Why is Misdiagnosis of von Willebrand Disease Still Prevalent and How Can We Overcome It? A Focus on Clinical Considerations and Recommendations

Abstract

Despite von Willebrand disease (VWD) being the most common inherited bleeding disorder, its accurate diagnosis is frequently shrouded by diagnostic pitfalls. VWD is frequently under-diagnosed, over-diagnosed and misdiagnosed, leading to significant avoidable patient morbidity and health care system burden. At the heart of this dilemma lies the heterogeneity and complexity of von Willebrand factor (VWF) and associated defects, and the necessity of coalescing clinical and laboratory features to obtain an accurate diagnosis. Common pitfalls include poor clinical and scientific understanding and familiarity with VWD, incomplete clinical history and lack of routine use of standardised bleeding assessment tools (BAT), difficulty in accessing a comprehensive repertoire of laboratory tests, significant pre-analytical, analytical and post-analytical issues, and lack of expertise in laboratory testing and interpretation. Errors, resulting in under-diagnosis, over-diagnosis, and misdiagnosis of VWD, are presented and discussed. Strategies to minimise errors include better education of clinicians and laboratory staff on VWD, routine use of validated BAT, utilising a comprehensive gamut of laboratory investigations according to a standardised algorithm, and repeating testing to minimise pre-analytical errors. Recommendations on appropriate patient selection for VWD testing, how VWD should be investigated in the laboratory, and how to ensure test results are accurately interpreted in the correct clinical context are detailed.

The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

“…Such strategies may include targeting the upregulated VWF or decreased ADAMTS13 activity in patients with cardiac failure, in order to halt persistent endothelial dysfunction and disease progression. In patients with AVWS, a different approach is needed, including supportive therapies with VWF [6,8].…”

“…VWD can be classified as inherited, which can be further categorized into six different types (1, 2A, 2B, 2M, 2N, 3), and which results from a variety of mutations occurring throughout the VWF gene, or acquired, from a variety of conditions, including malignant disorders, aortic valve stenosis, or left ventricular assist devices [6,11,51,52]. Acquired VWD is more commonly called acquired von Willebrand syndrome (AVWS).…”

“…Inflammatory or ischemic endothelial activation results in the release of von Willebrand factor (VWF) from Weibel-Palade bodies held in endothelial cells [5]. VWF is a large, complex protein that has a crucial role in platelet adhesion and aggregation and is involved in both primary and secondary haemostasis [6]. VWF exists in plasma as multimers of increasing size, with the largest (high molecular weight; HMW) expressing the greatest functional activity.…”

“…A deficiency of VWF is associated with a congenital bleeding disorder called von Willebrand disease (VWD). In addition, the loss of VWF can occur in a variety of acquired conditions [6,7]. Of note, certain cardiac lesions, particularly aortic stenosis, can elongate VWF multimers in the shear field, resulting in proteolytic loss of the highest molecular weight forms, leading to subsequent loss of VWF activity and resultant bleeding [8,9].…”

“…Plasma VWF levels can be assessed by means of VWF antigen (VWF: Ag) [11,12] and/or a variety of activity assays [6,11,12]. The most common VWF: Ag assays comprise latex-enhanced immunoassays and enzyme-linked immunosorbent assays [11,12].…”