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A three-year contract research program to study the production of cryoprecipitate has been completed. The investigators have collaborated to propose changes in the methods of production of cryoprecipitate. The investigators believe that the problem of low and variable yield of cryoprecipitate can be overcome and cryoprecipitate can be produced which contains, on an average, at least 100 Factor VIII units in nearly every bag. It is emphasized that breaches of technique and time delays in cryoprecipitate processing must be scrupulously avoided to achieve optimum, standardized yields.

Data on home treatment for patients with haemophilia A (factor VIII deficient haemophilia) were compiled for 1975 and 1976 from questionnaires answered by directors of haemophilia centres throughout the United Kingdom. There were 48 haemophilia centres in 1975 and 71 in 1976. The number of patients on or in training for home treatment increased from 267 to 488 in the two years, and a further 241 haemophiliacs were considered suitable for home therapy by the end of 1976. Apart from a small (but increasing) number of haemophiliacs on prophylactic treatment, most patients were on low-dose (250-500 units) on-demand regimens, using a mean of 20 000 factor VIII units per patient per year in 1976. An estimated 55% of the blood product used for home therapy in the UK in 1976 was imported from commercial sources. Despite the fact that the numbers of patients on home treatment have increased, so that about 60% of the potential population were receiving or being considered for home treatment in 1976, inadequacies in the service still remain. In some centres follow-up is clearly inadequate; about 15% of patients still rely on cryoprecipitate; and too little money has been invested in making the NHS self-sufficient in factor VIII production.

SummaryThe incidence of known inhibitors among patients with severe classic hemophilia seen at Orthopaedic Hospital, Los Angeles, increased from 4.8 percent in 1967 to 7.8 percent in 1972. Possible reasons for the increase may include : 1. selective referral of patients with inhibitor to this center and 2. a three-fold increase in the frequency of plasma product infusion and an eight-fold increase in the factor VIII units infused per year per patient. The incidence of inhibitors was highest among young children; in 1972, 14.6 percent of children under age 10 years and 6 percent of older patients had inhibitors. Several patients developed inhibitors in late adolescence or adulthood, some after little exposure to blood products, and others after many more than a hundred accumulated days of exposure. Anamnestic responses to plasma product infusions occurred in all children under age 4 with inhibitors and all older patients with pre-infusion inhibitor titers of at least two units. Some adolescent or adult patients with low-titer inhibitors received plasma products on several occasions without developing higher titers but later responded to another infusion with a marked rise in titer.

A new method for factor VIII concentrate preparation is proposed. The method is the collection of cryoprecipitate after sedimentation at 4 C in a jacketed glass vessel. The final product is standardized (4.0 +/- 0.3 factor VIII units per ml) and can be infused in hemophilic patients regardless of their ABO blood type. Factor VIII recovery (52.2 +/- 6.4%) is comparable to other processes.

In Pennsylvania, the prevalence of hemophilia is one per 10,000 males. Factor VIII deficiency is five times more frequent than Factor IX deficiency, and 34% of the patients have no relatives affected with the disease. The mean age is 23 years old, and 50% of the patients are less than 20 years old. Approximately one-third of the patients with Factor VIII deficiency and one fourth of the patients with Factor IX deficiency have levels of less than 0.01 mu/ml. By clinical criteria, 55% of those with Factor VIII deficiency are severe compared to 45% of those with Factor IX deficiency. Factor VIII-deficient patients are treated an average of 18 times per year compared to ten times per year for patients with Factor IX deficiency. Hemarthroses account for 70% of the hemorrhages treated and for 40% of the concentrate usage. Home therapy patients use an average of 45,950 Factor VIII units per year at a cost of ø170 per patient and their use accounts for 60% of the total Factor VIII usage of 1.7 million units. Less than five days per patient per year are lost from school or work because of bleeding, and patients are hospitalized for bleeding an average of only two to three days per patient year. Adverse immediate reactions to therapy are infrequent. Five percent of patients have persistence of the hepatitis B virus, and 7.5% have inhibitors. The mortality rate is 0.04% per year, with half of the deaths being hemophilia-related.

Attendances at the Regional Haemophilia Reference Centre in the Edinburgh Royal Infirmary have been analysed over a period of five years from 1969 to 1973. Of 77 patients registered in 1969, 64 had haemophilia A (factor VIII deficiency) and 13 had haemophilia B (factor IX deficiency). In 1973 the numbers were 68 and 14 respectively. An increased attendance at the Centre from 123 in 1969 to 624 in 1973 was noted. This was due to patients reporting earlier and more frequently for outpatient treatment of haemarthroses which occurred with the greater availability of supplies of factor VIII. The number of admissions for inpatient treatment did not change significantly over the period. Haemarthrosis of the knee was the commonest dominant lesion. The amount of replacement therapy in the form of fresh frozen plasma, cryoprecipitate, antihaemophilic fraction, and factors II, IX, and X concentrate used in the Centre (ie, excluding that used for elective procedures) increased from 2704 donor units in 1969 to 8778 donor units in 1973, the main increase being in cryoprecipitate. The number of factor VIII units used per patient attending per year, for both elective and emergency treatment in haemophiliacs, is recorded and discussed as are its effects on the treatment patterns of patients and the implications for the future.

An extensive programme of home administration of factor VIII replacement therapy has been proposed for the haemophiliacs of the Edinburgh Area following the successful training of self-administration therapy in the Haemophilia Centre. A study of 1 moderate and 1 severe haemophiliac, whose factor VIII requirements for the year 1974 were compared with factor VIII usage for “on demand” out-patient therapy at the Centre in 1973, showed these quantities to be 14,380 as compared with 18,100 factor VIII units in the first patient and 46,380 as compared with 38,725 factor VIII units in the severely affected patient. From these figures, and, knowing that the average number of factor VIII units used per patient per years was 8,116 for the moderate and 11,592 for the severe haemophiliacs, it has been calculated that home treatment would require 6,000–10,000 factor VIII units per patient per year for those moderately affected and 9,000–14,000 factor VIII units per patient per year for the latter class. The advantages and hazards of home treatment are discussed and evaluated in the light of the two patients studied and the self-administration programme of therapy at present in operation.

The factor VIII activity in cryoprecipitates prepared from plasma separated from whole blood stored for 21 days was examined. The concentration of factor VIII in plasma separated from outdated blood averaged less than 25 per cent of that found in fresh plasma, and the cryoprecipitate prepared from outdated plasma averaged only 23 factor VIII units per bag. A significant amount of free hemoglobin was present in cryoprecipitates prepared from outdated plasma. Factors in the decrease in plasma factor VIII activity in stored whole blood include both degradation and a change in the cryoprecipitability of factor VIII itself. The findings indicate that cryoprecipitate prepared from plasma separated from outdated blood is of little therapeutic effectiveness.

In studies on continuous infusion of factor VIII for treatment of patients with classic hemophilia, the following regression equation was derived for patients with a factor VIII half-time (T/2) of 13.4 hr± 0.6: Y = (3.1±1.8) + (23.4±0.7)X, where Y is plasma factor VIII units/dl and X is factor VIII dose-rate in units/kg/hr; or, essentially Y = 23.4X. Preliminary studies suggested that the plasma factor VIII level could be correlated with dose-rate for any T/2 as follows: if Y = 23.4X for T/2 of 13.4 hr, then Y = (1.75)(13.4)X where 1.75 is an empiric constant; therefore, Y = (1.75)(T/2)X where T/2 may be any measured plasma factor VIII half-time after a single infusion. The validity of this equation and its application to design of continuous infusion of factor VIII were supported in studies during orthopaedic and dental surgical episodes of three hemophilic patients with factor VIII half-times ranging from 0.7 to 6 hrs. For example, following synovectomy and radial head excision of the left elbow in a child with T/2 of 4 hrs, a plasma factor VIII level of 76 to 86 units/dl was observed during continuous infusion of 9.4 factor VIII units/kg/hr; for this dose-rate and T/2, the expected factor VIII level is 66 units/d1, i.e., 1.75 × 4 × 9.4. This approach is not applicable to design of therapy for patients with potent factor VIII inhibitors (above 20 Bethesda units/m1) in whom T/2 may not be measurable.

Antihemophilic factor concentrate was given on fixed schedules to adults with severe classic hemophilia who had very frequent hemorrhages. While receiving 250 factor VIII units a day, the subjects had almost half as many bleeding episodes as during a baseline period; on a regimen of 500 factor VIII units a day, bleeding episodes occurred about one fourth as often as during the baseline period. When a large dose, 2,000 factor VIII units, was given once a week, no bleeding episodes occurred in the first 48 hours, but occurred again in midweek when factor VIII levels had returned to baseline values. Prophylaxis in hemophilia with factor VIII concentrate is feasible and beneficial; the expense may not be much greater than that of treating random hemorrhages.