Calcium-dependent platelet aggregation through the interaction between phosphatidylserine and LOX-1

Abstract

Aims Platelet aggregation at the injured surface of blood vessels plays a crucial role in arterial thrombosis. Platelet aggregation in plasma has been analysed in the presence of calcium chelator to avoid coagulation. Here, we describe a novel mechanism of platelet aggregation that involves calcium-dependent binding between phosphatidylserine (PS) and lectin-like oxidized LDL receptor-1 (LOX-1), and the contribution of platelet LOX-1 to arterial thrombosis. Methods and results In vitro , LOX-1 gene deletion and anti-LOX-1 antibody suppressed the aggregation of platelets from mice and humans, respectively, in the absence of calcium-chelating citrate, but not in the presence of citrate. LOX-1 blockade and annexin V, in parallel, suppressed platelet aggregation and shifted the population of aggregates from large to small in size. Simultaneous application of anti-LOX-1 antibody and annexin V did not exert additive suppressive effects on aggregation. On activation, platelets exposed LOX-1 and PS and bound to a PS-coated surface in an LOX-1-dependent manner. In vivo , both LOX-1 deletion and anti-LOX-1 antibody significantly suppressed thrombus formation in mice and rats, respectively. Furthermore, platelet transfusion from LOX-1 knockout to wild-type mice still showed the suppressive effects of LOX-1 gene deletion, suggesting that platelet LOX-1 promoted thrombus formation. Conclusion LOX-1 blockade could be a novel approach to prevent platelet aggregation and thrombosis.