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Coagulation Disorders
Identification and Functional Characterisation of von Willebrand Disease
Emmanuel J Favaloro
Professor, Department of Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, New South Wales
Abstract
The identification and functional characterisation of von Willebrand disease (VWD) is challenging due to clinical uncertainty and limitations
in test processes and panels used by laboratories, and because the classification scheme does not always permit unequivocal assignment
of subtype. This article reviews contemporary alternatives to classic diagnostic approaches, including the incorporation of extended core
test panels inclusive of the collagen-binding assay and the potential for desmopressin (DDAVP) challenge not only to provide therapeutic
information but also to assist the better characterisation of individuals with defects or deficiencies in von Willebrand factor (VWF).
Supplementary assays such as the PFA-100
®
and the VWF propeptide assay following DDAVP challenge are also worth considering.
Keywords
Desmopressin (DDAVP), von Willebrand factor (VWF), von Willebrand disease (VWD), diagnosis, classification
Disclosure: The author has no conflicts of interest to declare.
Received: 15 May 2009 Accepted: 21 June 2009
Correspondence: Emmanuel J Favaloro, Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, NSW, Australia.
E: emmanuel.favaloro@swahs.health.nsw.gov.au
von Willebrand disease (VWD) is the most common inherited decreased VWF-dependent platelet adhesion without selective
bleeding disorder and is characterised by low levels of and/or deficiency of HMW VWF multimers. In practice, type 2M VWD
abnormal function in the plasma protein von Willebrand factor comprises a composite of different functional VWF defects and
(VWF). Typically, laboratory investigation entails initial plasma essentially any qualitative defect that cannot otherwise be
testing of factor VIII coagulant (FVIII:C), VWF protein antigen characterised within other type 2 VWD groups. The most common
(VWF:Ag) and VWF activity, which is classically assessed using the type 2M VWD variants so far identified display defective binding of
ristocetin co-factor (VWF:RCo) assay.
1–5
Newer tests of VWF function VWF to GPIba, but essentially (near) normal collagen binding.
include the collagen-binding assay (VWF:CB) and other putative
activity (VWF:Act) assays.
2–6
Depending on initial test patterns and Laboratory Identification of von Willebrand
local availability, supplementary laboratory testing may also Disease – Current Practice
employ VWF multimers, ristocetin-induced platelet agglutination The correct diagnosis of VWD requires both clinical and laboratory
(or aggregation) (RIPA), VWF–FVIII binding (VWF:FVIIIB) and, in some evaluation and evidence. An appropriate clinical evaluation is critical,
cases, genetic analysis.
1–7
and includes an assessment of personal and familial history of
bleeding/bruising, evaluation of recent medication and a physical
Six types of VWD can be defined: types 1, 2A, 2B, 2M, 2N and 3.
1–7
Type examination. Appropriate laboratory evaluation is also critical, but is
1 VWD is a partial quantitative defect and is simply defined by a often lacking. There are limitations in the tests used by most
reduction in plasma VWF; thus, the presenting VWF is essentially laboratories, test panels are often incomplete and interpretation of
‘qualitatively normal’. Type 3 VWD is defined by (virtual) complete test data is often inadequate.
deficiency of VWF, and is diagnosed when there is essentially no
measurable plasma VWF. Type 2 VWD defines qualitative defects of Laboratory Tests Used for the Identification and
VWF. Type 2A VWD is defined by decreased VWF-dependent platelet Characterisation of von Willebrand Disease
adhesion and a selective deficiency of high-molecular-weight (HMW) VWD is characterised by low levels of plasma VWF and/or abnormal
VWF multimers, which can arise from either decreased production or VWF function. Ideally, a laboratory investigation would entail a
increased plasma clearance. Type 2B VWD is defined by an increased panel of tests that would identify all possible presentations of VWD.
affinity of VWF for its platelet receptor, glycoprotein Ib alpha (GPIba). Depending on local preferences, currently available test panels may
This increased affinity typically (but not always) results in clearance include any combination of FVIII:C, VWF:Ag, VWF:RCo, VWF:CB,
of both HMW VWF and platelets from circulation, and thus (usually VWF:Act, VWF multimers, RIPA, VWF:FVIIIB and genetic analysis.
1–7
mild) thrombocytopenia. Type 2N VWD is characterised by markedly However, the actual tests, specific test methodologies and their
decreased binding affinity of VWF for factor VIII, and presents combinations, as used by individual laboratories, vary widely and
phenotypically like haemophilia A. Type 2M VWD is defined by this will influence, according to the specific investigation, the
© TOUCH BRIEFINGS 2009 25
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