PLATELET TRANSMEMBRANE SIGNALING RESPONSES TO COLLAGEN IN FAMILIAL HYPERCHOLESTEROLEMIA

Washed platelets from patients with familial hypercholesterolaemia (FH) were found to be more reactive towards collagen than those from control subjects. The dose required to achieve half maximum aggregation was found to be 0.6 ml(-1) for FH patients whilst that for control subjects was 1.25 mu g ml(-1). In both types of platelet, intracellular Ca2+ levels, as monitored by the Ca2+-dependent photoprotein, aequorin, rose on stimulation with collagen and then fell to basal levels, probably due to resequestration by the reticular system. This effect was not due to exhaustion of the supply of aequorin since sustained Ca2+ influx induced by the ionophore, A23187, gave a stable signal that did not return to baseline. Similarly, inositol 1,4,5, trisphosphate levels increased in the cytosol after stimulation and then fell to unstimulated values. When stimulated with collagen, platelets from FH patients showed a greater extent of cytoplasmic calcium mobilization (P < 0.05) when compared to controls, coupled with a greater extent of inositol phospholipid hydrolysis (P < 0.05). At doses of collagen sufficient to give either 100% or 50% aggregation, platelets from patients or control subjects showed the same amplitude of ATP release at either dose suggesting that the trigger for vesicle release is more sensitive in FH.