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Rationale and objectivesThe role of human lung megakaryocytes in homeostasis and their dynamics in disease states remain unknown. We sought to investigate whether megakaryocyte/platelet gene signatures are altered in IPF.MethodsWe analyzed publicly available transcriptome datasets of lung tissue, bronchoalveolar lavage (BAL) cells, and peripheral whole blood from IPF patients and healthy controls. Enrichment of megakaryocyte and platelet gene signatures in those datasets were estimated using xCell, a novel computational method. Furthermore, we analyzed whether mean platelet volume (MPV) and platelet counts in peripheral blood are associated with lung transplant-free survival in our IPF cohort.ResultsIn lung tissue, megakaryocyte gene signature enrichment scores were significantly lower in IPF than in controls. In BAL cells, platelet gene signature enrichment scores were significantly lower in IPF than in controls, and lower platelet scores were associated with lower lung transplant-free survival in IPF. In contrast, in blood, megakaryocyte scores were significantly higher in IPF than in controls, and higher megakaryocyte scores were associated with lower disease progression-free survival in IPF. Furthermore, higher MPV was associated with lower transplant-free survival in our IPF cohort, independent of age, sex, forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO).ConclusionsIn IPF, megakaryocyte/platelet gene signatures were altered in a compartment-specific manner. Moreover, those signatures and MPV in blood were associated with important clinical outcomes such as transplant-free survival. These findings provide new insights into altered megakaryocyte/platelet biogenesis in IPF and suggest the potential utility of megakaryocyte/platelet-based biomarkers in IPF.