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.
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Authors | Maha Othman, Harmanpreet Kaur, Jonas Emsley |
Journal | Seminars in thrombosis and hemostasis
(Semin Thromb Hemost)
Vol. 39
Issue 6
Pg. 663-73
(Sep 2013)
ISSN: 1098-9064 [Electronic] United States |
PMID | 23934752
(Publication Type: Journal Article, Review)
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Copyright | Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. |
Chemical References |
- Membrane Glycoproteins
- Platelet Glycoprotein GPIb-IX Complex
- adhesion receptor
- von Willebrand Factor
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Topics |
- Blood Platelets
(metabolism, physiology)
- Hemorrhage
(genetics, physiopathology)
- Hemostasis
(genetics, physiology)
- Humans
- Membrane Glycoproteins
(genetics, metabolism)
- Mutation
- Platelet Aggregation
(genetics, physiology)
- Platelet Glycoprotein GPIb-IX Complex
- von Willebrand Diseases
(diagnosis, genetics, physiopathology)
- von Willebrand Factor
(metabolism)
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