Identification of a monoclonal thrombin inhibitor associated with multiple myeloma and a severe bleeding disorder

Abstract

We investigated a patient with a long-standing IgGκ monoclonal gammopathy who developed severe haemorrhagic complications. At IgG concentrations of ~ 50 g/l the patient had severe bleeding associated with prolongation of the thrombin time, activated partial thromboplastin time, and reptilase time. Plasmapheresis resulted in improvement in the thrombin time and resolution of bleeding. Depletion of the IgG by absorption of plasma with protein G-Sepharose in vitro resulted in normalization of the thrombin time and reptilase time. The purified IgG bound to immobilized thrombin and immunoprecipitated human α-, β- and γ-thrombin but not prothrombin, other vitamin K-dependent coagulation factors, or fibrinogen. Purified IgG at concentrations > 1 x 10-2 g/l decreased (~ 50%) the rate of hydrolysis of a chromogenic substrate by thrombin. Addition of purified IgG to normal pooled plasma at concentrations > 1 x 10-2 g/l prolonged the thrombin time and activated partial thromboplastin time, but the reptilase time was prolonged only at IgG concentrations >1 g/l. This finding suggests that at low concentrations the IgG produces a specific antithrombin effect, but at higher concentrations it also affects fibrin polymerization; the combination of these effects probably produced clinical bleeding. This is the first report of a monoclonal antithrombin antibody associated with bleeding in a patient with multiple myeloma.