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Versiti experts create new test for von Willebrand disease

Milwaukee — September 07, 2023
Written By Robert Montgomery, MD

Versiti experts recently developed a better, more accurate test for diagnosis of von Willebrand disease.


Years ago, Versiti Blood Research Institute (VBRI) Hematologist and Senior Investigator Robert Montgomery, MD, saw a young, female, African American patient who was being evaluated for bleeding disorders before undergoing a tonsillectomy. “It was during the early days of DNA sequencing,” he said. “Testing showed that she had marked reduction in the activity of von Willebrand factor, but a normal-ish antigen.” Because of this, she was diagnosed with type 2M von Willebrand disease (VWD) and her tonsillectomy—a surgery known for its propensity for bleeding—was canceled.

Years later, Dr. Montgomery was surprised to see the same patient once again, who began menarche with no excessive bleeding. That got him thinking. “We had shown in earlier studies that both her brother and father had the same mutation,” he said. “The father went through open-heart surgery with no excessive bleeding. I thought, based on this, that this patient didn’t have a defect. It was a laboratory-positive diagnosis that was wrong.”

Though the patient was still technically diagnosed as having VWD, Dr. Montgomery recommended they move forward with her tonsillectomy and make provisions for treatment products during the operation. The patient came through surgery without bleeding problems—a clear indicator that she did not, in fact, have a bleeding disorder.

Problems with the old test

But Dr. Montgomery still needed to get to the bottom of why tests showed this patient had a bleeding disorder, when she did not. Analysis of a group of healthy research subjects showed that a common genetic mutation was present in 67% of African Americans and 17% of Caucasians that could cause false-positive VWD diagnoses. “Patients would be classified as having clear-cut von Willebrand disease, but they didn’t,” Dr. Montgomery said. “African Americans in particular would be over-diagnosed, when they were actually normal.” So, he set out to create a more accurate test to diagnose patients with suspected VWD.

Developing a new, more effective test

If it weren’t for Dr. Montgomery’s patient who was misdiagnosed, prompting further comparison between African Americans and Caucasians with bleeding disorders, physicians and researchers may have never known that the test was erroneous. “It was the availability of research that enabled identifying the need for a new test,” he says.

To develop a more precise test for VWD, researchers used approximately 100,000 patient samples, some of which came from the same individual over the course of 15-20 years, partly because von Willebrand factor is known to increase with age. “Having those samples and being able to understand how DNA changes VWF has enabled us to paint a clearer picture about what is normal and abnormal,” Dr. Montgomery said.

Versiti’s new test uses an assay with a gain-of-function (or modified) protein to better, more accurately diagnose patients with von Willebrand disease. “This assay was discovered at VBRI. It avoids the problems with traditional testing, which can be erroneous in approximately 50% of African Americans and up to 20% in all other races for those with a common genetic variant,” Dr. Montgomery said. “This assay bypasses that problem. We’re making this assay accurate and reproduceable to more accurately and better diagnose individuals with VWD.”

About the expert: Robert Montgomery, MD, is a senior investigator at Versiti Blood Research Institute and a professor of pediatric hematology in the Department of Pediatrics at the Medical College of Wisconsin.

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Robert Montgomery, MD
Dr. Montgomery is a senior investigator at Versiti Blood Research Institute whose work focuses on understanding bleeding and clotting disorders.
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