SAN DIEGO (360Dx) — A new laboratory-developed assay that more accurately measures platelet binding activity of von Willebrand factor (VWF) in patients is now available for the first time in the US, offering a potentially more accurate diagnosis, as well as better treatment, for von Willebrand disease.
According to the BloodCenter of Wisconsin, which is offering the test, called the VWF GPIbM Activity assay, it is more accurate than standard tests now used in the US. By detecting qualitative defects in the blood-clotting protein VWF, the new test reduces variability for more precise, reliable, and sensitive results.
The CLIA- and College of American Pathologists-certified test is now available to the more than 1,200 clinical laboratories and hospitals served by BloodCenter of Wisconsin’s Diagnostic Laboratories nationwide. All testing is provided by the blood center's hemostasis reference lab in Milwaukee, with a standard turnaround time of seven days or less, but the goal is to reduce time-for-answer as the test becomes the standard for diagnosing von Willebrand disease in the US, said Scott Grady, portfolio manager for hematology at Milwaukee-based BloodCenter of Wisconsin, a nonprofit affiliate of Versiti.
The fee for the new test is identical to VWF Ristocetin Cofactor Activity test, the current standard diagnostic test for von Willebrand disease, and is reimbursable by Medicare and Medicare, he said.
Grady explained that the new test is an enzyme-linked immunosorbent assay that measures the interaction of a patented gain-of-function GPIb construction with VWF in a patient sample. It employs patented technology similar to tests that have been used in Europe and Canada for several years, but had been unavailable in the US until now, said Ken Friedman, medical director of the Hemostasis Reference Laboratory at BloodCenter of Wisconsin, associate medical director of BloodCenter’s Comprehensive Center for Bleeding Disorders, and associate professor at the Medical College of Wisconsin.
The test is launching only now because the process of discovery, applied research and clinical development, and validation of a new test requires rigor to ensure the highest quality results, said Grady, though the BloodCenter published research about the test originally in the journal Blood in February 2011.
BloodCenter of Wisconsin owns the patent for this technology in the US, while other entities own the patents for similar technology in Canada and Europe, Scott said.
Von Willebrand disease, which occurs in both men and women, is thought to be the most common bleeding disorder, affecting up to 1 percent of the population. It is an inherited genetic disorder characterized by either quantitative or qualitative defects caused by an alteration or deficiency of VWF. The disease has three major subtypes: partial quantitative deficiency or type 1; qualitative deficiency or type 2; and virtually complete deficiency or type 3.
This disease is difficult to diagnose and may be underdiagnosed because many people with this bleeding disorder have mild signs and symptoms, including easy bruising, excessive nose bleeds, bleeding gums, or abnormally heavy bleeding during menstruation. Diagnosis usually involves a review of the patient's personal and family history of bleeding and a clinical evaluation for more common reasons for bleeding, supplemented with laboratory tests. The assessment is used to determine bleeding risk before surgery and other invasive procedures, and to diagnose reasons for unexplained hemorrhaging.
A reason von Willebrand disease subtype may be misdiagnosed is that the standard test, which uses ristocetin to induce platelet aggregation as measure of VWF platelet binding function, is very imprecise and has poor sensitivity, Friedman said. “The lower limit to the standard assay is 10 to 20 IUs per dL,” he said explained. “Our assay improved the lower-limit of detection to 2 units per deciliter.
“We also got around an artifact that occurs in ristocetin-dependent assays by using a mutant glycoprotein Ib (GPIb), developed by researchers at BloodCenter,” Friedman explained, noting that this artifact is caused by a common genetic polymorphism in patients, and healthy individuals may confound an accurate diagnosis of VWD. GPIb is a component of the GPIb-V-IX complex on platelets that binds with VWF to allow platelet adhesion and clotting to occur at the site of vascular injury.
“Every test has a certain amount of variation in measurements,” he continued, “but we get a better, more precise read because the old test has more noise around values.”
The VWF GPIbM Activity test, by itself, however, cannot diagnose von Willebrand disease. “Due to the complexity of VWD, multiple tests are necessary to accurately diagnose this disease,” Grady stressed, noting that the GPIbM test will be one of the primary tests used to evaluate VWD, replacing the unreliable ristocetin test. Other diagnostics technologies test for factor antigen, which determines the level of VWF in blood by measuring a certain protein; Factor VIII clotting activity; and VWF multimers.
The precision, reliability, and sensitivity of all these tests is critical to support diagnosis and guide the most effective treatment, Grady said, noting that BloodCenter offers one of the most comprehensive functional and genetic test menus in the nation for diagnosing VWD. That menu is paired with multidisciplinary expertise that includes consultation by BloodCenter’s medical directors.
Annette Von Drygalski, director of the Hemophilia and Thrombosis Treatment Center at UC San Diego Health and a BloodCenter of Wisconsin customer, has been anticipating availability of the new test, which she noted has been under development for some time. The test currently available for von Willebrand disease is 50 years old and has not changed much, she said, noting that it relies on clumping of platelets in ristocetin. Results between labs can also vary by as much as 20 percent to 50 percent, and test results can be influenced by the patient’s sex, age, and daily fluctuations in antigen factor.
“If it works, this test will be more quantifiable, sensitive, reliable, accurate, and reproducible,” Drygalski said.
There is no cure for von Willebrand disease, but it can be managed, Friedman noted. Treatment, which is tailored to the subtype, is generally initiated before planned invasive procedures or in response to bleeding. This includes giving desmopressin, a synthetic of the antidiuretic hormone vasopressin that stimulates release of VWF endogenously stored in the body, increasing its concentration in plasma.
VWF replacement therapy, which uses human plasma–derived, viral-inactivated concentrates of VWF, also may be given intravenously prior to an invasive procedure. A recombinant von Willebrand factor, Vonvendi, was approved by the US Food and Drug Administration in 2015, but is not widely used in the US because of its high cost, Friedman said.
Additionally, antifibrinolytic drugs, such as aminocaproic acid and tranexamic acid, may also be used orally or intravenously to treat mild bleeding, and topical agents, such as fibrin sealants, can be used as an adjunct therapy during dental surgery or for surface wound bleeding unresponsive to drugs and concentrates.