Faculty Collaboration Database

Clinical and laboratory phenotype variability in type 2M von Willebrand disease. J Thromb Haemost 2017 Aug;15(8):1559-1566

Date

05/26/2017

Pubmed ID

28544236

Pubmed Central ID

PMC5538962

DOI

10.1111/jth.13742

Scopus ID

2-s2.0-85021241191 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

UNLABELLED: Essentials The pathophysiology of type 2M von Willebrand disease (VWD) is poorly understood. Sequence variations in type 2M VWD subjects were characterized. A high degree of clinical and laboratory variability exists within type 2M VWD variants. Some type 2M variants may share features of type 2A VWD.

SUMMARY: Background von Willebrand factor (VWF) is a multimeric coagulation factor that tethers platelets to injured subendothelium. Type 2M von Willebrand disease (VWD) is characterized by a qualitative defect in VWF with preserved multimer distribution. Objectives Through the Zimmerman Program for the Molecular and Clinical Biology for VWD, five VWF sequence variations were studied in subjects diagnosed with type 2M VWD. Methods Bleeding phenotype was assessed using the ISTH bleeding assessment tool. Full-length VWF gene sequencing was performed for each subject. Each variant was placed into a recombinant VWF vector using site-directed mutagenesis and expressed in HEK293T cells as homozygous or heterozygous VWF. Variant expression, collagen binding and platelet GPIbα binding were studied through ELISA assays. Multimer analysis was performed by gel electrophoresis. Results Bleeding scores were elevated for all subjects except for the p.P1162L and p.R1374C variants. Although all had reduced VWF ristocetin cofactor activity/VWF antigen ratios on plasma testing, recombinant VWF did not show a classic type 2M phenotype for any of the five variants. Homozygous expression of variants p.D1283Y, p.R1349C, p.R1374C and p.I1453N was consistent with type 2A VWD, although all had normal expression as heterozygous recombinant VWF. Variant p.P1162L had normal VWF expression and function, consistent with the lack of bleeding symptoms. Conclusions Although originally classified as type 2M VWD, these homozygous recombinant VWF variants do not fulfill complete 2M VWD diagnostic criteria. A better classification schema and improved testing for putative type 2M variants is needed in order to effectively diagnose and treat affected patients.

Author List

Doruelo AL, Haberichter SL, Christopherson PA, Boggio LN, Gupta S, Lentz SR, Shapiro AD, Montgomery RR, Flood VH

Authors

Veronica H. Flood MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged, 80 and over
Blood Coagulation
Case-Control Studies
Collagen
Female
Genetic Predisposition to Disease
Genetic Variation
HEK293 Cells
Hemorrhage
Heterozygote
Homozygote
Humans
Male
Middle Aged
Pedigree
Phenotype
Platelet Glycoprotein GPIb-IX Complex
Protein Binding
Protein Multimerization
Severity of Illness Index
Transfection
United States
von Willebrand Disease, Type 2
von Willebrand Factor