Abstract
(1) Background: Prostacyclin analogues (epoprostenol, treprostinil, and iloprost) induce vasodilation in pulmonary arterial hypertension (PAH) but also inhibit platelet function. (2) Objectives: We assessed platelet function in PAH patients treated with prostacyclin analogues and not receiving prostacyclin analogues. (3) Methods: Venous blood was collected from 42 patients treated with prostacyclin analogues (49.5 ± 15.9 years, 81% female) and 38 patients not receiving prostacyclin analogues (55.5 ± 15.6 years, 74% female). Platelet reactivity was analyzed by impedance aggregometry using arachidonic acid (AA; 0.5 mM), adenosine diphosphate (ADP; 6.5 µM), and thrombin receptor-activating peptide (TRAP; 32 µM) as agonists. In a subset of patients, concentrations of extracellular vesicles (EVs) from all platelets (CD61+), activated platelets (CD61+/CD62P+), leukocytes (CD45+), and endothelial cells (CD146+) were analyzed by flow cytometry. Platelet-rich thrombus formation was measured using a whole blood perfusion system. (4) Results: Compared to controls, PAH patients treated with prostacyclin analogues had lower platelet reactivity in response to AA and ADP (p = 0.01 for both), lower concentrations of platelet and leukocyte EVs (p ≤ 0.04), delayed thrombus formation (p ≤ 0.003), and decreased thrombus size (p = 0.008). Epoprostenol did not affect platelet reactivity but decreased the concentrations of platelet and leukocyte EVs (p ≤ 0.04). Treprostinil decreased platelet reactivity in response to AA and ADP (p ≤ 0.02) but had no effect on the concentrations of EVs. All prostacyclin analogues delayed thrombus formation and decreased thrombus size (p ≤ 0.04). (5) Conclusions: PAH patients treated with prostacyclin analogues had impaired platelet reactivity, EV release, and thrombus formation, compared to patients not receiving prostacyclin analogues.
Highlights
Pulmonary arterial hypertension (PAH) is a devastating and incurable disease leading to right-heart failure and premature death [1]
Of the 128 patients who were treated with prostacyclin analogues or Endothelin receptor antagonists (ERA)/PDE5i in the Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, European Health Centre Otwock, Poland between July 2017 and November 2019, 80 patients were included in the study, 42 patients in the study group, and 38 patients in the control group
Among the patients treated with prostacyclin analogues, 30 patients were treated with treprostinil, 8 with epoprostenol and 4 with iloprost
Summary
Pulmonary arterial hypertension (PAH) is a devastating and incurable disease leading to right-heart failure and premature death [1]. In patients with PAH, elevated pressure in the pulmonary arteries is a consequence of increased concentrations of the vasoconstricting substances (thromboxane A2, endothelin 1) and decreased concentrations of vasodilating substances (nitric oxide, prostacyclin) [2]. This elevated ratio between vasoconstricting and vasodilating mediators leads to remodeling of the pulmonary arterioles, increased contractility of the arterioles, and thrombus formation in the lumen [2]. Increased shear stress in the pulmonary circulation activates platelets, which play a crucial role in the development and progression of PAH through the secretion of vasoconstricting, proinflammatory, and prothrombotic mediators, thereby promoting further remodeling [3]. EVs seem to modulate the development and progression of PAH, with their role depending on the EV cellular origin, molecular cargo, and exposed molecules
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