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Potentiating role of Gas6 and Tyro3, Axl and Mer (TAM) receptors in human and murine platelet activation and thrombus stabilization

Summary.  Background: Interaction of murine Gas6 with the platelet Gas6 receptors Tyro3, Axl and Mer (TAM) plays an important role in arterial thrombus formation. However, a role for Gas6 in human platelet activation has been questioned. Objective: To determine the role of Gas6 in human and murine platelet activation and thrombus formation. Methods and Results: Gas6 levels appeared to be 20‐fold higher in human plasma than in platelets, suggesting a predominant role of plasma‐derived Gas6. Human Gas6 synergizes with ADP–P2Y12 by enhancing and prolonging the phosphorylation of Akt. Removal of Gas6 from plasma impaired ADP‐induced platelet aggregation. Under flow conditions, absence of human Gas6 provoked gradual platelet disaggregation and integrin αIIbβ3 inactivation. Recombinant human Gas6 reversed the effects of Gas6 removal. In mouse blood, deficiency in Gas6 or in one of the TAM receptors led to reduced thrombus formation and increased disaggregation, which was completely antagonized by external ADP. In contrast, collagen‐induced platelet responses were unchanged by the absence of Gas6 in both human and mouse systems. Conclusions: The ADP–P2Y12 and Gas6–TAM activation pathways synergize to achieve persistent αIIbβ3 activation and platelet aggregation. We postulate a model of thrombus stabilization in which plasma Gas6, by signaling via the TAM receptors, extends and enhances the platelet‐stabilizing effect of autocrine ADP, particularly when secretion becomes limited.