Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J Thromb Haemost 2009 Nov;7(11):1832-9
Date
08/22/2009Pubmed ID
19694940Pubmed Central ID
PMC3825106DOI
10.1111/j.1538-7836.2009.03594.xScopus ID
2-s2.0-70449436494 (requires institutional sign-in at Scopus site) 76 CitationsAbstract
BACKGROUND: Type 2M von Willebrand disease (VWD) is characterized by a qualitative defect in von Willebrand factor (VWF) and diagnosed by a disproportionate decrease in VWF ristocetin cofactor activity (VWF:RCo) as compared with VWF antigen (VWF:Ag).
OBJECTIVE: We report here on the spurious diagnosis of VWD in a patient with a sequence variation in the ristocetin-binding domain of VWF.
PATIENTS/METHODS: The index case had a VWF:RCo of 11 IU dL(-1), with VWF:RCo/VWF:Ag ratio of 0.09. DNA sequencing revealed a novel P1467S mutation in a known ristocetin-binding region of the A1 domain. Because of the discrepancy between the laboratory findings, consistent with type 2M VWD, and the patient's lack of bleeding symptoms, further studies were performed to determine whether this mutation affected VWF function or merely reduced its ability to interact with ristocetin.
RESULTS: Studies with recombinant VWF showed normal platelet binding with botrocetin, but a significant decrease in binding in response to ristocetin. Ristocetin-induced binding to recombinant GPIb was also absent, but normal binding was seen when a gain-of-function GPIb construct was used in the absence of ristocetin. VWF function under shear stress was normal when analyzed with a cone and plate(let) analyzer.
CONCLUSIONS: The decreased VWF:RCo seen with the P1467S sequence variation likely represents an artifact as a result of the use of ristocetin to measure VWF activity. The normal VWF function in other assays correlates with the lack of hemorrhagic symptoms, and suggests the need for more physiologically relevant assays of VWF function.
Author List
Flood VH, Friedman KD, Gill JC, Morateck PA, Wren JS, Scott JP, Montgomery RRAuthors
Veronica H. Flood MD Chief, Professor in the Pediatrics department at Medical College of WisconsinKenneth D. Friedman MD Professor in the Medicine department at Medical College of Wisconsin
Robert R. Montgomery MD Emeritus Professor in the Pediatrics department at Medical College of Wisconsin
John Paul Scott MD Emeritus Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Binding SitesChild
Female
Humans
Mutation, Missense
Platelet Function Tests
Protein Binding
Ristocetin
von Willebrand Diseases
von Willebrand Factor
