Faculty Collaboration Database

Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease. Haemophilia 2013 Jul;19(4):590-4

Date

03/19/2013

Pubmed ID

23496210

Pubmed Central ID

PMC3688679

DOI

10.1111/hae.12117

Scopus ID

2-s2.0-84879459941 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

Type 2M von Willebrand disease (VWD) includes qualitative defects in von Willebrand factor (VWF) function, with normal multimer distribution but a defect in VWF activity with respect to platelet or collagen binding. We characterized novel VWF gene mutations found in type 2M VWD subjects enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Subjects were enrolled based on a pre-existing diagnosis of type 2M VWD. Testing included full-length gene sequencing, VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding and multimer distribution. Recombinant VWF variants were synthesized using site-directed mutagenesis and expressed in HEK293T cells. Platelet binding was measured by flow cytometry with fixed platelets and ELISA with recombinant glycoprotein Ibα (GPIbα). Four novel VWF A1 domain mutations were found in individuals with type 2M VWD: S1358N, S1387I, S1394F and Q1402P. All subjects had a history of bleeding, VWF:RCo < 40 IU dL(-1) , VWF:RCo/VWF:Ag ratios <0.6 and normal multimer distribution. No defect in expression, secretion, or multimerization was found for any of the mutations. All showed decreased binding to intact platelets, and decreased or absent binding to a mutant GPIbα construct with spontaneous VWF binding. 1387I had decreased binding to all collagen types tested. 1402P had reduced binding exclusively to type VI collagen. Type 2M VWD is a heterogeneous category comprised of both collagen- and platelet-binding defects. Understanding the precise defect for each mutation may ultimately lead to better diagnosis and treatment.

Author List

Larsen DM, Haberichter SL, Gill JC, Shapiro AD, Flood VH

Author

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

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

Blood Platelets
Collagen
Female
HEK293 Cells
Humans
Mutant Proteins
Mutation
Platelet Glycoprotein GPIb-IX Complex
Protein Binding
Protein Multimerization
Recombinant Proteins
Ristocetin
von Willebrand Disease, Type 2
von Willebrand Factor