title: Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura.
abstract: ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation through cleavage of von Willebrand factor (VWF) multimers. In humans, genetic or acquired deficiency in ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP), a condition characterized by thrombocytopenia and hemolytic anemia with microvascular platelet thrombi. In this study, we report characterization of mice bearing a targeted disruption of the Adamts13 gene. ADAMTS13-deficient mice were born in the expected mendelian distribution; homozygous mice were viable and fertile. Hematologic and histologic analyses failed to detect any evidence of thrombocytopenia, hemolytic anemia, or microvascular thrombosis. However, unusually large VWF multimers were observed in plasma of homozygotes. Thrombus formation on immobilized collagen under flow was significantly elevated in homozygotes in comparison with wild-type mice. Thrombocytopenia was more severely induced in homozygotes than in wild-type mice after intravenous injection of a mixture of collagen and epinephrine. Thus, a complete lack of ADAMTS13 in mice was a prothrombotic state, but it alone was not sufficient to cause TTP-like symptoms. The phenotypic differences of ADAMTS13 deficiencies between humans and mice may reflect differences in hemostatic system functioning in these species. Alternatively, factors in addition to ADAMTS13 deficiency may be necessary for development of TTP.
authors.affiliation: National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Banno
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Okuda
authors.forename: Shigenori
authors.initials: S
authors.lastname: Honda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyata
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kato
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000071120:ADAMTS13 Protein; D000743:Anemia, Hemolytic / Q000097:blood / Q000235:genetics / Q000473:pathology; D000818:Animals; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006487:Hemostasis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008666:Metalloendopeptidases / Q000097:blood / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness / Q000235:genetics*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000235:genetics* / Q000473:pathology; D013045:Species Specificity; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein