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Semin Thromb Hemost 2013; 39(06): 663-673
DOI: 10.1055/s-0033-1353442
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Platelet-Type von Willebrand Disease: New Insights into the Molecular Pathophysiology of a Unique Platelet Defect

Maha Othman
1   Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
2   St Lawrence College Kingston, Ontario, Canada
,
Harmanpreet Kaur
1   Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
,
Jonas Emsley
3   School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, United Kingdom
› Author Affiliations
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Publication History

Publication Date:
11 August 2013 (online)

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Abstract

Compared with coagulation factor defects, little attention is given to defects of platelet function as causes of rare bleeding disorders. Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant bleeding disorder and is unique among platelet disorders because it is characterized by platelet hyperresponsiveness rather than decreased function. The disease is caused by gain-of-function mutations in the platelet GP1BA gene, which codes for the platelet von Willebrand factor (VWF) receptor, GPIbα. Only five mutations (four missense and one deletion) have so far been reported. Affected patients suffer from mild to moderate mucocutaneous bleeding, low VWF activity compared with antigen, decreased high-molecular-weight VWF multimers, variable degree of thrombocytopenia and typically platelet aggregation in response to low concentrations of ristocetin. All reported PT-VWD missense mutations occur within the R-loop of GPIbα and it was speculated that the introduction of short branched chain mutations such as Val in PT-VWD stabilized the extended β-hairpin. Examination of this theory by surveying all the available GPIbα structures showed that a distinct conformation predominates for the R-loop when GPIbα is not bound to VWF-A1 and this provides the framework of a new hypothesis for the molecular basis of PT-VWD. Worldwide efforts to improve diagnosis of PT-VWD continue, and international systematic studies are required to further our understanding of the phenotype and the influence of the hyperresponsive GPIbα beyond hemostasis.

Keywords

GPIbα - platelet glycoproteins - platelet functional defects - gain-of-function mutations - crystal structure of GPIb-VWF complex
 

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