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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  CD 39 (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 ‐ CD 39 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 ‐ CD 39 did not increase bleeding time in an in vitro assay simulating primary hemostasis. In a mouse model of ferric chloride–induced arterial thrombosis,  GPVI ‐ CD 39 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.

ADPase CD39 Fused to Glycoprotein VI‐Fc Boosts Local Antithrombotic Effects at Vascular Lesions