Prevalence and characterization of anti-VWF antibodies in a population of subjects with type 3 VWD.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative defects in the von Willebrand factor protein (VWF). Type 3 VWD has a severe bleeding phenotype caused by the absence of VWF where treatment usually involves replacement therapy with VWF-containing products. The immune system can react to the VWF product and form anti-VWF antibodies to neutralize or clear the VWF which can compromise efficacy of treatment or lead to anaphylaxis. Current diagnostic testing is limited to the detection of anti-VWF antibodies that neutralize VWF binding to platelets by using a ristocetin cofactor assay. We set out to develop assays to identify both neutralizing and non-neutralizing antibodies to screen, quantify, and characterize anti-VWF antibodies in samples from the Zimmerman Program, a large multicenter study of VWD subjects. We detected anti-VWF IgG or IgM antibodies in 18% of 49 unrelated type 3 VWD individuals. The antibodies ranged in concentration and consisted of 33% non-neutralizing and 67% neutralizing to factor VIII, collagen III, platelet GPIbα, and/or collagen IV binding. Of the positive type 3 VWD samples, 8/9 were IgG which were further subclassified into mostly IgG1 and IgG4 antibodies. Through a series of testing methods, we identified VWF specific antibodies in 9 unrelated type 3 VWD individuals with varying demographics, bleeding phenotypes, and genetic variants. This anti-VWF antibody testing strategy provides a useful tool to assess risk and better navigate treatment options for type 3 VWD patients.