ABSTRACT
von Willebrand disease (VWD) is the most common inherited bleeding disorder and arises
from deficiencies and/or defects in the plasma protein von Willebrand factor (VWF). VWD is classified into six different types, with type
1 identifying a (partial) quantitative deficiency of VWF, type 3 defining a (virtual)
total deficiency of VWF, and type 2 identifying four separate types (2A, 2B, 2M, and
2N) characterized by qualitative defects. The classification is based on phenotypic
assays including factor VIII coagulant, VWF antigen, and VWF activity, primarily by
ristocetin cofactor and collagen binding, as supplemented by additional testing. In
Australia, >30 pathology-based laboratories perform VWD testing, and tests and test
panels reflect a wide variety of practice. In our own referral laboratory, diagnosis
is a staged process reflecting a combination of clinical and laboratory findings with
a large panel of tests. We also use data from desmopressin trials to assist in VWD
type assignment. The current report presents an overview of the VWD diagnostic process
as applied within Australia, includes summary data from the Australian Bleeding Disorders
Registry, and provides specific details of the diagnostic and management practice
undertaken in our reference laboratory, which also maintains a local bleeding disorders
database. This database currently contains 4070 entries, including 1832 suspected
or confirmed cases of VWD. Excluding 311 as yet unclassified cases, 1254 cases (82.4%)
would define (potential) quantitative deficiencies of VWF (“low VWF” or type 1 VWD),
241 (15.8%) qualitative defects (type 2 VWD), and 23 (1.5%) type 3 VWD. Most of the
quantitative defects reflect only mild loss of VWF, and <15% of total cases would
be identified to have VWF levels <35U/dL. Most cases of type 2 remain unclassified
(34.9%) because available data are limited. Type 2A and 2M VWD represent the most
common qualitative defects, representing 22.8% and 22.2% of defined type 2 VWD cases.
Type 2B and 2N reflect 8.3% and 12.9%, respectively, of type 2 VWD cases.
KEYWORDS
von Willebrand disease - VWD - diagnosis - desmopressin - DDAVP - collagen binding
- genetic testing
REFERENCES
- 1
Sadler JE, Budde U, Eikenboom JC Working Party on von Willebrand Disease Classification
et al.
Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.
J Thromb Haemost.
2006;
4
(10)
2103-2114
- 2
Favaloro EJ.
von Willebrand disease: local diagnosis and management of a globally distributed bleeding
disorder.
Semin Thromb Hemost.
2011;
37
(5)
000
- 3
Favaloro EJ.
Identification and functional characterization of von Willebrand disease.
US Hematology.
2009;
2
(1)
16-23
- 4
Favaloro EJ.
Toward a new paradigm for the identification and functional characterization of von Willebrand disease.
Semin Thromb Hemost.
2009;
35
(1)
60-75
- 5
Favaloro EJ.
An update on the von Willebrand factor collagen binding assay: 21 years of age and beyond adolescence
but not yet a mature adult.
Semin Thromb Hemost.
2007;
33
(8)
727-744
- 6
Favaloro EJ.
Rethinking the diagnosis of von Willebrand disease.
Thromb Res.
2011;
127
(Suppl 2)
S17-S21
- 7
Favaloro EJ, Krigstein M, Koutts J, Brighton T, Lindeman R.
Genetic testing for the diagnosis of von Willebrand disease: benefits and limitations.
J Coag Disorders.
2010;
2
37-47
- 8
Favaloro EJ.
Genetic testing for von Willebrand disease: the case against.
J Thromb Haemost.
2010;
8
(1)
6-12
- 9
Favaloro EJ, Lippi G, Franchini M.
Contemporary platelet function testing.
Clin Chem Lab Med.
2010;
48
(5)
579-598
- 10
Favaloro EJ, Bonar R, Kershaw G et al.
Reducing errors in identification of von Willebrand disease: the experience of the Royal College of Pathologists of Australasia
quality assurance program.
Semin Thromb Hemost.
2006;
32
(5)
505-513
- 11
Favaloro EJ, Bonar R, Meiring M, Street A, Marsden K. RCPA QAP in Haematology .
2B or not 2B? Disparate discrimination of functional VWF discordance using different
assay panels or methodologies may lead to success or failure in the early identification
of type 2B VWD.
Thromb Haemost.
2007;
98
(2)
346-358
- 12
Favaloro EJ, Mohammed S, McDonald J.
Validation of improved performance characteristics for the automated von Willebrand factor ristocetin cofactor activity assay.
J Thromb Haemost.
2010;
8
(12)
2842-2844
- 13
Favaloro EJ.
Evaluation of commercial von Willebrand factor collagen binding assays to assist the discrimination of types
1 and 2 von Willebrand disease.
Thromb Haemost.
2010;
104
(5)
1009-1021
- 14
Favaloro EJ, Lippi G, Adcock DM.
Preanalytical and postanalytical variables: the leading causes of diagnostic error
in hemostasis?.
Semin Thromb Hemost.
2008;
34
(7)
612-634
- 15
Favaloro EJ, Thom J, Patterson D et al.
Desmopressin therapy to assist the functional identification and characterisation
of von Willebrand disease: differential utility from combining two (VWF:CB and VWF:RCo)
von Willebrand factor activity assays?.
Thromb Res.
2009;
123
(6)
862-868
- 16
Favaloro EJ, Thom J, Patterson D et al..
Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor
concentrate therapy in von Willebrand disease.
Blood Coagul Fibrinolysis.
2009;
20
(6)
475-483
- 17
Coleman R, Favaloro EJ, Soltani S, Keng TB.
Acquired von Willebrand disease: potential contribution of the VWF:CB to the identification
of functionally inhibiting auto-antibodies to von Willebrand factor.
J Thromb Haemost.
2006;
4
(9)
2085-2088
- 18
Meijer P, Haverkate F.
An external quality assessment program for von Willebrand factor laboratory analysis: an overview from the European concerted
action on thrombosis and disabilities foundation.
Semin Thromb Hemost.
2006;
32
(5)
485-491
- 19
Favaloro EJ.
Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the
diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD): a rebuttal.
J Thromb Haemost.
2008;
6
(11)
1999-2001, author reply 2002–2003
- 20
Facey DA, Favaloro EJ, Maxwell E, Baker R, Hertzberg MS.
Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families:
phenotype and genotype correlations.
Am J Hematol.
2000;
63
(4)
197-199
- 21
Rodgers SE, Lerda NV, Favaloro EJ et al.
Identification of von Willebrand disease type 2N (Normandy) in Australia: a cross-laboratory investigation
using different methods.
Am J Clin Pathol.
2002;
118
(2)
269-276
- 22
Favaloro EJ, Patterson D, Denholm A et al.
Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination
mixing assay and confirmed by genetic analysis.
Br J Haematol.
2007;
139
(4)
623-626
- 23
Favaloro EJ, Mohammed S, Koutts J.
Identification and prevalence of von Willebrand disease type 2N (Normandy) in Australia.
Blood Coagul Fibrinolysis.
2009;
20
(8)
706-714
- 24
Rodgers SE, Lloyd JV, Mangos HM, Duncan EM, McRae SJ.
Diagnosis and management of adult patients with von Willebrand disease in South Australia.
Semin Thromb Hemost.
2011;
37
(5)
000-000
- 25
Federici AB, Bucciarelli P, Castaman G et al.
Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients.
Semin Thromb Hemost.
2011;
37
(5)
000-000
- 26
Federici AB, Mannucci PM, Castaman G et al.
Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients
with von Willebrand disease type 2B: a cohort study of 67 patients.
Blood.
2009;
113
(3)
526-534
- 27
Frontroth JP, Hepner M, Sciuccati G, Feliú Torres A, Pieroni G, Bonduel M.
Prospective study of low-dose ristocetin-induced platelet aggregation to identify
type 2B von Willebrand disease (VWD) and platelet-type VWD in children.
Thromb Haemost.
2010;
104
(6)
1158-1165
- 28
Favaloro EJ.
Phenotypic identification of platelet-type von Willebrand disease and its discrimination from type 2B von Willebrand disease: a question of 2B or not 2B? A story of nonidentical twins?
Or two sides of a multidenominational or multifaceted primary-hemostasis coin?.
Semin Thromb Hemost.
2008;
34
(1)
113-127
- 29
Hamilton A, Ozelo M, Leggo J et al.
Frequency of platelet type versus type 2B von Willebrand disease. An international registry-based study.
Thromb Haemost.
2011;
105
(3)
501-508
- 30
Othman M.
Platelet-type von Willebrand disease: a rare, often misdiagnosed and underdiagnosed bleeding disorder.
Semin Thromb Hemost.
2011;
37
(5)
000
- 31
de Wee EM, Leebeek FWG, Eikenboom JCJ.
Diagnosis and management of von Willebrand disease in The Netherlands.
Semin Thromb Hemost.
2011;
37
(5)
000
- 32
Keeney S, Collins P, Cumming A, Goodeve A, Pasi J.
Diagnosis and management of von Willebrand disease in the United Kingdom.
Semin Thromb Hemost.
2011;
37
(5)
000
- 33
James PD, Lillicrap DP.
The diagnosis and management of von Willebrand disease in Canada.
Semin Thromb Hemost.
2011;
37
(5)
000
- 34
Favaloro EJ, Bukuya M, Martinelli T et al.
A comparative multi-laboratory assessment of three factor VIII/von Willebrand factor concentrates.
Thromb Haemost.
2002;
87
(3)
466-476
- 35
Favaloro EJ, Lloyd J, Rowell J et al.
Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with
von Willebrand disorder. A randomised cross-over, multi-centre study.
Thromb Haemost.
2007;
97
(6)
922-930
- 36
Shortt J, Dunkley S, Rickard K, Baker R, Street A.
Efficacy and safety of a high purity, double virus inactivated factor VIII/von Willebrand factor concentrate (Biostate) in patients with von Willebrand disorder requiring invasive or surgical procedures.
Haemophilia.
2007;
13
(2)
144-148
- 37
Dunkley S, Baker RI, Pidcock M et al.
Clinical efficacy and safety of the factor VIII/von Willebrand factor concentrate BIOSTATE in patients with von Willebrand's disease: a prospective multi-centre study.
Haemophilia.
2010;
16
(4)
615-624
Emmanuel J FavaloroPh.D. F.F.Sc. (RCPA)
Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR)
Westmead Hospital, WSAHS, Westmead, NSW, 2145, Australia
Email: emmanuel.favaloro@swahs.health.nsw.gov.au
