Increased Plasma P-Selectin and Decreased Thrombomodulin in Pulmonary Arterial Hypertension Were Improved by Continuous Prostacyclin Therapy

Abstract

Background-Thrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. Methods and Results-To assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (PϽ0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (PϽ0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (PϽ0.05). Conclusions-Decreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury. (Circulation. 2000;102:2720-2725.)

Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension

“…Endothelial dysfunction of the pulmonary vasculature is characterized by inflammation, impaired vasoactive balance, platelet activation, and in situ thrombosis (1)(2)(3). Increased afterload leads to RV strain and dysfunction, with resultant release of molecular mediators from the heart.…”

“…Markers of inflammation (IL-6, tumor necrosis factor [TNF], and C-reactive protein [CRP]) are increased in patients with PAH (5-7). Markers of platelet and endothelial dysfunction, such as von Willebrand factor (vWF), soluble P selectin, b-thromboglobulin (BTG), and thromboxane B 2 (TX), are also elevated in patients with PAH (2,(8)(9)(10). Higher levels of BNP and NT-pro-BNP, indicators of ventricular stretch, are associated with an increased risk of death in patients with PAH (11,12).…”

Relevance of Angiopoietin‐2 and Soluble P‐Selectin Levels in Patients with Pulmonary Arterial Hypertension Receiving Combination Therapy with Oral Treprostinil: A FREEDOM‐C2 Biomarker Substudy

“…Our sP-selectin data provide some support for this: the mean level in our study population at baseline was 76.6 ng/mL, compared with previously reported baseline levels of 243-367 ng/mL in patients with PAH and 99-132 ng/mL in control subjects. 23,24 One other study that reported low baseline levels of sP-selectin (88.3 ng/mL in patients with PAH associated with connective tissue disease and 45.2 ng/mL in control subjects) also showed an increase in sPselectin from baseline after study treatment. 25 However, the median Ang-2 level at baseline in our study (8.7 ng/mL) was broadly consistent with baseline levels in earlier PAH studies in which Ang-2 decreased in response to treatment (6.5 ng/mL 8 and ∼9 ng/mL 7 [estimated from graph]).…”

Where do we go from here? Reappraising the data on anticoagulation in pulmonary arterial hypertension

“…This contrasts with the medications reported in COMPERA, where far fewer patients were reported to be on prostacyclin analogues. Prostacyclin therapy not only provides vasodilation in PAH, but has also been shown to alter hemostatic and platelet pathways, possible decreasing the in situ thrombosis and hypercoagulability observed in patients with PAH (3,7,(30)(31)(32). Of note, bleeding risks are increased in patients with iPAH, CTD-PAH and chronic thromboembolic pulmonary hypertension when vitamin K antagonists (VKA) were used in conjunction with prostacyclin (33).…”