Apologies have been received from Dr. D. DiMichele and Dr. R. Schwaab for their absence.
Final Reports
The Nijmegen-Kingston modification of the Bethesda assay has been published as a SSC Communication for Thrombosis and Haemostasis (Thromb. Haem., 1998; 79, 872).A manuscript on the North American Immune Tolerance Registry is soon to be expected (Dr. D. DiMichele).
The final report on the Registry of Factor VIII and IX Concentrates was presented by Dr. C. Kasper. The Subcommittee approved the report and it will be forwarded to members of the F VIII/IX SSC followed by submission to ISTH for publication. The FVIII/IX SSC recommended an ongoing update of the registry be made available on the ISTH homepage on the Internet.Ongoing Activities
No activities were reported from the working group formed last year on unexpected bleeding in haemophiliacs treated with protease inhibitors. In discussion, the SSC suggested that case-controlled studies should be performed and links established to the North American Haemophilia Society Study Group in this area, and that this effort be coordinated by Dr. Thyn Yee of the Royal Free Hospital.
Dr. G. White stressed the advantage of using PTPs for study of viral safety and immunogenicity of novel or modified products, and was asked to draft a letter to the Editor of Thrombosis and Haemostasis on the matter, passing the letter through the Chair.
Dr. Berntorp had reported to the Chair that inclusion of patients was slow for the safety study of non-infected patients studied by PCR technology, and there was no new data to present this year.
On behalf of Drs. P. Mannucci, C.A. Ludlam and himself, Dr. F. Hill presented the latest version of the amended protocol for safety studies in PUPs. Following discussion, it was recommended that this be the final version passed to the members of the F VIII/IX SSC for final comments prior to submission to ISTH for publication as a recommendation.Standardization Issues
Dr. A. Hubbard reported on the collaborative study for the replacement of the existing WHO Standard for Plasma F VIII/vWF.Dr. T. Barrowcliffe reported on the Collaborative Study for the replacement of the existing WHO Standard for Concentrates (new Standard: 6th International Standard). There was a significant increase of around 20% by the chromogenic method as compared to the one-stage technique. Dr. Barrowcliffe will contact participating laboratories and return to the F VIII/IX SSC with more information.
Dr. T. Barrowcliffe reported on the SSC/5 "Field Type" Collaborative Study on Concentrates, one involving F VIII, the other involving F IX, and proposed a further exercise by October 1998.Dr. M. Weinstein reported on the status of the MEGA-II and hoped to have product vialled by the autumn.
Dr. A. Hubbard reported on the proposed International Standard on F VII Concentrate.
Lastly, Dr. E. Gray summarized data on her study of FIXa standard material, and suggested a future proposal of an International Standard.FVIII Assay Discrepancies
Dr. M. Mikaelsson summarized three studies on the characterization of recombinant factor VIII with and without B-domain, and high purity plasma-derived factor VIII, demonstrating equivalence of activity measured by chromogenic assay and antigen content. In vitro studies showed that excess phospholipid reduces chromogenic activity, particularly for the B-domainless recombinant FVIII. Pharmacokinetic comparisons showed that the use of a consistent assay yielded expected results for both B-domainless recombinant and high purity plasma-derived products.
Dr. D. Owens presented a follow-on study from that presented by Dr. C. Lee at last year's meeting showing that the use of a concentrate standard for assay of both product and post-transfusion samples yielded recoveries close to those expected for both recombinant and plasma-derived FVIII.
In discussion it was agreed that Dr. Barrowcliffe would write a letter of recommendation on this approach to pharmacokinetic studies for forwarding to the FVIII/IX SSC chairman. It was noted that this approach only addresses pharmacokinetic assessments, and not the link between these and patient dosing required for pharmacodynamic considerations.
Dr. J. Ingerslev summarized results from his centre demonstrating an excess of one-stage over chromogenic activity when assessing 68 patients with mild haemophilia, such that 12% of patients would be reclassified as moderate. Similar data had been published by Dr. Mazurier and shown to be associated with mutations at around residue 530 of FVIII.
Dr. Oldenburg presented six cases from four mild haemophilic families in whom chromogenic activity was normal despite one-stage coagulant activities being reduced and showed an association with mutations at residues 720 or 1689.Inhibitors
Dr. Lusher summarized the results on transient inhibitors from the three recombinant FVIII PUP studies, suggesting that these might be characterized as (1) low level inhibitors present in serial samples but then disappearing, but associated with low recoveries while present, (2) low level in serial samples which then disappear but reappear later (3) inhibitors only ever described in single samples (probably false positives). In discussion the need for a consistent definition of inhibitor type, the need to define tolerance therapy regimes and the option of linking inhibitor type with specific FVIII gene defects were raised.
On behalf of Dr. F. Rosendaal, Dr. J. Ingerslev made a formal proposal to form a Working Party on the Nomenclature of Inhibitors
Dr. S. Kitchen presented data from recent NEQAS studies among 67 UK haemophilia laboratories, showing a wide variation in inhibitor potency assessment for three (two haemophiliac and one acquired) inhibitor plasma. He proposed that a similar exercise be undertaken internationally, led by Prof. E Preston, under SSC auspices, and invited interested laboratories to participate in this.
Dr. C. Hay presented the outcome of a recent meeting in Bonn on the planned "International Controlled Comprehensive Cohort Study of Immune Tolerance Induction." The plan is to recruit 150 patients over two to three years and compare a low and a high dose regime in this area. After some discussion the meeting agreed that the proposal merited support of the FVIII/IX subcommittee and that it would be circulated to invite their support.
Dr. J. Ingerslev reported that Dr. G. Mariani was inviting participation in a new registry of any patients entered into tolerance regimes, with a view to linking this to data on their gene changes.
Dr. Oldenburg provided a summary of recent progress on the FVIII gene mutations and HLA types associated with the formation of FVIII inhibitors. Together with Dr. Schwaab he proposed the formation of a "Working Group on the Surveillance of Genetics and the Development of Inhibitors."Miscellaneous
Dr. W. Schramm gave a presentation on a multicentre European study comparing the costs of prophylactic and on-demand therapy of haemophilia, and providing some data on the improved quality of life afforded by the more expensive prophylactic option.SUMMARY OF NEW ACTIVITIES
Formation of new Working Groups on: