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Common VWF sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with type 1 VWD. Res Pract Thromb Haemost 2018 Apr;2(2):390-398

Date

07/27/2018

Pubmed ID

30046743

Pubmed Central ID

PMC5974909

DOI

10.1002/rth2.12077

Scopus ID

2-s2.0-85076700342   3 Citations

Abstract

:

Background: Genetic variation in the VWF gene is associated with von Willebrand factor (VWF) and factor VIII (FVIII) levels in healthy individuals.

Objectives: We hypothesized that VWF sequence variants associated with higher VWF or FVIII could impact the diagnosis of type 1 von Willebrand disease (VWD).

Methods: We examined VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF propeptide (VWFpp), and FVIII levels along with VWF gene sequencing in 256 healthy control and 97 type 1 VWD subjects as part of a cross-sectional study.

Results: We found several VWF sequence variants (VWF c.2880G>A and VWF c.2365A>G(;)c.2385T>C, found in linkage disequilibrium) associated with higher VWF and FVIII levels in healthy controls (< .001 for both variants). In addition, these variants were significantly more common in controls than in subjects diagnosed with type 1 VWD and VWF:Ag <30 (< .005). The decreased variant frequencies in type 1 VWD was not seen in other VWD types. VWF:Ag, VWF:RCo, and FVIII were not statistically different in type 1 VWD subjects who had these VWF variants compared to type 1 VWD patients without them. There was no difference in ABO blood group, VWF propeptide levels (excluding subjects with known VWF clearance defects), or bleeding score using the ISTH bleeding assessment tool.

Conclusions: These data suggest that certain VWF sequence variants associated with elevated FVIII and VWF levels may protect against reduced VWF levels. These findings were independent of other pathogenic sequence variants in VWF, suggesting a possible independent effect of c.2880G>A and c.2365A>G(;)c.2385T>C on VWF levels.

Author List

Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, Friedman KD, Montgomery RR

Authors

Veronica H. Flood MD Professor in the Pediatrics department at Medical College of Wisconsin
Kenneth D. Friedman MD Professor in the Medicine department at Medical College of Wisconsin
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin