Decreased circulating thrombomodulin is improved by tadalafil therapy in hypoxemic patients with advanced pulmonary arterial hypertension

• In the Eisenmenger syndrome (ES) pulmonary vasculopathy is associated with hypoxemia.
• Thrombomodulin, a “parallel” endothelial thrombin receptor is decreased in ES.
• Tadalafil is an approved vasodilator for pulmonary arterial hypertension.
• Hypoxemia and circulating thrombomodulin are improved by tadalafil in ES.
• Tadalafil has effects beyond simple vasodilatation is ES.

IntroductionAdvanced pulmonary arterial hypertension (PAH) in patients with congenital cardiac communications and right-to-left shunting (Eisenmenger syndrome – PAH-ES) is associated with hypoxemia and decreased circulating levels of thrombomodulin (TM), probably reflecting decreased endothelial TM production. The combination of these two factors has been shown to induce fibrin deposition, with increased risk of thrombosis, a well known complication in this syndrome.Patients and methodsWe tested the hypothesis that vasodilator therapy with the phosphodiesterase-5 inhibitor tadalafil, an approved drug for management of PAH could improve endothelial dysfunction markers, in particular plasma TM, in addition to improving the physical capacity (expected effect of pulmonary vasodilatation) in PAH-ES patients. This was a prospective observational study of treatment-naïve patients subjected to specific PAH therapy. Fifteen patients aged 12 to 51 years (median 30 years) were treated for 6 months with a single daily dose of 40 mg oral tadalafil. The physical capacity (distance walked during the 6-min walk test – 6MWD), systemic oxygen saturation and laboratory parameters were measured at baseline, and 90 days and 180 days of treatment.ResultsPlasma TM, which was decreased at baseline compared to controls (p < 0.001) increased at 90 and 180 days (p = 0.003), and this was directly related (r = 0.57, p = 0.026) to improvement of oxygen saturation (p = 0.008). Heightened baseline tissue-type plasminogen activator decreased during treatment (p = 0.010), while heightened von Willebrand factor antigen remained unchanged. The 6MWD improved significantly (p < 0.001).ConclusionTadalafil therapy improved circulating TM and tissue-type plasminogen activator, in addition to improving the physical capacity and oxygen saturation in PAH-ES patients.