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Fucosylated glycosaminoglycan (FG) from sea cucumber is a potent anticoagulant by inhibiting intrinsic coagulation tenase (iXase). However, high-molecular-weight FGs can activate platelets and plasma contact system, and induce hypotension in rats, which limits its application. Herein, we found that FG from T. ananas (TaFG) and FG from H. fuscopunctata (HfFG) at 4.0 mg/kg (i.v.) could cause significant cardiovascular and respiratory dysfunction in rats, even lethality, while their depolymerized products had no obvious side effects. After injection, native FG increased rat plasma kallikrein activity and levels of the vasoactive peptide bradykinin (BK), consistent with their contact activation activity, which was assumed to be the cause of hypotension in rats. However, the hemodynamic effects of native FG cannot be prevented by the BK receptor antagonist. Further study showed that native FG induced in vivo procoagulation, thrombocytopenia, and pulmonary embolism. Additionally, its lethal effect could be prevented by anticoagulant combined with antiplatelet drugs. In summary, the acute toxicity of native FG is mainly ascribed to pulmonary microvessel embolism due to platelet aggregation and contact activation-mediated coagulation, while depolymerized FG is a safe anticoagulant candidate by selectively targeting iXase.

The Toxicology of Native Fucosylated Glycosaminoglycans and the Safety of Their Depolymerized Products as Anticoagulants