Effects of inhaled nitric oxide on hemostasis in healthy adults treated with heparin: a randomized, controlled, blinded crossover study

Twelve healthy adult males were enrolled in a single-center, randomized, single-blind, four-way crossover trial. Subjects received 80 ppm NO or medical air (placebo) inhalation for 30 min with simultaneous injection of placebo or heparin. Aspirin capsules were used as a positive control. Parameters of hemostasis were measured before treatment and at post-treatment intervals.Activated clotting time (ACT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) increased only in groups that received heparin. Areas under the curve for ACT in heparin groups receiving inhaled NO were judged to be equivalent to those receiving medical air for both 0- to 4-h (ratio: 1.00; 90% CI, 0.90-1.11) and 0- to 24-h time intervals (ratio: 1.01; 90% CI, 0.92-1.12). Changes in bleeding time and platelet aggregation were observed only in aspirin groups. No clinically significant changes in hemoglobin, red blood cell counts or haematocrit were observed in any group.Inhaled NO, when administered with heparin, exhibited no significant additive effects on ACT, PT, aPTT, bleeding time or platelet aggregation.Nitric oxide (NO) is produced endogenously and plays an important role in a range of physiologic functions including the regulation of vascular smooth muscle tone, as well as the modulation of platelet function via the guanylate cyclase signaling pathway [1]. Inhaled NO is approved for the treatment of term and near-term (> 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it selectively relaxes the pulmonary vasculature, reduces right to left shunting of poorly oxygenated blood, and thereby improves oxygenation [2-4]. The vasodilatory effects of inhaled NO are localized to the pulmonary vasculature because NO is immediately converted to nitrite and methemoglobin [5]. However, there are potential but as yet hypothetical systemic effects of inhaled NO, including possible peripheral eff