Two Faces of the Same Thrombus: Molecular Phenotypes of Thromboinflammation in Acute Pulmonary Embolism and the Path to Phenotype-Guided Risk Stratification

Acute pulmonary embolism (PE) is a potentially fatal cardiovascular emergency where early risk assessment determines treatment escalation. Clinical scores like PESI and sPESI are useful but capture only a single moment and cannot track evolving biological processes: coagulation on inflamed endothelium, nitric oxide signaling loss, and right ventricular pressure overload. Circulating biomarkers provide direct readouts of these events. This review proposes that acute PE molecular pathophysiology organizes into two overlapping phenotypes—two faces of the same thrombus. The first is a predominantly thromboinflammatory phenotype, driven by neutrophil extracellular traps (NETs), complement activation, and endothelial injury; the second is a predominantly myocardial phenotype, driven by right ventricular pressure overload and subendocardial ischemia. We examine each phenotype’s molecular basis and appraise how far corresponding biomarkers—D-dimer, cardiac troponins, natriuretic peptides, GDF-15, H-FABP, sST2, complement activation products, and inflammatory indices—have moved into clinical practice. Two issues deserve attention: biomarker kinetics during the first 72 h after symptom onset, and whether intermediate-risk patients can be separated into meaningful molecular phenotypes. We address implementation barriers: lack of harmonized assays, undefined decision thresholds, and absence of prospective multicenter validation. This narrative review connects disease mechanisms to which patients are most likely to deteriorate and outlines a research agenda for phenotype-guided risk stratification.