Hemophilia: The Mechanism of Development and Action of an Anticoagulant Found in Two Cases

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Abstract
The presence of a circulating anticoagulant which could prolong the coagulation time of normal blood was demonstrated repeatedly in the blood of 2 patients with hemophilia during their hemorrhagic episodes. The anticoagulant was not antagonistic to any one of the components of the classical theory of coagulation. By electrophoretic fractionation of the plasma into 4 fractions, it was found that all fractions except that containing only [gamma] globulin inhibited the coagulation of normal plasma. The anticoagulant is apparently a [gamma] globulin and appeared only after repeated transfusions of whole blood or injns. of antihemophilic globulin . To test whether it may be the result of an "immunization" of the patient with some substance in normal blood or Fraction I of Cohn but lacking in the patient''s blood, pre-cipitin tests were done using the sera of the 2 patients against serial dilutions of Fraction I, containing a known amt. of protein and at pH 7.0. There were positive precipitins in the sera of both patients. The anticoagulant was then shown to inhibit directly antihemophilic globulin. An hypothesis is presented to explain the presence of the anticoagulant in the 2 patients. The explanation proposed for the development of a refractory state to transfusion in the 2 subjects, based upon an immunologic response to injns. of a globulin fraction deficient or lacking in their blood, may also be the underlying factor in the refractory phase manifested by many hemophiliacs.