High-molecular-weight fucosylated glycosaminoglycan induces human platelet aggregation depending on α_IIbβ₃ and platelet secretion

Fucosylated glycosaminoglycan (FG) from sea cucumbers has been reported to have anticoagulant effects via targeting intrinsic tenase. However, FG from natural source also potentially poses risks due to its FXIIa activation and platelet aggregating effects. Here, we found that the effect of FG on human platelet aggregation depended on both the sulfation pattern and chain length. FGs with higher content of Fuc_2S4S and larger molecular weight (≥14 kD) had stronger activity. Both platelet aggregation and P-selectin expression induced by TaFG (an FG from Thelenota ananas) were decreased as the molecular weight reduced. Ticagrelor, aspirin and wortmannin completely blocked the secretion (ADP) but only partially blocked the aggregation induced by TaFG. Tirofiban an α_IIbβ₃ antagonist however potently inhibited both the secretion and aggregation, with IC₅₀ of 6.01 ± 1.1.97 nM. Furthermore, TaFG could bind to human α_IIbβ₃ with high affinity, and the affinities of two FGs were paralleled with their activity in platelet aggregation or activation. These results indicated that α_IIbβ₃ played an important role in TaFG-induced platelet aggregation which was mediated by PI3K, and that platelet secretion was required for the amplification of aggregation.