Collagen Response and Glycoprotein VI Function Decline Progressively as Canine Platelets Age in vivo

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Abstract
Summary: Clinical and experimental observations suggest that platelet function deteriorates quickly with cell age. However, efforts to define agedependent alterations have detected only modest biochemical changes occurring late in the cell life span. In this report, we demonstrate two significant alterations of the collagen response occurring during in vivo aging of canine platelets: a progressive increase in the EC50 for collagen types I, III and V and the emergence of a population of aged platelets which are refractory to collagen. Experiments with convulxin, a specific agonist for the collagen receptor glycoprotein VI (GPVI), also demonstrate an age-dependent decline in activation and the appearance of a non-reactive, aged population as observed with native collagens. Our studies indicate that canine platelets have two distinct binding levels for FITC-labeled convulxin and that the higher binding level disappears upon cell aging. During these studies one dog (#428) was identified whose platelets not only failed to demonstrate an age-dependent decrease in convulxin reactivity but also maintained a high convulxinbinding ability throughout their otherwise normal life span. Transfusion of biotinylated platelets from control dogs into dog #428 showed that the expected changes in collagen response and GPVI function did not occur in the transfused platelets. These observations demonstrate that the canine platelet response towards collagen is strongly dependent upon cell-age and suggest that this functional decline is at least partly due to an extrinsic-mediated alteration, possibly proteolytic, of GPVI.This work was supported in part by grants HL53585 and HL68129 from the National Institutes of Health (GLD) and the Swiss National Science Foundation (SSMBS grant, LA; grant 31-52396.97, KJC). This work has been presented at the XVIII Congress of the International Society on Thrombosis and Haemostasis (Paris, 2001).