iMer, a naturally occurring MERTK splice variant, binds to GAS6 to decrease platelet activation and thrombus formation Open Access

• iMer, an isomer of MERTK, decreases human platelet activation and murine thrombosis, but does not promote increased tail clip bleeding.

• The activity involves direct binding of iMer to GAS6.

Unopposed platelet activation can be associated with pathologic thrombosis. An intact GAS6/MERTK signaling pathway contributes importantly to potentiating platelet activation triggered by molecular agonists ex vivo and thrombus stabilization in vivo. We describe herein the inhibition of platelet function and stable thrombus formation conferred by iMer, a naturally occurring MERTK splice variant, that acts as a GAS6 decoy receptor and decreases phosphorylation of MERTK. Human and murine platelets incubated with this truncated protein demonstrate reduced activation in ex vivo assays including aggregometry (similar to treatment with anti-GAS6 antibody), expression of P-selectin, spreading on collagen, and accumulation on collagen at a venous shear rate. Wild-type C57BL/6 mice treated with iMer had improved survival in a collagen/epinephrine-induced pulmonary embolism model, without increase in tail bleeding time on preliminary analysis. Taken together, these findings confirm prior data suggesting the importance of GAS6-MERTK signaling in platelet activation and thrombus formation and highlighting the potential therapeutic implications of targeting this pathway as a means of treating or preventing thrombosis.