A group of hematologists, involved with hemophilia research and care in the U.S.A., met under the sponsorship of the Division of Blood Diseases and Resources of the National Heart and Lung Institute. In order to improve future communication among ourselves, we decided to alter our individual methods of measurement of inhibitors to the extent necessary to permit a uniform, although arbitrary, description of inhibitor units. We agreed to the following standards: (1) The incubation mixture consists of one part citratecl patient plasma, undiluted or diluted, plus an equal part of citrated pooled normal human plasma. (2) A control incubation mixture consists of equal parts of normal pooled plasma and imidazole buffer, as formulated by Dr. Biggs. (3) The mixtures are incubated at 37° C for two hours. (4) Assays specific for Factor VIII are then performed and the Factor VIII activity in the patient mixture is divided by the Factor VIII activity in the control mixture to determine the percent residual Factor VIII activity. (5) A patient plasma giving a residual Factor VIII activity of 50 percent in this test is said to contain one “Bethesda unit” of inhibitor per ml. (6) On a graph, the log percent residual Factor VIII activity is plotted against inhibitor units. If the residual Factor VIII activity of the incubation mixture is between 75 and 25 percent, the inhibitor units are read from the graph. Plasmas containing strong inhibitors are diluted with imidazole buffer before being placed in the incubation mixture. A dilution is sought which will result in a residual Factor VIII activity between 75 and 25 percent. The units of inhibitor read from the graph are then multiplied by the dilution factor to determine the number of Bethesda units of inhibitor per ml of undiluted patient plasma.We invite interested colleagues to join us in the use of this method, and we invite discussion of better methods of describing inhibitor potency.

No abstract

The study reported here was designed to measure the efficacy and safety of a vapor-heated anti-inhibitor coagulant complex (FEIBA-VH) for the treatment of bleeding episodes in patients with hemophilia A who have inhibitors to factor VIII (FVIII). FEIBA-VH, a second-generation complex, is vapor-heated for 10 hours at a temperature of 60 degrees C and a pressure of 1190 millibar (mbar) and for 1 additional hour at 80 degrees C and 1375 mbar. The current study was performed because of concern that this vapor-heating process would reduce the efficacy of FEIBA-VH as compared with non-heat-treated FEIBA (FEIBA). Forty-one patients received FEIBA-VH for 106 evaluable bleeding episodes. Ninety-three (88%) episodes were controlled, and 13 (12%) were not. Eighty-three (79%) episodes were controlled within 36 hours of the first infusion. No significant toxicity was seen. These results were compared with those of an earlier study with FEIBA. FEIBA-VH was at least as effective as FEIBA in controlling bleeding episodes and can be compared favorably to any reported treatment of bleeding episodes in hemophiliacs with inhibitors to FVIII.

Activated prothrombin complex concentrates have been used to treat bleeding episodes for patients who have developed an inhibitor to factor VIII (FVIII). FEIBA-Vh (FVIII bypassing activity, FEIBA) has been used since 1970 for this purpose and with FVIII for immune tolerance programmes. Studies have not been presented to show the safety and efficacy of FEIBA when given over a long period of time to prevent haemophilic arthropathy with bleeding into the joints of these patients. This study was undertaken to ascertain the outcome of haemophilic arthropathy with FEIBA prophylaxis. Data were collected on seven patients with known long-standing high-titre FVIII inhibitors given FEIBA prophylaxis for 3-6(1/2) years. Patients were given 50-100 units of FEIBA three to four times weekly. A functional joint evaluation revealed some degree of arthropathy already present in all patients at time of prophylaxis initiation. Safety was measured by medical status, evidence of thrombosis, life-threatening bleeding and inhibitor titre. Efficacy was measured for joint outcome by a functional physical therapeutic scale. At the conclusion of the study, efficacy was mixed as all of the joints for which the patients were placed on prophylaxis had progressed and developed synovitis. Two patients had a functional improvement in their arthropathy, and all were functional enough to attend regular school. The product was deemed safe for long-term use, as there were no complications of therapy with no thrombosis, no life-threatening bleeding episodes and no anamnesis caused by FEIBA alone. Inhibitor titres fell in all patients over the course of the study. Total product usage ranged from approximately 9373-15,571 U kg(-1) year(-1). FEIBA is safe for long-term prophylaxis when given in the recommended dosage for an extended period of time. Efficacy to prevent arthropathy could not be seen as all patients had some degree of arthropathy at time of prophylaxis initiation. An additional study needs to be performed using FEIBA before arthropathy has developed.