Genetic and biological determinants of pulmonary embolism: Insights from Mendelian randomization studies

Table 2 Pathophysiological mechanisms of pulmonary embolism in relation to Mendelian randomization evidence

Mechanism	Description	Clinical relevance	MR-informed associations
Thrombus formation	Formation of clots in deep veins driven by Virchow’s triad: Endothelial injury, hypercoagulability, and venous stasis	Risk of embolization to the pulmonary circulation; prevention primarily via anticoagulation	MR-specific associations not directly evaluated
Pulmonary vascular obstruction	Occlusion of pulmonary arteries leading to increased vascular resistance and right ventricular afterload	May result in right ventricular dysfunction and hemodynamic instability requiring urgent intervention	Renal dysfunction (reduced eGFR) associated with increased PE susceptibility
Gas exchange impairment	Ventilation-perfusion mismatch resulting in hypoxemia due to increased dead space ventilation	Manifests as dyspnea and hypoxemia; supportive oxygen therapy required	Obesity-related metabolic traits show variable MR associations
Inflammatory response	Cytokine release, NET formation, and oxidative stress contribute to thromboinflammation	Potential role of anti-inflammatory pathways in disease modulation	Reduced HLA-DR-positive NK cell traits associated with increased PE risk
Endothelial dysfunction	Endothelial injury promotes activation of coagulation pathways and thrombus formation	May contribute to chronic thromboembolic pulmonary hypertension	MMP19 associated with increased PE risk; MMP12 shows inverse association
Metabolic dysregulation	Obesity and metabolic imbalance promote a pro-inflammatory and prothrombotic state	May influence risk stratification and long-term outcomes	BMI and gut microbiota traits show variable MR associations
Coagulation cascade activation	Activation of clotting pathways through tissue factor exposure and thrombin generation	Guides use of anticoagulant therapies	Not directly evaluated in MR studies included in this review

NET: Neutrophil extracellular traps; eGFR: Estimated glomerular filtration rate; PE: Pulmonary embolism; MR: Mendelian randomization; MMP: Matrix metalloproteinases.