Genetic and Clinical Determinants of Chronic Thromboembolic Pulmonary Hypertension: The Role of PAI-1 Polymorphism

TL;DR

This study finds that age, comorbidities, and a specific genetic variant (PAI-1 4G/5G) are linked to the development of chronic thromboembolic pulmonary disease after acute pulmonary embolism.

Contribution

The study identifies the PAI-1 4G/5G polymorphism as a novel genetic predictor of chronic thromboembolic pulmonary disease.

Findings

17 out of 204 patients developed chronic thromboembolic pulmonary disease during follow-up.

The PAI-1 4G/5G polymorphism was significantly associated with chronic thromboembolic pulmonary disease.

Comorbid diseases and elevated cardiac biomarkers were independent predictors of chronic thromboembolic pulmonary disease.

Abstract

Chronic thromboembolic pulmonary disease (CTEPD) is a severe long-term complication of acute pulmonary thromboembolism (PTE). Its pathogenesis is multifactorial, involving incomplete thrombus resolution, hemodynamic burden, comorbidities, and genetic factors. However, the contribution of inherited thrombophilic mutations to CTEPD development remains controversial. This retrospective cohort study included 204 patients diagnosed with acute PTE at a tertiary referral center between December 2023 and December 2024. Baseline demographic, clinical, laboratory, and echocardiographic data were collected. Genetic analysis assessed Factor II, Factor V Leiden, MTHFR C677T, MTHFR A1298C, Factor XIII V34L, and PAI-1 4G/5G polymorphisms. Patients were followed for at least 12 months for the development of CTEPD, defined according to guideline-based hemodynamic and imaging criteria. During follow-up, 17 patients (8.3%) developed CTEPD. Patients with CTEPD were significantly older and had higher baseline and follow-up systolic pulmonary artery pressure (sPAP) (p < 0.001), elevated NT-proBNP and troponin levels (both p < 0.001), and more frequent comorbidities, including cardiac and renal disease. Multivariate logistic regression identified comorbid diseases (HR: 0.17, 95% CI: 0.039–0.80, p = 0.025) and genetic thrombophilic factors (HR: 0.30, 95% CI: 0.10–0.91, p = 0.034) as independent predictors. Among genetic variants, only the PAI-1 4G/5G polymorphism was significantly associated with CTEPD (p = 0.001). Our study demonstrates that advanced age, comorbid diseases, elevated cardiac biomarkers, and genetic predisposition are associated with the development of CTEPD after acute PTE, while the PAI-1 4G/5G polymorphism may contribute to CTEPD susceptibility within a multifactorial context.