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VWF 3D animation

How is von Willebrand disease diagnosed?

Dr. Jürgen Patzke

Diagnosis of von Willebrand disease (VWD) is a complex process that can require several medical visits and laboratory assessments. In addition to the patient’s clinical history and bleeding symptoms, the results of certain laboratory tests need to be evaluated. 

What is von Willebrand disease?

Von Willebrand disease is the most frequently inherited human bleeding disorder, which is characterized by a reduction or dysfunction of von Willebrand factor (VWF), a protein in the blood that acts as a key player in hemostasis. A deficiency or dysfunction of von Willebrand factor can lead to severe bleeding that is hard to stop.

VWF testing guidelines

Which laboratory tests are used in the diagnosis of von Willebrand disease?


According to  the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease, the first level diagnostic panel should include:

  • VWF antigen test 
  • Platelet-dependent VWF activity test
  • FVIII activity test 

After this first line of tests, additional testing may include:

  • Collagen binding-activity
  • VWF multimer assessments
  • Factor VIII-binding test
  • Genetic testing

VWF activity assay panel glossary

Activity assays are part of the recommended assay panel and measure the function of VWF. They help identify qualitative and quantitiative defects of the protein and are therefore a crucial part of the initial testing panel for VWD.

The table below lists different assay principles (adapted from Bodo et al., 20151 and Higgins and Goodwin, 20192) used in commercially available assays.

Recommended by the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease as first line assays are VWF:RCo, VWF:GPIbM or VWF:GPIbR.

Abbreviation

Description

VWF:RCo

Ristocetin cofactor activity: all assays that use platelets and ristocetin

VWF:GPIbR

All assays that are based on the ristocetin-induced binding of VWF to a recombinant WT GPIb fragment

VWF:GPIbM

All assays that are based on the spontaneous binding of VWF to a gain-of-function mutant GPIb fragment

Unique assay principle

How is VWF activity measured with the INNOVANCE VWF Ac assay?

The INNOVANCE® VWF Ac assay from Siemens Healthineers uses a mutated version of the platelet-binding receptor, the so-called GPIb receptor, of the von Willebrand factor molecule, which is bound to latex particles. This mutated receptor binds to the VWF molecule spontaneously, which allows particle agglutination to occur without ristocetin.


On the analyzer, Reagent III, containing the GPIbα fragment, is mixed with Reagent II, Owren's Veronal Buffer, and the patient’s plasma sample. VWF contained in the sample binds to the gain-of-function GPIbα fragment without support from shear stress, ristocetin, or any other agent. After 120 seconds of incubation, Reagent I, which contains the microparticles, is added as the starting reagent (See figure below). The binding of the microparticles to the VWF/GPIbα complex is measured as an increase in turbidity, which is caused by particle agglutination. 


The INNOVANCE VWF Ac assay's unique technology enables increased precision and is less susceptible to effects of certain polymorphism variants.

Step 1

Step 2

Step 3

    Assay performance

    INNOVANCE VWF Ac assay performance

    Over the past 10 years, several studies have utilized the assay and several benefits have been noted:

    • High analytical sensitivity1 and precision3
    • Good comparability/ correlation to VWF:RCo assay4
    • Improved detection of functional abnormalities5
    • Insensitivity to polymorphism P.P1467S and P.D1472H6

    In the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease, the panel suggests newer assays to measure VWF platelet-binding activity (e.g., VWF:GPIbM, VWF:GPIbR) rather than VWF:RCo due to their:

    • Lower coefficient of variation and higher reproducibility compared to VWF:RCo
    • Concern that D1472H sequence variant may lead to overdiagnosis of VWD by the VWF:RCo method

    Literature Compendium: A review of guidelines and utility in diagnosis
    (INNOVANCE VWF Ac assay)

    INNOVANCE VWF Ac Assay literature guide

    Download a review of current guidelines and recommendations for von Willebrand testing


    • Current recommendations and guidelines for von Willebrand testing
    • Reviews of von Willebrand disease testing
    • Studies reviewing the performance of INNOVANCE VWF Ac assay

    ...and much more!

    About Dr. Jürgen Patzke

    Dr. Jürgen Patzke not only invented the INNOVANCE VWF Ac assay, but also developed the ristocetin cofactor assay BC von Willebrand Reagent. He has worked on the ISTH/SSC and CLSI committees on von Willebrand factor and has become a Siemens Healthineers senior key expert in the field of hemostasis.

    Watch scientific webinars and educational videos about VWD diagnostics and physiological backgrounds

    Free webinar: Current advances in the diagnosis of von Willebrand disease

    Join Dr. K Friedman, Medical College of Wisconsin, U.S., and Dr. J. Patzke, Siemens Healthineers, Germany, as they share insights on von Willebrand disease diagnostics and related guidelines.

    Coming soon:
    Video: Primary hemostasis cascade

    Navigate through our interactive cascade videos to learn more about how hemostatic processes play a role in protecting the body from excessive or insufficient clotting and the role pharmaceutical therapies can play in regulating hemostatic balance.

    Select Science Webinar

    Watch this Webinar to join Dr. Edward Wong exploring current diagnostic approaches of von Willebrand disease and the advantages of new testing strategies.

    Credits for VWF-3D graphic:
    PDB: 1SQ0

    Dumas JJ, Kumar R, McDonagh T, Sullivan F, Stahl ML, Somers WS, Mosyak L. Crystal structure of the complex of the wild-type von Willebrand factor A1 domain and glycoprotein Ib alpha at 2.6 angstrom resolution. 2004. doi: 10.2210/pdb1SQ0/pdb

    Dumas JJ, Kumar R, McDonagh T, Sullivan F, Stahl ML, Somers WS, Mosyak L. Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations. J Biol Chem. 2004;279:23327-34. doi: 10.1074/jbc.M401659200

    1

    Bodó I, et al. JTH. 2015. doi.org/10.1111/jth.12964

    Castaman  G, et al. Expert opinion on orphan drugs. 2019. doi.org/10.1080/21678707.2019.1609352

    Geisen U, et al. Thromb Res. 2014. doi.org/10.1016/j.thromres.2014.04.033

    Szederjesi A., et al. JTH. 2018. doi.org/10.1111/jth.14206

    2

    Higgins RA, Goodwin AJ. Am J Hematol. 2019. doi.org/10.1002/ajh.25393

    3

    Favaloro EJ, et al. Thromb Res. 2018. doi.org/10.1016/j.thromres.2018.04.015

    Graf L, et al. Int J Lab Hematol. 2014. doi.org/10.1111/ijlh.12218

    Szederjesi A, et al. JTH. 2018. doi.org/10.1111/jth.14206

    4

    de Maistre E, et al. Thromb Haemost. 2014. doi.org/10.1160/TH14-02-0108

    Favaloro EJ, et al. Thromb Res. 2016b. doi.org/10.1016/j.thromres.2015.12.010

    Florin, C., et al. Ann Biol Clin. 2016. doi.org/10.1684/abc.2016.1145

    5

    Graf L, et al. Int J Lab Hematol. 2014. doi.org/10.1111/ijlh.12218

    Higgins RA, Goodwin AJ. Am J Hematol. 2019. doi.org/10.1002/ajh.25393

    6

    Lassalle F, et al. Poster presented at ISTH congress. 2020. academy.isth.org/isth/2020/milan/296705/fanny.lassalle.the.vwf.variant.d1472h.affects.vwf.binding.to.ristocetin.in.html

    Moonla C, et al. Clin Appl Throm Haemost. 2019. doi.org/10.1177/1076029619866916

    Szederjesi, A, et al. JTH. 2018. doi.org/10.1111/jth.14206

    Szederjesi, A., et al. JTH. 2020. doi.org/10.1111/jth.14971

    Vangenechten, I., et al. JTH. 2018. doi.org/10.1111/jth.14145


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