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Coagulation Disorders
Laboratory Diagnosis of von Willebrand Disease
Muriel Meiring,
1
Philip N Badenhorst
2
and Mareli Kelderman
3
1. Associate Professor and Specialist Scientist; 2. Professor and Chairman; 3. Medical Technologist,
Department of Haematology and Cell Biology, University of the Free State
Abstract
von Willebrand disease (VWD) is a bleeding disorder caused by either quantitative (type 1 and 3) or qualitative (type 2) defects of von Willebrand
factor (VWF). No single available test provides appropriate information about the various functions of VWF, and the laboratory diagnosis of VWD
is based on a panel of tests, including the measurement of factor VIII coagulant activity (FVIIIC), VWF antigen levels (VWF:Ag), VWF activity as
measured by the ristocetin co-factor activity (VWF:RCo), the collagen-binding activity of VWF (VWF:CB), VWF multimer analysis, ristocetin-
induced platelet agglutination (RIPA), the factor-VIII-binding assay of plasma VWF and VWF propeptide levels. Due to the heterogeneity of VWF
defects and the variables that interfere with VWF levels, a correct diagnosis of types and subtypes may sometimes be difficult, but is very
important for therapy. Furthermore, the RCo assay and the RIPA test are based on platelet agglutination in reaction with the non-physiological
antibiotic ristocetin. These tests also have low sensitivity and are difficult to standardise. Therefore, several analyses (tests) are required to
diagnose VWD and it is important to be aware of the pitfalls to which these tests are subjected in terms of the diagnosis. In this article, the
laboratory diagnosis of patients with type 1, 2A, 2B, 2M, 2N and 3 VWD will be explained by using a modified algorithm that was first
proposed by the guidelines for diagnosis and treatment of VWD in Italy.
Keywords
von Willebrand factor, von Willebrand disease, classification, subtypes
Disclosure: The authors have no conflicts of interest to declare.
Received: 14 May 2009 Accepted: 4 June 2009
Correspondence: Muriel Meiring, Department of Haematology and Cell Biology, University of the Free State, Bloemfontein, 9300, South Africa. E:
gnhmsmm.md@ufs.ac.za
von Willebrand disease (VWD) is a bleeding disorder caused by Type 3 VWD is the least common subtype and reflects a virtually
quantitative or qualitative defects of von Willebrand factor (VWF). VWF complete absence of VWF. Again, DDAVP treatment is not effective in
is a high-molecular-weight (HMW) glycoprotein that plays an essential type 3 VWD. The current treatment of choice for type 3 VWD, as well
part in the early phases of haemostasis by promoting platelet as most type 2 VWD, is transfusional therapy with plasma-derived
adhesion to the subendothelium and platelet aggregation under high FVIII/VWF concentrates.
3
shear stress conditions.
1
VWF is also the carrier of factor VIII (FVIII) in
plasma, and a deficiency or abnormality of VWF also results in an Type 2 VWD is a quantitative defect that is subdivided into four
impairment of blood coagulation. By the non-covalent interaction subtypes (2A, 2B, 2M and 2N VWD). Type 2A refers to variants with
between VWF and FVIII, FVIII is protected against binding to decreased platelet-dependent function and is associated with the
membrane surfaces and to proteolytic attack by a variety of serine absence of HMW multimers; type 2B refers to variants with
proteases, including activated protein C.
2
In the majority of cases, increased affinity for platelet glycoprotein 1bα; type 2M refers to
VWD is a congenital disease that is inherited in an autosomal- variants with decreased platelet-dependent function not caused by
dominant fashion. Patients with VWD may have had a mild, moderate the absence of HMW multimers; and type 2N refers to variants with
or severe bleeding tendency since childhood, usually proportional to markedly decreased affinity for FVIII. DDAVP treatment is not
the degree of the VWF defect. Inherited VWD has been classified into recommended in patients with type 2 VWD, as it would only increase
three types that reflect its pathophysiology. Type 1 VWD is the dysfunctional VWF.
characterised by partial quantitative deficiency of VWF. It is the most
common type, with a prevalence of about 80%. The mechanisms Platelet-type VWD (PT-VWD) is a rare autosomal-dominant bleeding
involved include reduced synthesis and secretion of VWF or increased disorder. The genetic defect is in platelets rather than VWF, and
clearance of VWF from plasma.
3
The treatment is simple, as the disease is characterised by abnormally high binding affinity of the
1-deamino-8-D-arginine vasopressin (DDAVP) causes the release of platelets to the VWF, similar to type 2B VWD.
4
Therefore, most people
structurally normal VWF from endothelial stores. However, in patients with PT-VWD are misdiagnosed as type 2B VWD. However, these may
with increased clearance of VWF, DDAVP treatment would not be require different therapeutic management, so discrimination is clinically
effective as VWF in plasma is cleared very quickly from the circulation. important. The spectrum and severity of VWD is wide, ranging from a
Therefore, it is important to diagnose patients with an increased few doubtful haemorrhagic symptoms to severe life-threatening
clearance rate of VWF. bleeding episodes. This is due not only to the heterogeneous VWF gene,
© TOUCH BRIEFINGS 2009 33
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