Ristocetin dependent cofactor activity in von Willebrand disease diagnosis: Limitations of relying on a single measure

• Published in: Research and practice in thrombosis and haemostasis 2022-10, Vol.6 (7), p.e12807-n/a, Article e12807
• Main Authors: Christopherson, Pamela A., Haberichter, Sandra L., Flood, Veronica H., Sicking, Ursula O., Abshire, Thomas C., Montgomery, Robert R., Weiler, H., Lillicrap, D., James, P., O’Donnell, J., Ng, C., Di Paola, J., Sadler, B., Bennett, C., Sidonio, R., Manco‐Johnson, M., Journeycake, J., Zia, A., Lusher, J., Rajpurkar, M., Shapiro, A., Lentz, S., Gill, J., Leissinger, C., Ragni, M., Tarantino, M., Roberts, J.
• Format: Article
• Language: English
• Subjects: African Americans; Antigens; Brief Reports; clinical laboratory tests; Ethnicity; genetic polymorphism; Glycoproteins; Hematology; Laboratories; Pediatrics; Ristocetin cofactor; von Willebrand disease; von Willebrand factor
• ISSN: 2475-0379; 2475-0379
• DOI: 10.1002/rth2.12807

Von Willebrand disease (VWD) is a common inherited bleeding disorder, however the diagnosis can be complicated by a subjective bleeding history and issues with some current von Willebrand factor (VWF) laboratory assays. In the Zimmerman Program, we sought to determine how often a type 1 diagnosis was based on a single low VWF ristocetin cofactor (VWF:RCo) level resulting from the common genetic variant p.D1472H or an isolated assay issue, if that low value was corroborated by the VWF glycoprotein‐IbM (VWF:GPIbM) assay, and if retesting confirmed original levels. New patients being evaluated for bleeding were consented. Analysis included VWF sequencing, bleeding scores, and comparisons of local VWF antigen (VWF:Ag) and VWF:RCo to central VWF:Ag and VWF:GPIbM. A total of 18% of VWD subjects had a low local VWF:RCo, but normal VWF:Ag and normal central testing including VWF:GPIbM. Seventy percent of the low VWF:RCo cohort had no pathogenic VWF variants; however, 33% carried p.D1472H. Low VWF:RCo subjects with follow‐up local testing within 2 years showed those with p.D1472H continued to have low VWF:RCo and VWF:RCo/VWF:Ag ratio with normal VWF:GPIbM. Subjects without p.D1472H had an increase mean VWF:RCo, resulting in 59% with normal levels on repeat testing. The diagnosis of VWD based on a single low VWF:RCo but normal VWF:Ag, was often attributed to p.D1472H or variability in VWF:RCo that was eliminated with VWF:GPIbM. Our study suggests that using VWF:RCo alone for diagnostic purposes may be insufficient while repeat VWF:RCo or VWF:GPIbM testing can be valuable in establishing a VWD diagnosis.