Von Willebrand disease (VWD) is the most common hereditary bleeding disorder but one of the most difficult to diagnose, especially type 1 VWD. Recurrent challenges include the need to complete several assays of von Willebrand factor (VWF) activity and lack of consensus surrounding the acceptable standard for diagnosis. Consequently, improving current diagnostic techniques, as well as implementing new methods, is essential to ensure patients are provided optimal care.

In a review article published in Current Opinion in Hematology, Veronica H Flood, MD, of the department of pediatrics at the Medical College of Wisconsin in Milwaukee, and colleagues summarized the current literature surrounding the diagnosis of type 1 VWD. They also reviewed new advances in genetic testing for VWF, which could serve as a potential alternative to conventional laboratory methods.

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Overview of Genetic Dysfunction

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In contrast to type 2 VWD, type 1 VWD may include genetic defects in the coding region of the VWF gene. These mutations vary from insertions and deletions to point mutations that produce missense or nonsense mutations. With conventional sequencing methods, insertions and deletions can be missed, which has historically precluded the clinical use of genetic-based diagnostic techniques. These limitations are not typically seen in type 2 VWD as genetic defects are usually present in the DNA region specific to the impacted functional region.

Because of the high degree of polymorphism seen in the VWF gene, entire genome or exome sequencing may be required for diagnosis; in other instances, the VWF gene may be analyzed directly if a particular coagulation defect is suspected. In type 1 VWD, certain high frequency variants have been linked to disease etiology, but recent data have highlighted the potential role of novel variants in type 1 VWD. The high degree of variability seen in the VWF gene is certainly a key contributor to the disease phenotype, but not all defects will ultimately lead to VWD.

Modifier Genes and Diagnosis

In addition to defects in VWF, several genes independent of the VWF locus have been shown to affect VWF levels. The most described modifier gene is ABO, though others such as CLEC4M, STAB2, and STXBP5 also exist. Blood group O levels of less than 50 IU/dL are routinely used to establish a diagnosis of VWD, but some individuals with blood type O also meet this criteria despite being healthy. Some experts have proposed that low VWF may be more suitably described as a risk factor for bleeding instead of as the basis for bleeding.