Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing “outside-in” signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the β(3) integrin, thereby amplifying outside-in signaling via α(IIb)β(3). Blocking the Gas6-R–α(IIb)β(3) integrin cross-talk might be a novel approach to the reduction of thrombosis.