title: Laboratory assessment as a critical component of the appropriate diagnosis and sub-classification of von Willebrand's disease.
abstract: von Willebrand's disease (VWD) is now recognized to be most common inherited bleeding disorder. It arises from defects or deficiencies in a protein called von Willebrand factor (VWF). VWD is a heterogeneous disorder, and patients are typed according to pathophysiology. The correct diagnosis and sub-classification of a patient's VWD is crucial because the presenting biological activity of VWF determines the haemorrhagic risk, and since subsequent clinical management will differ accordingly. Although clinical assessment of the propositus will provide the initial clue to, or an index of clinical suspicion for, a diagnosis of VWD, it is the laboratory process that will confirm or discount the diagnosis. A variety of assays may be employed by the laboratory undertaking the investigation, and these will not necessarily be restricted to an assessment of VWF. Due to the limitations of each potential laboratory assay, and because of VWD heterogeneity, no single test procedure is sufficiently 'robust' to permit detection of all VWD variants. This situation often leads to some clinical confusion in the process of laboratory interpretation regarding the likelihood of VWD, and the subtype of VWD. Classically, the test panel might include any combination of the following: (i) determination of (skin) bleeding times, (ii) VWF antigen (VWF:Ag) levels, (iii) 'functional' activity of Factor VIII (i.e. FVIII:coagulant or FVIII:C), (iv) 'functional' activity of VWF (e.g. Ristocetin Cofactor [VWF:RCof] assay), and/or Ristocetin induced platelet aggregation [RIPA] analysis), and (v) assessment of the VWF molecular weight or structural profile (i.e. VWF multimeric analysis or VWF:Multimers). There have also been a number of new diagnostic developments, and these are beginning to significantly influence the overall clinical VWD-diagnostic process. These include automation of existing assay procedures, a relatively new functional VWF assay called the Collagen Binding Assay (VWF:CBA), new automated platelet function analysers such as the PFA-100 and the Xylum Clot Signature Analyser, and specific VWF:FVIII binding assays. The current report focuses on the recommended laboratory process for investigation of VWD. An analysis of this process shows that selection of an appropriate test panel is a critical component for the proper diagnosis and classification. This review also outlines those new and emerging technologies that will help streamline the diagnostic process. Because VWD is just one manifestation of a 'bleeding' disorder (albeit the most common), the review also briefly mentions other related diagnostic processes and general approaches to the investigation of 'bleeding disorders'. The review also provides two algorithms to assist clinicians in making appropriate diagnostic choices in response to the clinical findings. A number of summary tables describing each laboratory assay in detail, and summarising the likely diagnostic findings for each Type of VWD, are also provided. This review should be of value to both haemostasis scientists and clinical specialists involved in VWD diagnosis.
authors.affiliation: Department of Haematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, WSAHS, Australia. emmanuel@icpmr.wsahs.nsw.gov.au
authors.forename: E J
authors.initials: EJ
authors.lastname: Favaloro
mesh_terms: D019411:Clinical Laboratory Techniques / Q000592:standards; D003661:Decision Support Techniques; D003937:Diagnosis, Differential; D006474:Hemorrhagic Disorders / Q000175:diagnosis; D006801:Humans; D017410:Practice Guidelines as Topic; D014842:von Willebrand Diseases / Q000097:blood / Q000145:classification* / Q000175:diagnosis*