PAR1 Inhibition Vorapaxar as a Potential Therapeutic Approach in Chronic Thromboembolic Pulmonary Hypertension

<bold>Background:</bold> Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a rare but severe cardiovascular disease, with one of its primary causes are incomplete dissolution of thrombi in the pulmonary arteries. In the processes of thrombus formation and dissolution, Protease-Activated Receptor 1 (PAR1) plays a crucial role, yet its specific involvement in CTEPH remains unclear. <bold>Methods:</bold> We collected tissue samples from pulmonary endarterectomy (PEA) procedures in CTEPH patients and cultured primary endothelial cells from these patients and assessed the functional changes in endothelial cells stimulated by thrombin and its inhibitor vorapaxar, utilizing EdU incorporation and tube formation assays. Subsequently, we employed a murine inferior vena cava (IVC) stenosis model to simulate thrombus dissolution and orally administered vorapaxar to validate its effects on thrombus dissolution. <bold>Results:</bold> Firstly, we observed that thrombin mediated excessive proliferation of endothelial cells (P ≤ 0.0001), disrupting their tube-forming abilities，vorapaxar significantly inhibited this process (P ≤ 0.0001). In the murine IVC model, we found that thrombus mass and volume gradually decreased over time (N = 10), consistent with thrombus dissolution. Furthermore, after administering vorapaxar for 7 days, we observed a significant reduction in thrombus mass and volume (P = 0.002, N = 10), and the vorapaxar group exhibited faster dissolution of thrombi over time compared to the control group. Conclusion(s) In conclusion, we have found that PAR1 plays a significant role in the progression of CTEPH and the PAR1 inhibitor vorapaxar shows potential efficacy in inhibiting thrombus dissolution.