toxin; D014859:Warfarin; D005169:Factor VIII
keywords: Anthrax; coagulation factor VIII; hemorrhage; lethal toxin