Twenty-two patients with classic hemophilia were studied from the point of view of refractoriness to the usual coagulation-promoting effect of whole blood, and of chemically prepared plasma fractions. Of these, 5 patients showed clinical and laboratory evidence of refractoriness to therapy. All had previously received by intravenous injection for therapeutic purposes during bleeding episodes large amounts of plasma fractions in addition to whole blood and plasma. Subsequently, each refractory patient exhibited a poor clinical response to therapy during hemorrhagic episodes. Thus, despite the administration of whole blood, plasma, or plasma derivatives in amounts which were usually effective, bleeding continued unabated and the blood coagulation time was not significantly reduced.

An anticoagulant distinct from antithrombin, antithromboplastin, antiprothrombin and heparin was demonstrated in the plasma of each patient. Each had adequate amounts of fibrinogen and prothrombin in the circulating plasma. However, antibodies were demonstrated in the plasma of each patient by means of precipitin reactions with antigens possessing antihemophilic activity, including various plasma derivatives and Fraction I of Cohn. No such antibodies were demonstrable in a normal individual, in 2 anemic patients who had received many transfusions of whole blood, or in a patient with afibrinogenemia who had received large amounts of antihemophilic globulin because of its fibrinogen content. Prompt reduction in plasma anticoagulant activity, in precipitin titer, and coagulation time were effected only by the administration of large quantities of fresh whole blood. A secondary rise of antibodies always followed such a procedure within several days. When therapy was withheld, the anticoagulant effect and precipitin titer decreased in one patient over a period of six months and in another, had essentially disappeared by the end of a year.

From these studies the following conclusions may be drawn:

1. A refractory state in hemophilia may develop following the therapeutic use of whole blood, plasma or chemically prepared plasma fractions.

2. This state is characterized by defective clinical and laboratory responses to therapy with whole blood, plasma or plasma fractions. An anticoagulant is demonstrable in the plasma as well as precipitins to various plasma derivatives possessing antihemophilic activity.

3. The formation of antibodies is apparently an immunologic response to a substance closely associated with antihemophilic activity in normal blood and in plasma derivatives previously employed in therapy.

4. The refractory state can be promptly and temporarily abolished and good clinical and laboratory responses can be effected by transfusions of very large amounts of fresh whole blood.

5. Because of their demonstrated ability to act as antigens in certain hemophilic patients, whole blood, plasma and chemically prepared plasma fractions should be withheld unless their employment as an emergency therapeutic measure is necessary.

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