The Subcommittee met Sunday, June 21, at the E1 room Cankarjev Dom, Ljubljana, Slovenia, from 1:00 to 5:40. Presiding chair was Dr. Francesco Rodeghiero. Dr. J.E. Sadler could not attend.

Attendance was approximately 80.

Dr. A.B. Federici chaired the presentations of existing national registries of VWD. Some countries appear to have well-structured registries including Italy (Dr. A.B. Federici with 1,314 patients from 16 centers), U.K. (J. Pasi with 5,100 patients). Dr. Pasi, on behalf of Dr. Lillicrap, presented data on VWD in Canada (720 patients). Dr. M. Nishino reported data from the 1991 survey in Japan (735 patients); a national survey of 1998 is being analyzed. No registry or surveys are available in Germany, as reported by Dr. U. Budde. Dr. A.J. Cohen (reported by A.B. Federici) analyzed the current practice in the management of VWD in North America, based on a questionnaire mailed to 194 physicians. Dr. A. Srivrastava (India) is trying to set up a registry of VWD and hemophilia in his country, including the most severe cases (personal communication).

Dr. A.B. Federici presented a progress report on the International Registry on acquired von Willebrand syndrome, co-chaired with Dr. J. H. Rand. So far, 50 Centers have provided information on 209 cases.

The issue of molecular diagnosis of VWD was discussed in a "round table" chaired by Dr. I. Peake. Dr. Peake described a strategy including the need for full gene analysis in type 1 and 3 and for the distinction of mutations from polymorphisms. Each new mutation should be proved by linkage within the family, by analyzing mRNA and possibly by expressing the mutated gene. Dr. R. Schneppenheim added an important comment on this issue by emphasizing the need of detailed phenotypic study to guide the subsequent molecular strategies and provided data on a cytosine deletion in exon 18 in type 3 VWD in Europe. Dr. D. Meyer updated the results of the French Network on molecular abnormalities in type 2 VWD: 182 unrelated cases characterized either in Bicetre (D. Meyer) or Lille (C. Mazurier). Dr. J. Eikenboom addressed the problems in tracing the mutated allele in VWD with intragenic polymorphisms. This approach led to unequivocal results in type 2A, 2B, 2M (subtype "Vicenza") and type 3 VWD, but proved difficult in type 1.

Dr. P. Jones suggested to rename "von Willebrand disease" with "von Willebrand disorder" to diminish the impact of diagnosis, especially in mild cases, in patients and in the community.

Dr. Rodeghiero presented the final version of the project for a multicenter retrospective study on VWD type 1 diagnosis. The study implies direct reinvestigation of carriers of type 1 and 3 and their relatives. Interested centers are invited to participate.

Dr. B. Montgomery chaired a session on the standardization of laboratory diagnosis of VWD and presented data on 12 centers assaying VWF, RiCof, VIII:C and multimers and making a diagnosis in established type 1 and 2 VWD samples. This set of plasma samples was proposed for a multinational performance evaluation. Dr. E. Preston reported the results of the UK NEQAS on the performance of a new "functional" antigenic assay, using MoAbs that recognize a specific epitope on VWF interacting with GpIb. This method does not appear to correlate well with VWF:RiCof and might misdiagnose type 2A patients. Dr. A. R. Hubbard presented the results of the calibration studies involving 25 laboratories from 10 countries of the proposed 4th IS Factor VIII/VWF plasma (now intended also for VWF: collagen binding) in replacement of the current 3rd IS plasma.

Dr. C. Mazurier chaired a session on the measurement of VWF in concentrates for therapy of VWD. Dr. Mazurier stressed the importance that manufacturers clearly state the type and characteristics of the assay used to label the concentrate VWF content. The need for a reproducible assay, as well for a standard reference material and appropriate clinical trials, was further addressed by Dr. M.J. Weinstein. Accordingly, products can be licensed for the VWD indications based on pharmacokinetic measurements, clinical trials and demonstration of product consistency. Dr. T.W. Barrowcliffe presented data indicating that a plasma standard may not be entirely adequate for measuring VWF content in concentrates and that a concentrate standard may be useful to improve parallelism of bioassays. Furthermore, the wide difference in the ratios of VWF:Ag to FVIII:C in available concentrates hampers any comparison of their therapeutic effectiveness.

Dr. P.M. Mannucci emphasized the importance of basing substitutive therapy in VWD on FVIII:C. In rare instances, mucosal bleeding could require normalization of bleeding time.
 

SUMMARY OF SUBCOMMITTEE ACTIVITIES
 

The information provided by available national registries or surveys has been considered sufficient. Uniform entering criteria are needed before fostering additional national registries

Creation of a WP to prospectively evaluate diagnostic criteria for AVWS

Creation of a WP for molecular diagnosis of type 1 VWD

Further studies are needed before the "functional" ELISA can be proposed as a substitute of VWF:RC of activity

Updating of the International Registry on AVWS.

The WP on AVWS will prepare a protocol for prospective evaluation of AVWS diagnosis.

Activation of the multicenter, retrospective study for the diagnostic criteria for type 1 and type 3 VWD.

Creation of a WP to test the ability to diagnose VWD subtypes through a kit of VWF plasma and concentrates standards, and plasma samples from VWD subtypes and controls.

The proposal that the 4th IS be assigned the mean of the estimates vs. the 3rd IS and the local plasma pools for VWF:Ag and VWF:Rcof will be submitted to the members of the Subcommittee.

The WP for VWF assay in concentrates will cooperate with FDA and NIBSC to establish a new concentrate standard to be calibrated against normal plasma.