title: Autoantibody against prothrombin aberrantly alters the proenzyme to facilitate formation of a complex with its physiological inhibitor antithrombin III without thrombin conversion.
abstract: Acquired coagulation factor inhibitors include pathologic immunoglobulins that specifically bind to coagulation factors and either neutralize their procoagulant activity, accelerate their clearance from the circulation, or have proteolytic activity to degrade them into inactive polypeptides. Here, an autoantibody against prothrombin is described in a patient with serious hemorrhagic diatheses. The autoantibody exerts its influence by a previously unknown mechanism in which it inhibits coagulation through aberrant activation of the proenzyme in a catalytic manner. The antibody-bound prothrombin formed a stable stoichiometric complex with antithrombin III, consisting of intact prothrombin and an antithrombin III molecule cleaved at the (393)Arg-(394)Ser bond. The antibody dissociated from prothrombin after the complex formation with antithrombin III. Although the bound antibody elicited protease activity from prothrombin, the complex was not able to convert fibrinogen to fibrin or to activate protein C. Thus, this is the first description of an autoantibody that induces protease-like activity from a human proenzyme, permitting subsequent neutralization by its physiological inhibitor. (Blood. 2001;97:3783-3789)
authors.affiliation: Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Madoiwa
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: J
authors.initials: J
authors.lastname: Mimuro
authors.forename: S
authors.initials: S
authors.lastname: Furusawa
authors.forename: T
authors.initials: T
authors.lastname: Koyama
authors.forename: T
authors.initials: T
authors.lastname: Sugo
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
authors.forename: Y
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000595:Amino Acid Sequence; D000990:Antithrombin III / Q000378:metabolism*; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D001778:Blood Coagulation Disorders / Q000209:etiology* / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D000939:Epitopes / Q000032:analysis; D005340:Fibrinogen / Q000378:metabolism; D006406:Hematoma / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D011516:Prothrombin / Q000276:immunology* / Q000378:metabolism; D012187:Retroperitoneal Space / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D000990:Antithrombin III; D011516:Prothrombin; D005340:Fibrinogen; D012697:Serine Endopeptidases