A Snail Galactosed Glycosaminoglycan Inhibits Thrombosis without Affecting Hemostasis via Disrupting FIXa-FVIIIa...

Thrombosis underlies many life-threatening cardio-cerebrovascular diseases. Although existing anticoagulants are effective in treating thrombotic diseases, their application is limited due to the concern of bleeding. New anticoagulants that preserve hemostasis have significant clinical importance. Herein, a novel galactosylated glycosaminoglycan, with unique sequence and sulfate substitutions, was isolated from the snail Camaena cicatricose (CCG). Administration of CCG effectively inhibited thrombus formation in a rat venous thrombosis model, which is positively correlated with its ex vivo anticoagulant activity (APTT prolongation), with much lower bleeding risk compared with heparins. It is also effective in preventing thrombosis in the rat arterial-venous shunt model and endotoxin-treated mice. CCG inhibited coagulation by selectively targeting iFXase enzyme complex (FIXa-FVIIIa), in an antithrombin (AT)-independent manner. CCG can bind to FIXa with high affinity and decrease the affinity of FIXa-FVIIIa, with no effect on the FIXa activity. Compared with heparins, it cannot bind to AT and exhibits high selectivity for iFXase inhibition, consistent with its absence of the specific heparin pentasaccharide sequence. Overall, the snail galactosed glycosaminoglycan inhibits thrombosis without affecting hemostasis via disrupting iFXase (FIXa-FVIIIa). CCG may represent a promising candidate for thrombosis treatment without increased bleeding risk.