A familial platelet function disorder associated with abnormal signalling through the glycoprotein VI pathway


Dr Scott Dunkley, Institute of Haematology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia.
E-mail: scott.dunkley@email.cs.nsw.gov.au


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 γ-chain (FcRγ), which contains a cytoplasmic immunoreceptor tyrosine-based activation motif domain, involved in activation of Syk, and a signalling cascade leading to (i) activation of αIIbβ3, 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 αIIbβ3-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 αIIbβ3), but platelet aggregation to GPVI agonists, collagen, collagen-related peptide, or convulxin, was defective. Both GPVI/FcRγ expression and ligand-induced GPVI ectodomain shedding were normal, confirming expression of functional GPVI/FcRγ, but suggesting a signalling defect downstream of Syk. A genetic defect in GPVI/Fcγ signalling compromising platelet function is hypothesised in this family.