Abstract
BACKGROUND: Thrombosis and endothelial injury are pathologic hallmarks of pulmonary arterial hypertension (PAH). We aimed to evaluate whether markers of endothelial dysfunction and coagulation in the blood would provide insight into disease activity, treatment response, and outcomes in PAH. METHODS: We prospectively collected baseline and 3-month follow-up blood samples from treatment-naïve patients with PAH (n = 22) and those who had a clinical indication to intensify therapy (n = 19). In addition, we recruited 12 healthy people and clinically stable patients with PAH (n = 45) as controls who had 2 blood samples collected twice within 14 days. We generated platelet-free plasma and measured D-dimer, angiopoietin-2, thrombin time, soluble P-selectin, von Willebrand factor, and vascular endothelial growth factor. We assessed treatment response with Reveal Lite 2 scores (all patients had N-terminal-pro-brain natriuretic peptide, 6-minute walk, and functional class assessment at both visits) and followed clinical outcomes for 3 years. RESULTS: Angiopoietin-2 levels were elevated and fell in response to effective therapy (drop in Reveal Lite 2 score). At follow-up, persistently elevated angiopoietin-2 levels predicted clinical events and even identified low-risk participants who subsequently had events. D-dimer levels were also elevated in patients with PAH but did not change in response to therapy. Several other abnormalities in endothelial and platelet activation were identified (including elevated soluble P-selectin, elevated von Willebrand factor, and elevated vascular endothelial growth factor) but these did not change with treatment or predict outcome. CONCLUSIONS: Angiopoietin-2 and D-dimer are elevated in patients with PAH and may add prognostic information to routine clinical assessment.