ADPase CD39 Fused to glycoprotein VI-Fc boosts local antithrombotic effects at vascular lesions

Background-gpvi (glycoprotein vi) is the essential platelet collagen receptor in atherothrombosis. dimeric gpvi-fc (revacept) binds to gpvi binding sites on plaque collagen. as expected,it did not increase bleeding in clinical studies. gpvi-fc is a potent inhibitor of atherosclerotic plaque-induced platelet aggregation at high shear flow,but its inhibition at low shear flow is limited. we sought to increase the platelet inhibitory potential by fusing gpvi-fc to the ectonucleotidase cd39 (fusion protein gpvi-cd39),which inhibits local adp accumulation at vascular plaques,and thus to create a lesion-directed dual antiplatelet therapy that is expected to lack systemic bleeding risks. methods and results-gpvi-cd39 effectively stimulated local adp degradation and,compared with gpvi-fc alone,led to significantly increased inhibition of adp-,collagen-,and human plaque-induced platelet aggregation in multiplate aggregometry and plaque-induced platelet thrombus formation under arterial flow conditions. gpvi-cd39 did not increase bleeding time in an in vitro assay simulating primary hemostasis. in a mouse model of ferric chloride-induced arterial thrombosis,gpvi-cd39 effectively delayed vascular thrombosis but did not increase tail bleeding time in vivo. conclusions-gpvi-cd39 is a novel approach to increase local antithrombotic activity at sites of atherosclerotic plaque rupture or injury. it enhances gpvi-fc-mediated platelet inhibition and presents a potentially effective and safe molecule for the treatment of acute atherothrombotic events,with a favorable risk-benefit ratio. © 2017 the authors and medtronic.