Platelet indices as prognostic biomarkers in lung cancer: A meta-analysis and Mendelian randomization study

BACKGROUND: Platelet indices (PIs) - including platelet count (PC), plateletcrit (PCT), mean platelet volume, and platelet distribution width (PDW) - are routinely assessed in clinical practice. Although observational studies have reported associations between PIs and lung cancer outcomes, the dose-response relationship and causality remain unestablished. This study aims to determine prognostic thresholds of PIs and elucidate their causal roles in lung cancer. METHODS: We systematically reviewed PubMed, Medline, and Web of Science (through December 2024) for studies on PIs and lung cancer prognosis. Hazard ratios (HRs) were pooled via random-effects models. Dose-response thresholds were identified using restricted cubic splines and generalized least squares. Two-sample Mendelian randomization (MR) analyses with inverse variance weighting assessed causality, complemented by sensitivity analyses (MR-Egger, weighted median). RESULTS: In the meta-analysis of 62 studies (N = 38,562 patients), elevated PC (HR = 1.016, 95% CI: 1.009 to 1.024) and PCT (HR = 1.704, 95% CI: 1.040-2.790) independently predicted poorer overall survival. A nonlinear dose-response relationship revealed that each 109/L increase in PC conferred a 4.2% higher risk of adverse prognosis in non-small cell lung cancer (HR = 1.042, 95% CI: 1.029 to 1.056), with a critical threshold at 177.5 × 109/mL. MR analyses demonstrated population-specific causality: a 1-SD increase in PC elevated lung cancer risk by 33% in East Asians (OR = 1.33, P < .001), while in Europeans, equivalent increments in PC and PCT increased small cell lung cancer (SCLC) risk by 17% (OR = 1.17, P = .01) and 19% (OR = 1.19, P < .001), respectively. Additionally, higher PDW was causally linked to a 6% increased lung cancer risk (OR = 1.06, P = .02). CONCLUSION: This first study integrating dose-response meta-analysis and MR evidence identifies PC and PCT as robust prognostic biomarkers for lung cancer, with population-specific causal effects. The identified PC threshold (177.5 × 109/mL) provides a clinically actionable tool for NSCLC risk stratification, highlighting the translational potential of routine PIs monitoring in oncology practice.