1. Two cases of hemophilia are presented in whom the development of a circulating anticoagulant was detected. This anticoagulant was demonstrated in the whole blood, plasma, and serum of both patients.
2. Both patients became refractory to treatment with either fresh whole blood, plasma, or antihemophilic globulin (Fraction I of Cohn). In fact, the anticoagulant apparently made its appearance as a result of repeated transfusions or injections of antihemophilic globulin.
3. The anticoagulant in each case was shown not to inhibit any of the elements participating in the classical theory of clotting, i.e., prothrombin, thromboplastin, thrombin or fibrinogen. It was also demonstrated that this anticoagulant was not related to heparin in its mechanism of action.
4. Electrophoretic fractionation of the plasma was carried out, and it was found that the anticoagulant was associated with the gamma globulin fraction of plasma.
5. The demonstration of specific precipitin titres in the serum of each of these patients against antihemophilic globulin seemed to indicate that the mechanism of action of the anticoagulant was to inhibit the action of antihemophilic globulin. This was further substantiated by the in vitro inhibition of the ability of antihemophilic globulin to accelerate the coagulation time of ordinary hemophilic blood.
6. A hypothesis is presented to explain the appearance of the anticoagulant. It is believed that these two hemophiliacs are deficient in or lack antihemophilic globulin in their blood, and hence repeated injections of the globulin either in the form of whole blood, plasma, or Fraction I of Cohn results in "isoimmunization" against the injected globulin. The resulting antibodies inhibit any antihemophilic globulin which may then be injected and hence explain the refractory state exhibited by these two cases. Blood from these patients containing these antibodies likewise exerts an anticoagulant influence when added to normal blood by the same mechanism.
7. A discussion of the implications of this phenomenon in the development of a refractory phase in hemophilia is presented.