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Coagulation Disorders
Figure 1: Simplified Algorithm Describing a Possible Approach to Improving the Identification and
Functional Characterisation of von Willebrand Disease
4
VWD diagnostic screen:
VWF:Ag, VWF:CB, FVIII:C
Abnormal, or borderline All convincingly normal:
VWF results (ie VWF:Ag and/or FVIII:C>50%; VWF:Ag and
VWF:CBA <74%, FVIII:C<50%) VWF:CB>75%
Repeat if necessary;
perform VWF:RCo.
1. Initial suspicion low: no further investigation
2. Initial suspicion strong; request repeat testing
Low/abnormal results for confirmation; if still normal: consider testing
(all or some) for factor deficiencies/platelet function.
Review test patterns; if
appropriate, perform DDAVP trial
Concordant (i.e. test
Non-concordant (i.e. discrepant test values)
values are similar)
All VWF test values VWF undetectable
CB/Ag and/or RCo/Ag ratio <0.7 FVIII:C/VWF:Ag ratio <07
low (repeat to confirm) (repeat to confirm)
(repeat to confirm) (repeat to confirm)
Type 2 VWD
Type 1 VWD Type 3 VWD
VWF:FVIII binding assay:
(VWF:Mult normal (VWF:Mult and
FVIII bound to VWF is:
distribution) RIPA absent
RIPA analysis: Reduced (ratio <0.7; Normal (ratio >0.7;
response to ristocetin is: repeat to confirm) repeat to confirm)
CB/Ag and RCo/Ag ratio <0.7 Reduced Enhanced
Type 2N VWD Haemophilia A
CB/Ag >0.7 and
(VWF:Mult and RIPA = normal)
Type 2A VWD
RCo/Ag ratio <0.7 RIPA mixing
studies
(VWF:Mult – loss
of HMW VWF)
Type 2M VWD Plasma defect Platelet defect
(VWF:Mult – no loss
of HMW VWF)
Type 2B VWD Pseudo-VWD
(VWF:Mult – loss of HME VWF)
VWD = von Willebrand disease; VWF = von Willebrand factor; Ag = antigen; RCo = ristocetin co-factor; CB = collagen binding; C = coagulant; RIPA = ristocetin-induced platelet agglutination;
DDAVP = desmopressin; Mult = multimer.
Type 2N von Willebrand Disease VWF:RCo testing is also performed where there is appropriate
Type 2N VWF defines dysfunctional VWF to FVIII binding and clinical evidence of significant muco-cutaneous bleeding and/or
individuals will present lower relative levels of plasma FVIII:C to VWF. when VWF:Ag and/or VWF:CB are ≤75%. VWD (as we currently know
The definitive phenotypic test for type 2N VWD, and to enable its it) can usually be excluded where VWF:Ag, VWF:CB and FVIII:C are
discrimination from haemophilia A, is the VWF:FVIIIB assay, with all >75%, as to date there have been no reported cases of VWD
genetic testing a feasible option.
2,7
showing such a pattern.
2–5
However, a reasonable caveat here is
that it is currently impossible to truly and entirely exclude VWD
Type 2M von Willebrand Disease using any currently applicable test panel, given that we are unable
Type 2M VWD comprises a variety of VWF defects, characterised by to evaluate all possible VWF functions using current tests.
some dysfunction of VWF that does not fit within the other type 2 Additional testing is warranted when VWF:Ag, VWF:CB and/or
VWD categories. The majority of type 2M VWD cases so far FVIII:C test results are ≤75% and/or there is compelling clinical
described show a selective VWF to GPIba-binding defect without a evidence of VWD-like bleeding symptoms. As shown in Figure 1,the
corresponding collagen-binding defect. Accordingly, these tend to subtype of VWD may then be surmised by the pattern of resultant
present with relatively lower VWF:RCo than VWF:Ag (or low RCo/Ag test findings, as expanded elsewhere in this article.
ratios), but relatively normal (or near normal) CB/Ag. However, a
small number of type 2M VWD cases showing a collagen-binding Evident Problems with Current
defect (with relatively normal GPIba binding) have been reported,
1–3
Identification and Laboratory Diagnosis
and these will show the opposing discordance pattern, i.e. low of von Willebrand Disease
relative CB/Ag but normal (or near normal) RCo/Ag ratios. Given appropriate selection and application of test methodologies
and panels, most cases of VWD will be appropriately identified and
A simplified algorithm highlighting the above patterns to permit a characterised. Nevertheless, the diagnosis of VWD remains
generalised means of identifying and characterising VWD can be problematic for a proportion of test cases due to the
seen in Figure 1. Our laboratory performs VWF:Ag, VWF:CB and under-recognised heterogeneity of VWD and because of current
FVIII:C testing on all cases being evaluated for possible VWD. test limitations.
1–5,8,12
For example, many investigators
6,8,12–23
have
28 EUROPEAN HAEMATOLOGY
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