Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project

Abstract

Key Points Several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among African Americans. Next-generation sequencing technology and improved genotype imputation can contribute to molecular genetics of VWD-related phenotypes.

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

“…on May 12, 2018. by guest www.bloodjournal.org From experiment, FVIII levels closely paralleled VWF antigen levels over the period of observation (Pearson's correlation coefficient 5 0.80, 95% CI 5 0.70-0.90), as similarly observed in humans. 36 Expression of ΔPro, D1D3-GS-CK, D1-D3, and D9D3 all resulted in markedly increased FVIII levels (P , .01 vs preinjection), ranging from 50% to 120% from day 1 through 4 weeks postinjection ( Figure 2B). truncD9D3 produced a minimal, transient elevation in FVIII levels.…”

“…Extending the circulatory lifetime of D9D3 by Fc fusion markedly prolongs endogenous FVIII survival in Vwf 2/2 mice but is insufficient to extend the FVIII t 1/2 in HA mice. Plasma FVIII levels closely correlate with plasma VWF levels 36 because of the dependence of FVIII on its tight interaction with VWF for stability in the circulation. 1 The VWF level we observed in C57BL/ 6J mice (3.4 mg/mL, Figure 2A) is ;1/3 of the average VWF level in healthy humans, consistent with a previous report.…”

A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders

“…Such variants include, for instance, the regulatory non-coding SNVs in RBM8A 17,18 responsible for Thrombocytopenia-Absent Radius (TAR) syndrome in the presence of a loss-of-function variant on the alternate haplotype, moderately common variants in VWF linked to reduced levels of the VWF protein [19][20][21] and the F5 Leiden 22 variant.…”

VWF sequence variants: a data goldmine

“…The majority of the total of 30 missense variants identified by the study had no significant association with VWF or FVIII levels, suggesting that they are neutral variants. 1 The VWF gene is relatively large, covering 178 kb of genomic DNA, with a 52-exon complementary DNA encoding the 2813 amino acids that comprise the large VWF monomer. Since the first sequence analysis of the gene in 1989, VWF has been recognized as having a high rate of sequence variation between individuals.…”