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Diagnosis of von Willebrand Disease: Two New Resources Clarify Complexity

The accurate diagnosis of von Willebrand disease (VWD) is crucial to its management. Therefore, the World Federation of Hemophlia (WFH) is pleased to announce the release of two new and complementary issues in the Treatment of Hemophilia (TOH) series covering the diagnosis and classification of VWD—TOH 55 Diagnosis of von Willebrand Disease: Phenotypic Characterization and TOH 56 Molecular Diagnosis of von Willebrand Disease. Both articles are available in English and Spanish.

Phenotype describes the set of observable characteristics of an individual (for example, hair colour, height, and behaviour). In the case of VWD, an example of a phenotypic characteristic may be the capacity of an individual’s von Willebrand factor (VWF) to bind factor VIII (FVIII). The term genotype refers to the genetic makeup of an individual, and the underlying genetic reason for a phenotype. For example, defects (mutations) or missing pieces (deletions) in the VWF gene may affect the binding of VWF to FVIII, and these abnormalities may be detected by molecular diagnostic techniques. These two articles review current approaches to diagnosing VWD by looking at the phenotype or the genotype of the patient.

In VWD, the diagnostic approach begins with the clinical assessment of a person with bleeding symptoms and a positive family bleeding history. TOH 55 Diagnosis of von Willebrand Disease: Phenotypic Characterization examines four key areas: an overview of VWD diagnosis, phenotypic diagnosis, classification of VWD, and diagnosis of VWD in low resource countries. TOH 55 guides the clinician or laboratory specialist through a sequence of increasingly specific laboratory tests necessary for an accurate diagnosis of VWD. The table below describes the uses and limitations of tests referred to as first and second level tests, and explains what these are. The article highlights why these tests are performed and how they are interpreted. In addition, each technique is linked to its corresponding detailed protocol in the WFH Laboratory Manual on the WFH eLearning Platform.


USE OF LABORATORY TESTS FOR PHENOTYPIC DIAGNOSIS OF VWD

First level
  • Measure plasma level of FVIII coagulant activity
  • Measure VWF antigen level
  • Measure platelet-dependent VWF function
Second level
  • Define and classify VWD variants
  • Used when VWF levels are low and/or when there is a discrepancy between the concentration of VWF and its platelet-dependent functions

TOH 55 describes the unique characteristics of the various types of VWD and highlights how each type is diagnosed using first and second level tests. The article concludes with a discussion of VWD diagnosis in low resource countries, describing how the bleeding disorder can be diagnosed with a few key tests. Clinicians and laboratory specialists in centres with limited resources will be interested to read why each test is considered essential and how these tests provide crucial information for the definitive diagnosis of VWD.

Characterization of VWF gene abnormalities is key to obtaining an accurate diagnosis of VWD when phenotypic tests are unavailable. Performing genetic tests on individuals who have undergone phenotype testing largely confirms the phenotypic diagnosis but may also offer additional useful information (such as a determination of when prenatal diagnosis is required). In the next table, we see that TOH 56 Molecular Diagnosis of von Willebrand Disease reviews three techniques in the diagnosis of genetic abnormalities in VWD, with each technique playing a distinct role. The article reviews the purpose and advantages of verifying genetic abnormalities against two online databases for known VWF mutations. Finally, the authors propose an interesting strategy for combining genetic tests and database searches to pinpoint where on the VWF gene mutations occur in VWD types 1 and 3.


TECHNIQUES USED IN THE GENETIC CHARACTERIZATION OF INDIVIDUALS WITH VWD
  • Direct DNA sequence (Sanger) analysis
  • Next generation sequence (NGS) analysis
  • Multiplex Ligation-dependent Probe Amplification (MLPA)

These two complementary articles—both available in English and Spanish—provide key guidance for clinicians and laboratory specialists in the complex pursuit of an accurate phenotypic diagnosis and molecular characterization of people suspected of having VWD. The WFH eLearning Platform also hosts a range of other VWD resources designed for people with bleeding disorders, caregivers, and medical professionals alike. Examples include the von Willebrand Disease eLearning Centre (available in English) and its corresponding patient booklet available in six languages (English, Spanish, French, Arabic, Russian, and Simplified Chinese). In addition, the WFH Congress eLearning Centre offers over 20 webcasts on VWD from the WFH 2016 World Congress and three videos of an international panel of experts discussing diverse VWD outreach strategies.

 

Fiona Robinson, Educational Materials Manager for the WFH, wishes to thank Georghia Michael and Angela Styhler for their contributions to this article.