Autoantibody against prothrombin aberrantly alters the proenzyme to facilitate formation of a complex with its physiological inhibitor antithrombin III without thrombin conversion

Acquired coagulation factor inhibitors include pathologic immunoglobulins t hat specifically bind to coagulation factors and either neutralize their pr ocoagulant activity, accelerate their clearance from the circulation, or ha ve proteolytic activity to degrade them into inactive polypeptides. Here, a n autoantibody against prothrombin is described in a patient with serious h emorrhagic diatheses, The autoantibody exerts its influence by a previously unknown mechanism in which it inhibits coagulation through aberrant activa tion of the proenzyme in a catalytic manner. The antibody-bound prothrombin formed a stable stoichiometric complex with antithrombin III, consisting o f intact prothrombin and an antithrombin III molecule cleaved at the (393)A rg-(394)Ser bond. The antibody dissociated from prothrombin after the compl ex formation with antithrombin III. Although the bound antibody elicited pr otease activity from prothrombin, the complex was not able to convert fibri nogen to fibrin or to activate protein C, Thus, this is the first descripti on of an autoantibody that induces protease-like activity from a human proe nzyme, permitting subsequent neutralization by its physiological inhibitor. (C) 2001 by The American Society of Hematology.