Common VWF Haplotypes in Normal African-Americans and Caucasians Recruited into the ZPMCB-VWD and Their Impact on VWF Laboratory Testing.

Von Willebrand disease (VWD) is a common bleeding disorder that has been reported to affect up to 1% of the population. Diagnostic testing for VWD relies on specific tests of von Willebrand factor (VWF) that include VWF antigen (Ag) and VWF ristocetin cofactor activity (RCo). Variability in these tests, especially in the RCo, has the potential to affect diagnosis of VWD. Clinically, the RCo/Ag ratio is used to identify patients with type 2M VWD, of which 35% of our local type 2M index cases were of African-American descent. As part of the ZPMCB-VWD, a large study of both healthy controls and patients with VWD, we evaluated VWF Ag, RCo, multimers, EU bleeding score, and VWF gene sequencing to look for mutations and/or common polymorphisms (SNPs) that might contribute to RCo measurement. Healthy controls completed a computerized version of the EU bleeding score and provided blood for clinical VWF testing. Since platelet VWF binding primarily involves the A1 domain of VWF, exon 28 gene sequencing was analyzed and common SNPs were identified, particularly in African-Americans (AA) with altered RCo/Ag ratios. Statistical comparisons were performed using t-tests. For the AA control group, the presence of specific exon 28 SNPs, including I1380V, N1435S, and D1472H, correlated with a low RCo/Ag. In controls, the 3 SNPs occurred together in 22% of AA and 1.5% of Caucasians. For AA controls with all 3 SNPs, the mean Ag was 155, RCo 115, and RCo/Ag 0.77, while for AA without the 3 SNPs, the mean Ag was 129, RCo 129, and RCo/Ag 1.01. The difference in RCo/Ag ratio was significant (p