SUMMARY Factor VIII-containing materials were administered to four severely affected haemophiliacs twice weekly in doses calculated to raise the factor VIII level to either 15 % or 30 % of average normal. The pooled results from those patients with statistically similar baseline bleeding frequencies showed a significant reduction in bleeding frequency on both doses in the first 48 hours. The 30 % dose produced a more significant reduction than the 15 % dose in the first 24 hours, but there was no significant difference between the two doses in the second 24 hours. It appears that to reduce the bleeding frequency of severely affected haemophiliacs by 60 % would require a two-and-ahalf-fold increase in therapeutic materials. A 90 % reduction would need nine times the amount of material currently in use.There have been great advances in the management of haemophiliac bleeds over the past decade but little attention has been paid to their prevention. Conflicting results have been reported in the trials of prophylaxis (Robinson et al., 1967;Nilsson et al., 1970;Ramsay and Parker, 1973). This may have been due in part to the several sources of potential observer and patient bias inherent in any attempt to evaulate such a regime. A double-blind controlled trial of prophylactic treatment has been carried out at the Treloar Haemophilia Centre (Aronstam et al., 1976) where personnel facilities and geographic considerations permit the separation of clinical management and trial administration. The weekly administration of factor VIII-containing material calculated to raise the factor VIII level to 0-25 IU/ml (25% of average normal) reduced the overall bleeding frequency in nine severe haemophiliacs by 15%. Analysis of the results on each individual day after a prophylactic dose showed a two-thirds reduction of bleeding frequency over the first two and one-third days. It was calculated that a two-and-a-half-fold increase in therapeutic materials would be needed to achieve this substantial reduction in bleeding frequency.In view of the implications for the limited financial and human resources available to service such a commitment, it is important to confirm these findings and to establish the lowest dose which might be "Present address:
SUMMARY The in vivo recovery of factor VIII has been estimated on 84 occasions in 53 severely affected adolescent haemophiliacs. There was wide individual variation in recovery, which was not affected by differences in the administered dose. Recovery increased steadily with increasing surface area, and it was only over a surface area of 1-7 m2 that a recovery of 2% of factor VIII per unit per kg became the norm. It is suggested that the only safe assumption to make below that surface area is an in vivo recovery of 1[5 %.The treatment of haemophilic haemarthroses with inadequate doses of factor VIII will predispose the joints to chronic synovitis, progressive arthropathy, and ultimately to crippling deformity.' There are, however, potentially harmful side effects associated with adequate and excessive exposure to factor VIIIcontaining materials,2 which also strain human and financial resources.3 Clearly, the use of the correct dose of factor VIII in varying situations is of great importance.Recent studies have identified minimum dosage schedules for bleeds of varying severity in specific sites,4 and in joints with or without previous and/or present damage. Patients and methodsThe subjects studied were 53 severely affected adolescent haemophiliacs (factor VIIIC < 1 %) resident at the Lord Mayor Treloar College. Blood samples were taken immediately before and between 20 and 30 minutes after infusions of factor VIII-containing material. Samples were immediately dispensed into plastic tubes containing 3 8 % sodium citrate (9 vols blood to 1 vol anticoagulant). The plasma was separated within two hours by centrifuging at 2000 g at 4°C and tested immediately.Factor VIIIC was tested by a two stage method modified from that of Denson." During the year in which the study took place, approximately 700 factor VIII assays were undertaken in our laboratory, 10 % of which were done in duplicate. Average variation between operators was never more than 10%.All weights and heights used were obtained within two months of the relevant estimation.
A high molecular weight sulphated (18.4%) proteoglycan was isolated from extracts of Codium fragile ssp. atlanticum by molecular exclusion chromatography on Sepharose 2B. Ion exchange chromatography, using Sepharose CL-6B, of lower molecular weight components eluted from the Sepharose 2B column gave two major products with sulphate contents of 10.2% and 7.5%, respectively. Anticoagulant activities of each of the three products were assessed using coagulation techniques and chromogenic substrate assays. An increase in anticoagulant effect was demonstrated by increasing concentration and sulphate content of each algal component. The mechanism of anticoagulant action was shown to be, principally, anti-thrombin in character due to potentiation of heparin cofactor II and antithrombin III activity. Although the anticoagulant substances described are unlikely to be used as antithrombotic therapeutic agents, they have uses as biomedical reagents for investigation of the processes of thrombin inhibition.
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