Recent advances in the diagnosis of von Willebrand disease

Von Willebrand disease (VWD) is caused by a quantitative or qualitative defect of von Willebrand factor (VWF). Despite its prevalence as the most common hereditary bleeding disorder and the associated morbidity, its diagnosis and classification remains a challenge. This is mainly attributed to the heterogeneity of the disorder, multi-faceted functions of VWF, limitations of diagnostic assays, and significant impacts of various patho-physiological processes on VWF. For the past few years, significant progress has been made in elucidating the structural basis of VWF activation and development of VWF activity assays. The O-glycosylated sequences flanking the VWF A1 domain constitute a discontinuous and force-sensitive autoinhibitory module (AIM), which regulates the VWF affinity for GPIbα. New options for laboratory assessment of VWF activity include VWF∶GPIbM and VWF∶GPIbNab. The former utilizes a recombinant gain-of-function GPIbα fragment that supports spontaneous binding to plasma VWF, with less variability and higher precision compared to the traditional ristocetin cofactor activity assay. The latter utilizes a VWF-activating nanobody targeting the AIM to activate VWF, demonstrating the highest sensitivity for high-molecular-weight multimers among contemporary assays in the preliminary study. In this review, we focused on recent developments in the field of VWD diagnosis and considered how these advances can improve diagnostic algorithms and patient care in clinical practice.