The Role of Platelets in Pulmonary Hypertension: From Activation to Pulmonary Vascular Remodeling—A Review Article

The article presents the results of a structured literature review of the past decade and focuses on the crucial role of platelets in the pathogenesis of pulmonary arterial hypertension (PAH). It explores how endothelial dysfunction initiates early prothrombotic signals that activate platelets, which, in response, adopt a pro-inflammatory phenotype, release cytokines and chemokines, and form aggregates with leukocytes, thereby modulating their migration and activity. A key feature of PAH is the “platelet paradox,” in which chronic in vivo activation coexists with reduced ex vivo reactivity due to functional exhaustion. Prolonged stimulation and disease progression lead to complex hemostatic dysregulation, characterized by heterogeneity in platelet phenotypes. At the same time, platelets undergo immunometabolic reprogramming, with a predominance of glycolysis, over oxidative phosphorylation, mitochondrial dysfunction, altered fatty acid oxidation (FAO), increased lactate production, and enhanced vesicle release. These phenomena sustain inflammation and promote pulmonary vascular remodeling. This study aims to review the current mechanisms of immunometabolic platelet activation in pulmonary arterial hypertension. It primarily focuses on platelet aspects as key elements in disease progression and as potential sources of new biomarkers and therapeutic targets.