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
