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QQ: VWF Activity

Here are the results of our January, 2018 Quick Question.

Stem: What method do you use to measure von Willebrand factor activity?
a. Ristocetin cofactor (VWF:RCo): 61% (32)
b. Collagen binding assay (VWF:CB): 6% (3)
c. VWF activity immunoassay (VWF:Act): 23% (12)
d. Ristoectin-triggered recombinant GP 1b immunoassay (VWF:GPIbR): 4% (2)
e. Non-ristocetin gain of function GP 1b immunoassay (VWF:GPIbM): 6% (3)
Total votes: 52
Thank you for participating in the survey. It appears the collagen binidng assay, which has been available since early in the 1990s, has gained little traction. While the ristocetin cofactor, collagen binding assay, and VWF activity immunoassay are familiar to most of us, here are excerpts from the draft for the sixth edition of Rodak’s Hematology, which will be published later in 2018, explaining the ristocetin-triggered recombininat GP 1b immunoassay and the non-ristocetin gain of function GP 1b immunoassay:

For answer d: The VWF:RCo has been successfully automated, but has been partially replaced by automated ristocetin-triggered non-platelet recombinant GPIb-based LIA and CLIA methods such as the HemosIL AcuStar VWF:GPIbR (IL-Werfen, Bedford, MA), which the International Society on Thrombosis and Haemostasis Standardization Subcommittee (ISTH-SSC) for von Willebrand factor labeled VWF:GPIbR in their 2014 annual minutes.

For answer e: A promising alternative to VWF:RCo and VWF:GPIbR is an assay that incorporates a gain-of-function high affinity recombinant GPIb protein that resembles the GPIb of PTVWD platelets. The GPIb binds the A1 domain of native VWF without the need for ristocetin. This assay has been commercialized as a LIA; Innovance VWF Ac (Siemens Healthcare Diagnostics, Inc., Deerfield, IL), and it appears to improve on ristocetin-based assays as it offers smaller VWF detection limits and less variability. The 2014 ISTH-SSC terms this assay VWF:GPIbM.

Comments (2)
Bleeding Disorders
Mar 19, 2018 12:28pm

From George, I agree with Dr.
I agree with Dr. Favaloro’s concern about our Quick Question and I appreciate particularly his advocacy for the VWF:CB assay, which has never gained a foothold in the US and which serves a useful purpose in identifying various type 2 VWD categories.

Mar 10, 2018 7:37pm

Hi George, I would like to
Hi George, I would like to point out a major flaw in your survey, as it only permits a single choice to be taken. VWF has many activities, including platelet binding (primarily via GPIb, but also via GPIIb/IIIa, now also termed integrin αIIbβ3), subendothelial matrix binding (primarily via collagen), and FVIII binding. Indeed, if VWF only bound to platelet GPIb, then there would be no means to anchor platelets to the site of vascular injury; hence, collagen binding is an integral activity of VWF.

Mutations in VWF, as leading to VWD, can occur at any region of the VWF molecule, and thus affect any of its functions. Thus, type 2N VWD for example, affects VWFFVIII binding. The assay needed to identify 2N VWD is called the VWF:FVIII binding assay, an activity assay of VWF, and missing from your survey.

Most labs only do a partial job at identifying VWD. Indeed, any lab that restricts its test activity repertoire to only cover GPIb binding, be it VWF:RCo, VWF:GPIbR or VWF:GPIbM, will miss or misdiagnose a significant proportion of VWD cases. Excluding VWF:CB from the repertoire will cause misdiagnosis of most type 2 VWD cases. Our lab has reported on this many times. See Favaloro EJ, Bonar RA, Meiring M, Duncan E, Mohammed S, Sioufi J, Marsden K. Evaluating errors in the laboratory identification of von Willebrand disease in the real world. Thromb Res. 2014;134:393–403, and Favaloro EJ, Bonar RA, Mohammed S, Arbelaez A, Niemann F, Freney R, Meiring M, Sioufi J, Marsden K. Type 2M von Willebrand disease–more often misidentified than correctly identified. Haemophilia, 2016;22:e145–55.

Even if labs performed VWF:CB, they could not select it in the survey unless they wanted to unselect one of the GPIb binding assays. The main reason that labs in the US, (probably representing the bulk of your survey responses) do not perform VWF:CB is that no FDA approved method is available–that is, reflecting a regulatory restriction, rather than lack of clinical utility. Regulatory restrictions are less onerous in Europe and Australia, where clinical utility still has a place, and many labs undertake VWF:CB testing, as discussed in one of my STH blogs several years ago. See Favaloro EJ, Plebani M, Lippi G. Regulation in hemostasis and thrombosis: part I-in vitro diagnostics. Semin Thromb Hemost. 2013;39:235–49.

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