What is the influence of race and ethnicity on the diagnosis of VWD?¶
Answer: Race and ethnicity bias VWD diagnosis in both directions — overdiagnosis from an assay artifact, and underdiagnosis from higher baseline VWF levels.
- Overdiagnosis — the D1472H polymorphism is common in Black patients (~2 of 3, vs ~1 of 6 White patients) and lowers measured VWF ristocetin cofactor activity (VWF:RCo), which can be misread as type 2M VWD. The seminal Blood study traced this to exon 28 polymorphisms that affect the ristocetin-based assay:
The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of "VWF activity" by this assay and may not reflect a functional defect or true hemorrhagic risk.
- Underdiagnosis — Black patients have higher average VWF:Ag (Black vs White women) and higher VWF and FVIII levels (African American adults vs other races), so genuine VWD can be missed against population-general reference ranges.
For broader population-level context, see Montgomery & Flood, What have we learned from large population studies of von Willebrand disease?.
Source: Laboratory-based inequity in thrombosis and hemostasis: review of the evidence