Platelet and megakaryocyte function in the pathogenesis of POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by multisystem manifestations and markedly elevated vascular endothelial growth factor (VEGF) levels, identified as a sensitive biomarker for disease progression. Serum VEGF exceeds plasma levels, implicating platelets as a potential reservoir of VEGF in POEMS syndrome. However, the precise cellular origin of VEGF and the underlying pathological mechanisms remain elusive and challenging to elucidate. We conducted the first comprehensive multi-omics analysis of platelets from patients with POEMS syndrome, integrating RNA sequencing and quantitative mass spectrometry-based proteomics. RNA sequencing revealed a distinct platelet transcriptome enriched for platelet activation-related genes. Flow cytometry and electron microscopy confirmed a highly activated platelet status. Mass spectrometry revealed an altered platelet proteome with upregulated protein synthesis and abundant ribosomes, indicating enhanced protein synthesis pathway in POEMS syndrome. Importantly, we demonstrated that the megakaryocyte-platelet axis, rather than plasma cells, is the primary source of excess VEGF. Platelet VEGF levels were significantly higher in patients than in healthy donors (P < 0.0001). VEGFA mRNA in situ hybridization confirmed significantly increased VEGFA expression in bone marrow megakaryocytes from patients (P < 0.01). These findings redefine the cellular origin of VEGF in POEMS syndrome and highlight the role of the megakaryocyte-platelet axis in the disease biology. Our study provides critical mechanistic insights into a long-standing mystery of this disorder, underscoring the need to further elucidate its functional interplay with clonal plasma cells.