Effects of nitric oxide on hemostasis with special attention to platelet function

Abstract

Endogenous endothelium-derived NO provides a continuous vasodilating effect, but may also in humans have an antithrombotic effect, which is exerted by inhibition of platelet function and by vasodilatation.

Inhalation of NO selectively relaxes the pulmonary vascular bed, without causing systemic hypotension. The selectivity for the pulmonary circulation is related to its short half-life in blood. Inhaled NO was thought to have no systemic effects until it was reported that the bleeding time increased during NO inhalation. It is of clinical importance to know more about the effects of inhaled NO on bleeding time and platelet function since NO is increasingly used to treat patients. A prolonged bleeding time might be hazardous when inhaled NO is administered to newborn babies, who have an increased risk of intracranial bleeding, but may also be an advantage when administered to patients with thrombo-embolic disorders.

The effect of NO inhalation on hemostasis was studied, with special attention to bleeding time, and platelet function. We found a slight increase of bleeding time during prolonged inhalation of NO (55 min) in a dose of 30 ppm, but no change during inhalation of 3 0 or 80 ppm during a shorter time period (15 min). No effect on platelet function was demonstrated. Subsequently a randomized, double blind, placebocontrolled crossover study in healthy volunteers was performed since the bleeding time measurement may be influenced by the person who performs the test. In this study, we found slight increases in bleeding time during inhalation of both NO (30 ppm) and placebo (air) gas.

The effects of L-NMMA infusion, a nonselective NO synthesis inhibitor, were studied after establishing a model with prolonged infusion. Infusion of L-NMMA (13.5 mg/kg/60 min) was well tolerated and inhibited endogenous NO production, as measured by a reduction of NO in nasal air, by approximately 65% and increased systemic vascular resistance. NO inhalation added during the last 30 min of infusion increased the bleeding time similarly with L-NMMA and placebo infusion. Neither L-NMMA nor NO inhalation had effects on circulating platelets.

Aspirin was used as a positive control in two of our studies. It was shown to markedly increase bleeding time, and to inhibit platelet function.

The in vitro effect of a NO donor, S-nitrosoglutathione (GSNO), on platelet function in the presence and absence of hemoglobin was studied. A tenfold higher concentration of GSNO was needed to inhibit platelet function in whole blood compared to platelet rich plasma. These results provide an explanation for the limited platelet inhibiting effects of NO in vivo, as opposed to in vitro.

In conclusion, NO inhalation had little or no effect on bleeding time or platelet function in healthy adult volunteers.