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Identification and Functional Characterisation of von Willebrand Disease
recently reported on diagnostic inconsistencies for VWD, including Figure 2: Summary of Discriminatory Post-desmopressin
a series of genetic/phenotypic studies using samples derived from
Changes in Hemophilia A and in Types 1, 2A and
2M von Willebrand Disease
26,41
‘expert’ VWD laboratories,
13–16
which identified that between 15 and
33% of cases originally identified as type 1 VWD could be
A.
reclassified as type 2. Thus, a large number of type 2 VWD cases
350
VWF:Ag
can be misidentified as type 1 VWD based on testing predominantly
VWF:Cb
300
using a core three-test panel of FVIII, VWF:Ag and VWF:RCo, even in VWF:RCo
VWD ‘expert’ laboratories. This situation mimics that identified by
FVIII:C
250
analysis of testing in ‘real-world’ laboratories comprising
predominantly ‘non-expert’ pathology-based clinics, and where
200
cases are derived from a mixed clinical referral base.
6,8,12,20–22
A
150
similar matter regarding the misdiagnosis of type 1 VWD as type 2
VWF or FVIII (U/dl)
VWD, and type 3 VWD as type 1 or type 2 VWD or vice versa, can 100
also be identified.
6,8,12,20
Most misdiagnoses occur in these
investigations either because of laboratory test panel limitations or
50
because of misinterpretations of test findings.
0
– + – + – + – + – + – +
VWD-1s VWD-1m VWD-1p H-A VWD-2a VWD-2m
Such misdiagnoses can have both therapeutic implications and B.
2.5
psychological effects on affected patients. Although misdiagnoses
CB/Ag
and misclassifications have multiple causes, errors are in part likely
RCo/Ag
due to the recognised limitations in the otherwise standard panel of
2.0
VWF:Ag, VWF:RCo and FVIII:C
2–6,8
as used by most laboratories for most
investigations. This would include the previously mentioned assay
1.5
limitations, including the lower test sensitivity limit, plus high
Ratio
relative assay variability or poor reproducibility, particularly for the
1.0
VWF:RCo assay. It has also previously been identified that the addition
of VWF:CB testing to such a test panel will consistently reduce error
rates in VWD diagnosis.
2–6,8,12
Additional examples related to the
0.5
misdiagnosis of VWD, and explanatory reasons are provided
elsewhere.
4
In brief, type 2A, 2M and 2B VWD are often misidentified 0.0
– + – + – + – + – + – +
as type 1 VWD because discordance of VWF:RCo and VWF:Ag (or a low VWD-1s VWD-1m VWD-1p H-A VWD-2a VWD-2m
RCo/Ag ratio) is not always apparent in single testing, and type 1 VWD
C.
is sometimes misidentified as type 2A or 2M VWD because false VWF
300
functional discordance (i.e. false low RCo/Ag ratio) is sometimes
identified. Occasionally, type 3 VWD is misidentified as type 1 or 2
250
VWD or haemophilia A. Interestingly, laboratories and clinicians
200
sometimes misinterpret laboratory test data.
12
Contrary to popular
misconceptions, performance of multimer analysis is not a
150
diagnostic panacea, although it is useful on occasion if performed
appropriately.
2–4
Indeed, in the real world of VWD testing, there is a
100
high rate of errors associated with multimer testing.
4,20
For example, A-100 C/Epi CT (seconds)
data from the European Concerted Action on Thrombosis Foundation
PF
50
External Quality Assurance (ECAT/EQA) programme recently showed
that laboratories will identify ‘abnormal’ multimer patterns including
0
– + – + – + – + – + – +
loss of HMW VWF in ≤20% of cases when testing normal plasma and
VWD-1s VWD-1m VWD-1p H-A VWD-2a VWD-2m
up to 50% of cases when testing a type 1 VWD sample. Thus, type 1
VWD samples were reported as type 2A or 2B in nearly 20% of test
A: Pre- and post-desmopressin (DDAVP) values for factor VIII (FVIII):coagulant (C) and various
VWF parameters. Dashed horizontal line indicates a nominal ‘normal’ cut-off value of 50U/dl.
cases involving multimer analysis. VWD-1s = ‘severe’ type 1 von Willebrand disease (VWD) patient group (baseline von
Willebrand factor [VWF] values <16U/dl); VWD-1m = ‘moderate’ type 1 VWD patient group
(baseline VWF values 16–35U/dl); VWD-1p = ‘possible mild’ type 1 VWD patient group
Towards a New Paradigm to Better Define (baseline VWF values 36–65U/dl); H-A = haemophilia A patient group; VWD-2A and
von Willebrand Disease
VWD-2M = types 2A VWD and 2M VWD patient groups, respectively. B: Pre- and post-DDAVP
ratios of collagen binding/antigen (CB/Ag) and ristocetin co-factor (RCo)/Ag for the same
Expansion to a Comprehensive Test Panel patient groups identified in A. Dashed horizontal line indicates a nominal ‘normal’ cut-off
that Includes the von Willebrand Factor:
value of 0.7 as discriminatory for functional VWF discordance (i.e. <0.7 is suggestive of
discordance, and may reflect a type 2 VWD pattern). C: Pre- and post-DDAVP PFA-100
®
Collagen Binding Assay closure-times (CTs) for the same patient groups identified in A. Dashed horizontal line
Due to diagnostic problems, laboratories and clinicians need additional
indicates the ‘normal’ cut-off value. In brief, type 1 VWD is typically characterised by
correction of PFA-100 CTs (C) and good incremental rises in FVIII:C and all VWF test
strategies to ensure the appropriate identification of VWD. In the parameters, although rises in VWF:CB tend to exceed those of VWF:Ag and VWF:RCo (A) and,
‘real-world VWD testing’ setting, the addition of a VWF:CB assay to
accordingly, rises in CB/Ag ratios may be observed, which tend to exceed RCo/Ag ratios (B).
In contrast, type 2A VWD is typically characterised by non-correction of PFA-100 CTs (C) and
the core three-test panel of FVIII, VWF:Ag and VWF:RCo as typically used good incremental rises in FVIII:C and VWF:Ag only (A); thus, CB/Ag and RCo/Ag both tend to
by most laboratories will substantially reduce the diagnostic error rate.
remain low (B). Finally, platelet-binding dysfunctional type 2M VWD is typically characterised
by non-correction of PFA-100 CTs (C) and good incremental rises in FVIII:C, VWF:Ag and
For example, the misidentification of type 2 VWD as type 1 VWD can be VWF:CB (A); thus, only RCo/Ag tends to remain low (B).
EUROPEAN HAEMATOLOGY 29
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