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Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost 2012 Jul;10(7):1417-24



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Scopus ID

2-s2.0-84863422773   46 Citations


BACKGROUND: von Willebrand factor (VWF) binds to subendothelial collagen at sites of vascular injury. Laboratory testing for von Willebrand disease (VWD), however, does not always include collagen binding assays (VWF:CB) and standard VWF:CB assays use type I and/or type III collagen rather than type VI collagen.

OBJECTIVES: We report here on several mutations that exclusively alter binding to type VI collagen.

PATIENTS/METHODS: Healthy controls and index cases from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity and VWF:CB with types I, III and VI collagen. VWF gene sequencing was performed for all subjects.

RESULTS: Two healthy controls and one type 1 VWD subject were heterozygous for an A1 domain sequence variation, R1399H, and displayed a selective decreased binding to type VI collagen but not types I and III. Expression of recombinant 1399H VWF resulted in absent binding to type VI collagen. Two other VWF A1 domain mutations, S1387I and Q1402P, displayed diminished binding to type VI collagen. An 11 amino acid deletion in the A1 domain also abrogated binding to type VI collagen.

CONCLUSIONS: VWF:CB may be useful in diagnosis of VWD, as a decreased VWF:CB/VWF:Ag ratio may reflect specific loss of collagen binding ability. Mutations that exclusively affect type VI collagen binding may be associated with bleeding, yet missed by current VWF testing.

Author List

Flood VH, Gill JC, Christopherson PA, Bellissimo DB, Friedman KD, Haberichter SL, Lentz SR, Montgomery RR


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

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

Case-Control Studies
Collagen Type VI
Models, Molecular
Protein Binding
Recombinant Proteins
von Willebrand Factor