PB0727 - The role of PCSK9 in megakaryocyte reconstitution following hematopoietic stem cell transplantation

Background: Hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematologic malignancies, aplastic anemia, and immunodeficiency syndrome. Thrombocytopenia (TP) is a pivotal cause of bleeding following HSCT, however, the specific pathogenesis remains incompletely understood. Proprotein convertase subtilisin / kexin type 9 (PCSK9), a target for lipid-lowering，exerts a crucial effect on platelet activation.

Aims: In this study we aimed to evaluate the impact of PCSK9 in megakaryocyte (MK) reconstitution following pediatric HSCT.

Methods: We included 54 TP children after HSCT as well as 32 good graft function (GGF) children and 36 healthy donors (HD) between 2021 and 2023 at Children's Hospital of Soochow University . Concentrations of serum Thrombopoietin (TPO), PCSK9, defensin alpha 1 (DEFA1) or chemerin were detected using ELISA. Hematoxylin-eosin and Giemsa staining were performed for bone marrow cell morphology identification. Flow cytometry was applied to assess lymphocyte subsets, inflammatory cytokines, CD36, LDLR and TPO receptor , reactive oxygen species and ploidy. The human megakaryoblastic leukemia cell line (Meg-01 cells) and human bone marrow cells were cultured for evaluating MK reconstitution .

Results: TP children who underwent HSCT exhibited inadequate MK reconstitution, coupled with impaired liver function and a disrupted immune system. Notably, the concentration of PCSK9 in serum was significantly higher in TP children after HSCT compared to those with good graft function (GGF) children and normal healthy donor (HD) children. Moreover, it showed a close association with blood lipids, liver function, subsets of lymphocytes, and inflammatory cytokines in TP children post allo-HSCT. Additionally, the active recombinant polypeptides of PCSK9 (PP) hindered the polyploidization of Meg-01 cells. Besides, it also inhibited proplatelet formation of human primary MKs derived from bone marrow.

Conclusion(s): These results suggest that PCSK9 exerts an effect on MK reconstitution after HSCT, it may hold significance in the treatment of TP among pediatric patients undergoing HSCT.