Patients with Bleeding Phenotype and Von Willebrand Exon 28 Polymorphism D1472H: A Retrospective Analysis At a Single Institution

The diagnosis and type of von Willebrand's disease (VWD) is based on the measure of von Willebrand's Factor (VWF) assays: VWF ristocetin cofactor activity (VWF:RCo), VWF antigen (VWF:Ag), VWRCoF:VWAg ratio, and VWF multimer analysis. Exon 28 genetic analysis is usually undertaken to evaluate for VWD type 2 in patients with very low VWF:RCo, abnormal VWF:RCo/VWF:Ag ratio or abnormal multimers. Exon 28 polymorphism D1472H is associated with significantly lower VWF:RCo/VWF:Ag ratio in healthy controls, due to altered ristocetin binding in the VWF:RCo assay. These findings do not reflect a true hemorrhagic risk. This common polymorphism may present a challenge for the accurate diagnosis of VWD in patients with bleeding symptoms. We sought to review our experience at a single institution to better characterize the clinical and laboratory phenotype among patients with symptomatic bleeding and confirmed VWF exon 28 polymorphism D1472H.

With IRB approval, patients with clinically significant bleeding who underwent VWF exon 28 analysis were identified between 1990 and 2011. A retrospective chart review was performed and patient demographics, clinical features, and laboratory data pertaining to hemostasis including exon 28 analysis were gathered. Descriptive statistics were performed on the data gathered.

Of 63 patients with symptomatic bleeding who underwent VWF exon 28 analyses, 23 had D1472H polymorphisms detected. Of these, 4 were homozygous, 19 were heterozygous; 8 were male, 15 were female. Median age at the time of presentation was 5 years (range 4 months - 15 years). Eighteen patients had a family history of bleeding, and 3 had at least one family member with a confirmed diagnosis of VWD. VWF assays for all patients with and without the polymorphism of interest are summarized in Table 1.

Sixteen (70%) patients were diagnosed with VWD; 9 patients had provisional type 1 VWD (VWF:RCo <30%, normal multimer), 2 had type 2A VWD, 2 had type 2B VWD, 1 had compound heterozygous type 1/type 2N, 1 patient had VWD/Hemophilia A, and 1 patient was completing evaluation with probable diagnosis of type 2 VWD.

Of the patients with the D1472H polymorphism and provisional diagnosis of type I VWD, 6 had normal/near-normal VWF:Ag and borderline low VWF:RCo (Table 2).

Based on our data, confirmation of a diagnosis of type 1 VWD can be a challenge for patients with symptomatic bleeding and low VWF:RCO activity in the presence of VWF exon 28 polymorphism D1472H. Low VWF:RCo activity (< 30%) has been an essential component for the diagnosis of VWD. In patients with VWF exon 28 D1472H polymorphism, the VWF:RCo is no longer a reliable measure of physiologic function. Clinicians need to be aware of this common polymorphism as patients presenting with normal or near-normal VWF:Ag, borderline low VWF:RCo and low ratios may not truly have VWD. Alternative ristocetin-independent VWF assays that rely on biologically relevant interactions of VWF with platelet glycoprotein IB are needed. On the contrary, patients with symptomatic bleeding and exon 28 D1472H polymorphism may have VWD as shown in our study. Detailed laboratory evaluation may help to further clarify the VWD status in these patients.

No relevant conflicts of interest to declare.