title: A familial platelet function disorder associated with abnormal signalling through the glycoprotein VI pathway.
abstract: The platelet collagen receptor, glycoprotein (GP)VI, of the immunoreceptor family forms a complex with the von Willebrand factor (VWF) receptor, GPIb-IX-V, critical for initiating thrombus formation. GPVI is co-associated with Fc receptor gamma-chain (FcRgamma), which contains a cytoplasmic immunoreceptor tyrosine-based activation motif domain, involved in activation of Syk, and a signalling cascade leading to (i) activation of alpha(IIb)beta(3), which binds VWF and fibrinogen and mediates platelet aggregation, and (ii) metalloproteinase-mediated shedding of the GPVI ectodomain (blocked by Syk inhibitors), a key mechanism for regulating GPVI surface expression. In this study, we report a familial case of abnormal platelet aggregation with dysfunctional signalling through GPVI that uniquely demonstrates divergent alpha(IIb)beta(3)-activating and GPVI-shedding pathways. The patient is a 60-year-old female with a history of immune disorders, excessive bleeding from childhood and a life-threatening haemorrhage post-trauma. Platelet aggregation to ADP, thrombin receptor-agonist peptide or ristocetin/VWF was normal (indicating normal expression and function of alpha(IIb)beta(3)), but platelet aggregation to GPVI agonists, collagen, collagen-related peptide, or convulxin, was defective. Both GPVI/FcRgamma expression and ligand-induced GPVI ectodomain shedding were normal, confirming expression of functional GPVI/FcRgamma, but suggesting a signalling defect downstream of Syk. A genetic defect in GPVI/Fcgamma signalling compromising platelet function is hypothesised in this family.
authors.affiliation: Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia. scott.dunkley@email.cs.nsw.gov.au
authors.forename: Scott
authors.initials: S
authors.lastname: Dunkley
authors.forename: Jane F
authors.initials: JF
authors.lastname: Arthur
authors.forename: Sue
authors.initials: S
authors.lastname: Evans
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gardiner
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Robert K
authors.initials: RK
authors.lastname: Andrews
mesh_terms: D001791:Blood Platelet Disorders / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D008875:Middle Aged; D010974:Platelet Aggregation; D010979:Platelet Function Tests; D010980:Platelet Membrane Glycoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI