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Prepublished online as a Blood First Edition Paper on January 30, 2003; DOI 10.1182/blood-2002-08-2591.
Submitted August 23, 2002
Accepted January 14, 2003
The low frequency allele of the platelet collagen signalling receptor glycoprotein VI is associated with reduced functional responses and expression
Lotta Joutsi-Korhonen, Peter A Smethurst*, Angela Rankin, Elaine Gray, Martin IJsseldijk, Catherine M Onley, Nicholas A Watkins, Lorna M Williamson, Alison H Goodall, Philip G de Groot, Richard W Farndale, and Willem H Ouwehand
Department of Haematology, University of Cambridge, Cambridge, United Kingdom
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Division of Haematology, National Institute for Biological Standards and Controls, Potters Bar, United Kingdom
Department of Haematology, University Hospital Utrecht, Utrecht, The Netherlands
Department of Clinical Biochemistry, University of Leicester, Leicester, United Kingdom
National Blood Service Cambridge Centre, Cambridge, United Kingdom
* Corresponding author; email: pas28{at}cam.ac.uk.
Interaction of platelets with collagen under conditions of blood flow is a multi-step process with tethering viaover glycoprotein (GP) IbIXV overvia von Willebrand factor, adhesion by direct interaction with the integrin GPIaIIa and signalling via GPVI. GPVI can be activatedspecifically agonised by cross-linked collagen related peptide (CRP-XL), which results in a signalling cascade very similar to that evoked by native collagen. The GPVI gene has two common alleles that differ by three replacements in the glycosylated stem and two in the cytoplasmic domain with frequencies of 0.8 and 0.2 respectively. We used CRP-XL to elucidate the variation in responses observed in platelet function between different individuals. We observed a three-fold difference in the response to CRP-XL in platelet aggregation when comparing platelets from 10 high frequency allele homozygotes with 8 low frequency ones (two-way ANOVA, p<0.0001). The difference in functional responses was reflected in fibrinogen binding and in downstream signalling events as measured by the tyrosine phosphorylation, the expression of P-selectin and the binding of annexin V and the generation of thrombin on the platelet surface (two-way ANOVA, p<0.001). There was also a trend of platelets homozygous for the low frequency allele to be less able to form a thrombus on a collagen surface in flowing whole blood or in the PFA-100 (t test, p=0.065 and p=0.061, respectively). The functional difference was correlated to, but not solely dependent on, a difference in total GPVIand membrane expressed GPVIion as measured by monoclonal and polyclonal GPVI antibodies. This study demonstrates for the first time that platelet function may be altered by allelic differences in GPVI.
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