Akt-Mediated Platelet Apoptosis and Its Therapeutic Implications in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with anti-platelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIba autoantibodies. Consistent with these findings, anti-GPIba monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIba antibody binding activates Akt which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIba antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling, or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal new pathogenic mechanisms of ITP with anti-GPIba autoantibodies, more importantly, suggest novel therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.