Spontaneous Inhibitors of Factor VIII

Factor‐VIII inhibitors accompanying severe allergic reactions to penicillin have now been described in six patients. The inhibitor in the present case was identified as an IgG‐globulin, and seemed to originate from the altered immunologic state induced by the allergic reaction, rather than being specifically related to penicillin or penicillin antibody. During the performance of these experiments it was observed that unusually strong solutions of penicillin were capable of removing antibody globulin from plasma. After incubation with penicillin, the Factor‐VIII inhibitors of non‐haemophilic origin (designated ‘spontaneous’inhibitors) appeared to retain greater activity than did those of haemophiliacs. The reason for this greater activity was made clear by an examination of the kinetics of the reaction between spontaneous inhibitors and Factor VIII. Spontaneous inhibitors were capable of inactivating amounts of Factor VIII out of proportion to their degree of dilution. They also inactivated the Factor VIII more rapidly than did haemophilic inhibitors, but permitted more residual Factor‐VIII activity. This residual activity was reduced more than expected by subsequent incubation with haemophilic inhibitors, and less than expected with spontaneous inhibitors. It was suggested that one molecule of a spontaneous inhibitor was capable of complexing more than one molecule of Factor VIII, but that the Factor‐VIII molecules in the complex retained some degree of Factor‐VIII activity. This activity could be removed by subsequent incubation with haemophilic inhibitors but not with spontaneous ones. Identification of the type of inhibitor was important from a therapeutic standpoint. While repeated additions of Factor VIII to the plasma of patients with inhibitors of haemophilic origin resulted in increasing levels of Factor VIII, such was not the case with spontaneous inhibitors. If the initial addition of Factor VIII failed to provide a therapeutic level, repeated additions were not likely to do so. Although the kinetics of the reaction between spontaneous inhibitors and porcine AHG were similar to those described with human Factor VIII, the inhibitors were always less active against the animal preparation. Treatment with d ‐penicillamine, high concentrations of penicillin, immunosuppressive agents, and corticosteroids proved to be of limited value in patients with spontaneous inhibitors. It was concluded that a vigorous attack on the coexistent disorder responsible for stimulating the production of the inhibitor offered the best prognosis for the patient.