Figure. The mechanism of immune thrombocytopenia

With the support of the National Natural Science Foundation of China (Project No.81130008, 81770117, 81770113), Prof. Kesheng Dai and his team have made significant progress in discovering a novel mechanism and therapeutic strategies of immune thrombocytopenia (ITP). The research results were published in Proceedings of the National Academy of Sciences（PNAS）on October 18, 2018, and entitled “Akt-mediated platelet apoptosis and its therapeutic implications in immune thrombocytopenia”. Dr. Rong Yan and Prof. Kesheng Dai are co-corresponding authors. The website link is: http://www.pnas.org/content/early/2018/10/17/1808217115.

ITP is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. Although much effort has been made, a portion of ITP patients appear refractory to conventional treatments and the mechanism remains elusive. Previous studies have verified that ITP patients with anti-GPIb-IX autoantibodies present more severe decreases in platelet count, and less responsive to conventional therapies, such as steroid treatments, intravenous immunoglobulin G (IVIG), and even splenectomy. In this study, the research team demonstrates that anti-GPIb-IX antibody binding activates Akt which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition, and induces platelet activation through Akt pathway simultaneously. Both platelet apoptosis and activation can cause phosphatidylserine (PS) exposure, resulting in phagocytosis of anti-GPIb-IX antibody-bound platelets by Kupffer cells in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling, or blockage of PS exposure could protect the platelets from clearance.

Therefore, the study reveals a pathogenic mechanism of ITP with anti-GPIba autoantibodies, and more importantly, suggests alternative novel therapeutic strategies for immune thrombocytopenia caused by autoantibodies or other pathogenic factors.

The dual roles of Akt in regulating activation and apoptosis in platelets. Akt, the downstream effector of PI3K, is activated after anti-GPIbα antibody binding. Akt activates platelets through Ca2+ elevation. Meanwhile, Akt activates PDE3A, leading to PKA inhibition and platelet apoptosis. The Akt-regulated activation and apoptosis signaling independently lead to PS externalization.