Saxatilin, a novel
disintegrin purified and cloned from the
venom of the Korean snake Gloydius saxatilis, strongly inhibits activation and aggregation of platelets.
Glycoprotein (
GP) IIb/IIIa receptor antagonists can resolve
thrombus, so
saxatilin might also have thrombolytic effects. We investigated the thrombolytic effects of
saxatilin in mice using a
ferric chloride-induced carotid arterial
thrombosis model. Thrombotic occlusion and
thrombus resolution were evaluated quantitatively by measuring blood flow in the carotid artery with an ultrasonic flow meter and calculating the degree of flow restoration on a minute-by-minute basis; results were confirmed by histological examination.
Saxatilin dissolved thrombi in a dose-dependent manner.
Saxatilin at 5 mg/kg restored blood flow to baseline levels. As
saxatilin dose increased, time to recanalization decreased. A bolus injection of 10% of a complete dose with continuous infusion of the remaining dose for 60 minutes resulted in effective recanalization without reocclusion. The thrombolytic effect of
saxatilin was also demonstrated in vitro using platelet aggregometry by administering
saxatilin in preformed thrombi.
Bleeding complications were observed in 2 of 71 mice that received
saxatilin.
Fibrin/
fibrinogen zymography and platelet aggregometry studies indicated that
saxatilin does not have fibrinolytic activity, but exerted its action on platelets.
Integrin-binding assays showed that
saxatilin inhibited multiple
integrins, specifically α2bβ3 (
GP IIb/IIIa), α5β1, αvβ3, αvβ1, and αvβ5, which act on platelet adhesion/aggregation.
Saxatilin inhibited multiple
integrins by acting on platelets, and was safe and effective in resolving thrombi in mice.