Prostacyclin Analogues Inhibit Platelet Reactivity, Extracellular Vesicle Release and Thrombus Formation in Patients with Pulmonary Arterial Hypertension

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.

Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension

“… 49 Interestingly, this effect differed between prostacyclin agents, as epoprostenol was associated with decreased EV concentrations, while treprostinil had no significant effect on EV levels. 49 …”

“…48 In a study of 80 patients with PAH, platelet and leukocyte EV concentration were significantly lower in individuals prescribed prostacyclin analogues when compared to those who were not. 49 Interestingly, this effect differed between prostacyclin agents, as epoprostenol was associated with decreased EV concentrations, while treprostinil had no significant effect on EV levels. 49 The role of circulating EVs in the pathobiology of PAH is plausible.…”

“…49 Interestingly, this effect differed between prostacyclin agents, as epoprostenol was associated with decreased EV concentrations, while treprostinil had no significant effect on EV levels. 49 The role of circulating EVs in the pathobiology of PAH is plausible. Indeed, they are important regulators of endothelial function, inflammation and coagulation, and levels can fluctuate with disease severity and therapeutic interventions in patients with PAH.…”

“…Similarly, the beneficial effects of prostacyclin therapy may be partly mediated by antiplatelet effects and modulation of specific EV concentrations. 49 , 80 …”

“…Similarly, the beneficial effects of prostacyclin therapy may be partly mediated by antiplatelet effects and modulation of specific EV concentrations. 49,80 Conversely, ET-1 activity is increased in PAH and mediates diverse effects including vasoconstriction, remodelling and proliferation via ET A and ET B receptors. 81 While the direct role of ET-1 in coagulation is unclear, six months of dual ET receptor antagonism with macitentan in patients with PAH due to congenital heart disease was associated with improvements in coagulation abnormalities.…”