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also encouraged to consider the views of experts in the field, that an individual will be misdiagnosed in around 25% of occasions
inclusive of recent guidelines.
using this test panel.
Adding a properly optimised VWF:CB assay
to this test panel will substantially reduce error rates, with
Conclusion remaining errors often associated with misinterpretation of
Historically, the diagnosis of VWD can be seen as a dynamically laboratory data rather than actual assay failures.
beginning with the global tests of coagulation, assay standardisation issues prevent the proper universal
several screening tests of platelet function that included the worldwide adoption of VWF:CB assays, and it is doubtful that any
skin-bleeding time and progression to detection of FVIII:C and commercial VWF:CB kit is currently truly fit for purpose.
VWF:Ag. During those years, the identification of VWD remained less
than optimal. The next tests of significance to emerge were those Accordingly, perhaps it is time to consider a paradigm shift to
based on ristocetin (VWF:RCo and RIPA), which appeared in enable the appropriate diagnosis and functional characterisation of
the 1970s. Although these permitted a sort of revolution in the an individual’s VWD, as depicted in Figure 3, and incorporating the
investigation of VWD, diagnosis remained problematic, given the poor use of a DDAVP challenge to identify functional changes in VWF
reproducibility of the VWF:RCo and the poor sensitivity of RIPA for over time. Combined use of the VWF:CB and VWF:RCo may better
VWD. The VWF:CB was originally described in 1986, and although now permit the differential functional characterisation of individuals
over 21 years of age, it still has to mature into a universally useful with types 1, 2A or 2M VWD, and use of the VWFpp assay may
assay, largely because of standardisation matters.
Interestingly, permit the identification of individuals with reduced VWF survival.
several international mutational VWD studies, which were expected Finally, the potential use of the PFA-100 in this setting also warrants
to provide some definitive answers regarding phenotype–genotype further investigation. ■
correlations in VWD, have instead shown a greater complexity within
VWD than previously recognised, and have also highlighted
Emmanuel J Favaloro is a Professor and Senior Scientist
significant error rates in the diagnosis and classification of VWD
in charge of the haemostasis laboratories at the
among expert laboratories.
Errors within the real world of Institute of Clinical Pathology and Medical Research
VWD investigation continue to cause misidentification of type 2 VWD
(ICPMR) at Westmead Hospital, part of the Sydney West
Area Health Service. He has co-authored over 200
as type 1 or 3 VWD, misidentification of type 1 VWD as type 2 or type
papers and is Editor in Chief of Seminars in Thrombosis
3 VWD and misidentification of type 3 VWD as type 1 or 2 VWD or and Haemostasis. Professor Favaloro is also Co-
even haemophilia A.
Many of these errors occur because of assay
Chairman of the International Society on Thrombosis
and Haemostasis (ISTH) Scientific Standardisation
limitations and the use of limited test panels. In particular, VWF:RCo
Committee (SSC) on von Willebrand factor (VWF), a member of the ISTH Working Party
generally shows poor inter-assay and inter-laboratory precision, and on coagulation standards, an Advisor to the Clinical and Laboratory Standards Institute
also the poorest lower limit of assay sensitivity.
(CLSI) Area Committee on Hematology and an advisory member of the Royal College
of Pathologists of Australasia (RCPA) Haematology Quality Assurance Programme
(QAP) Haemostasis Committee. Professor Favaloro’s primary interest is the diagnosis
The test combination of FVIII:C, VWF:Ag and VWF:RCo is the most of bleeding and thrombotic disorders, particularly in von Willebrand disease, and
common test panel used worldwide for the identification, diagnosis
developing and evaluating new or improved diagnostic processes.
and classification of individuals with VWD, but experience tells us
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32 EUROPEAN HAEMATOLOGY
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