Platelets are associated with poor prognosis in most tumors, but their specific pathogenic mechanism in osteosarcoma is not yet clear. The objective of this study is to conduct an in-depth analysis of how genes closely related to platelet function impact the prognosis of osteosarcoma patients. We hope that through this research, we can uncover the potential mechanisms of these genes in the development and progression of osteosarcoma, thereby providing new therapeutic strategies and theoretical foundations for improving the prognosis of osteosarcoma patients.We collected the blood routine test data of patients who were initially diagnosed with osteosarcoma at the Department of Bone Tumors, West China Hospital, from January 2012 to January 2022. By applying the LASSO-COX regression analysis, a statistical method, we found that the platelet count is associated with the prognosis of osteosarcoma patients. To further explore this relationship, we obtained single-cell data and bulk RNA data of osteosarcoma patients from the TARGET database and GEO database, respectively. By analyzing these data, we revealed at the transcriptomic level how platelets contribute to the poor prognosis in osteosarcoma patients.Platelets are associated with the prognosis of osteosarcoma patients (HR = 3.9, 95% CI = 1.9-8.1, P < 0.001). Through the analysis of transcriptomic data from the TARGET database and GEO database, we found significant heterogeneity in tumor-specific pathways and immune infiltration under different platelet-related gene expression patterns. Among these, TBXAS1 was identified as a key gene that affects the prognosis of osteosarcoma patients. In addition, single-cell data analysis showed that the platelet-related gene TBXAS1 is mainly enriched in macrophages, and markers of macrophages are significantly associated with poor prognosis in osteosarcoma patients.TBXAS1 is a key platelet-related gene that leads to poor prognosis in osteosarcoma, and this gene may affect the prognosis of osteosarcoma patients by interacting with macrophages.Copyright © 2024 Liu, Da, Mu, He, Li, Gong, Wang, Min, Lu and Tu.