Randomized, Placebo-controlled, Blinded and Cross-matched Study on the Antiplatelet Effect of Inhaled Nitric Oxide in Healthy Volunteers

SummaryThe platelet inhibitory effect of 0-40 ppm inhaled nitric oxide (NO) was investigated in healthy men and women. In both groups, ADPand collagen-induced platelet aggregation was significantly inhibited 20 (T20) and 40 min (T40) after the beginning of inhalation of 5, 10, and 40 ppm. Moreover, in both men and women, the in vitro bleeding time was significantly prolonged at T20 and T40 during inhalation of 40 ppm. Inhalation of NO also inhibited P-selectin expression at 5, 10, and 40 ppm and fibrinogen binding to the GPIIb/IIIa-receptor at 40 ppm. In conclusion, in healthy volunteers, the platelet inhibitory effect of inhaled NO was not dose-related, since it was significant at 5 and 10 ppm but did not increase during the administration of higher NO concentrations. In addition, gender-related differences were only observed in ADP-induced platelet aggregation at 10 ppm and in bleeding time prolongation at 40 ppm.

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Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-Selectin Expression, and Fibrinogen Binding In Vitro and In Vivo

Circulation ◽

10.1161/01.cir.97.15.1481 ◽

1998 ◽

Vol 97 (15) ◽

pp. 1481-1487 ◽

Cited By ~ 94

Author(s):

André Gries ◽

Christoph Bode ◽

Karlheinz Peter ◽

Axel Herr ◽

Hubert Böhrer ◽

...

Keyword(s):

Nitric Oxide ◽

Platelet Aggregation ◽

Human Platelet ◽

Inhaled Nitric Oxide ◽

Human Platelet Aggregation ◽

Fibrinogen Binding

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Inhaled nitric oxide inhibits human platelet aggregation, P-selectin expression, and fibrinogen binding in vitro and in vivo

Journal of Cardiothoracic and Vascular Anesthesia ◽

10.1016/s1053-0770(98)90251-8 ◽

1998 ◽

Vol 12 (6) ◽

pp. 715

Keyword(s):

Nitric Oxide ◽

Platelet Aggregation ◽

Human Platelet ◽

Inhaled Nitric Oxide ◽

Human Platelet Aggregation ◽

Fibrinogen Binding

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Ticlopidine Selectively Inhibits Human Platelet Responses to Adenosine Diphosphate

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646487 ◽

1991 ◽

Vol 66 (06) ◽

pp. 694-699 ◽

Cited By ~ 49

Author(s):

Marco Cattaneo ◽

Benjaporn Akkawat ◽

Anna Lecchi ◽

Claudio Cimminiello ◽

Anna M Capitanio ◽

...

Keyword(s):

Platelet Aggregation ◽

Adenosine Diphosphate ◽

Inhibitory Effect ◽

Clot Retraction ◽

Fibrinogen Binding ◽

Low Concentrations ◽

Binding Inhibition ◽

High Concentrations ◽

Formalin Fixed

SummaryPlatelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrihogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPIIb/IIIa monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their K d were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.

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Neither endogenous nor inhaled nitric oxide influences the function of circulating platelets in healthy volunteers

Clinical Science ◽

10.1042/cs0970345 ◽

1999 ◽

Vol 97 (3) ◽

pp. 345-353 ◽

Cited By ~ 9

Author(s):

Johanna ALBERT ◽

N. Håkan WALLÉN ◽

Nailin LI ◽

Claes FROSTELL ◽

Paul HJEMDAHL

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Heart Rate ◽

Healthy Volunteers ◽

Thrombin Generation ◽

Bleeding Time ◽

Flow Cytometric ◽

Fibrinogen Binding ◽

Inhaled No

Experimental models have indicated prothrombotic effects of inhibition of nitric oxide (NO) production, and anti-thrombotic effects of inhaled NO, but the influence of NO on platelet function in vivo in humans is not well established. We therefore investigated the effects of systemic inhibition of NO synthesis by NG-monomethyl-⌊-arginine (⌊-NMMA) and of NO inhalation on platelet function in vivo. On two occasions, ⌊-NMMA (13.5 mg/kg) or saline infusion was administered to 14 healthy volunteers in a double-blind cross-over study. After a 30 min infusion of ⌊-NMMA or placebo, NO inhalation (30 p.p.m) was added during the remaining 30 min of infusion, on both occasions. Measurements included filtragometry ex vivo (reflecting platelet aggregability), flow-cytometric evaluation of platelets in whole blood (fibrinogen binding and P-selectin expression), plasma β-thromboglobulin (reflecting platelet secretion), cGMP in platelets and plasma, thrombin generation markers (thrombin fragment 1+2 and thrombin–antithrombin complexes) in plasma, and bleeding time. l-NMMA increased blood pressure and decreased heart rate. NO inhalation did not influence blood pressure or heart rate, but caused a 3-fold elevation in plasma cGMP levels (P < 0.001). Neither ⌊-NMMA nor NO influenced filtragometry readings or flow-cytometric determinations of platelet fibrinogen binding and P-selectin expression. Furthermore, plasma β-thromboglobulin, platelet cGMP and thrombin generation markers were not influenced by either treatment. Bleeding time was not influenced by ⌊-NMMA compared with placebo, but was increased by ≈ 25% during NO inhalation (P < 0.01), whether NO synthesis had been inhibited or not. The prolongation of bleeding time by inhaled NO was not accompanied by any effect on the platelet variables assessed. The present results indicate that circulating platelets are not influenced by endogenous or inhaled NO, presumably due to the rapid inactivation of NO in the blood. This does not exclude possible effects of endothelial NO in the interface between the blood and the vessel wall.

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Inhibition of Platelet Aggregation by Inhaled Nitric Oxide in Patients with Acute Respiratory Distress Syndrome

Anesthesiology ◽

10.1097/00000542-199507000-00007 ◽

1995 ◽

Vol 83 (1) ◽

pp. 56-65. ◽

Cited By ~ 146

Author(s):

Charles Marc Samama ◽

Mohamed Diaby ◽

Jean-Luc Fellahi ◽

Ayoub Mdhafar ◽

Daniel Eyraud ◽

...

Keyword(s):

Nitric Oxide ◽

Acute Respiratory Distress Syndrome ◽

Platelet Aggregation ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Bleeding Time ◽

Distress Syndrome ◽

Inhaled Nitric Oxide ◽

Arterial Oxygenation ◽

Inhibition Of Platelet Aggregation

Background Nitric oxide inhibits platelet adhesion and aggregation in vitro. The aim of this prospective study was to assess the platelet antiaggregating activity of nitric oxide administered to patients with acute respiratory distress syndrome (ARDS) at increasing concentrations. Methods In six critically ill patients (mean age 37 +/- 16 yr) with ARDS (lung injury severity score > or = 2.2), the lungs were mechanically ventilated with inhaled nitric oxide (1, 3, 10, 30, and 100 ppm) randomly administered. Patients with cardiac dysrhythmias, septic shock, an underlying hemostasis disorder (constitutive or acquired), a platelet count less than 100 Giga/l, or a decreased platelet aggregation and those treated with antiplatelet or anticoagulant agents were excluded. Platelet aggregation was measured without nitric oxide and at each nitric oxide concentration in platelet-rich plasma issued from radial artery. Ivy bleeding time using a horizontal incision was simultaneously performed. Results After nitric oxide, a non-dose-dependent but statistically significant decrease in ex vivo platelet aggregation induced by three aggregating agents was observed: adenosine diphosphate = -56 +/- 18%, collagen = -37 +/- 18%, and ristocetin = -45 +/- 18% (P < 0.05). In each individual, Ivy bleeding time remained within normal values measured in healthy volunteers, and variations after nitric oxide did not correlate with changes in platelet aggregation. Simultaneously, arterial oxygenation improved significantly and pulmonary artery pressure decreased significantly. Conclusions In patients with ARDS and without preexisting coagulation disorders, the beneficial effects of inhaled nitric oxide on arterial oxygenation and pulmonary circulation are associated with a significant inhibition of platelet aggregation. This antithrombotic effect is not associated with a significant prolongation of the bleeding time.

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The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in neonates. † 886

Pediatric Research ◽

10.1203/00006450-199704001-00905 ◽

1997 ◽

Vol 41 ◽

pp. 150-150 ◽

Cited By ~ 4

Author(s):

Thomas N. George ◽

Karen J. Johnson ◽

James N. Bates ◽

Jeffrey L. Segar

Keyword(s):

Nitric Oxide ◽

Platelet Aggregation ◽

Bleeding Time ◽

Inhaled Nitric Oxide

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In Vivo and In Vitro Studies of the Inhibitory Effect of Propofol on Human Platelet Aggregation

Anesthesiology ◽

10.1097/00000542-199802000-00015 ◽

1998 ◽

Vol 88 (2) ◽

pp. 362-370 ◽

Cited By ~ 59

Author(s):

Hiroshi Aoki ◽

Toshiki Mizobe ◽

Shinji Nozuchi ◽

Noriko Hiramatsu

Keyword(s):

Platelet Aggregation ◽

Intracellular Calcium ◽

Bleeding Time ◽

Inhibitory Effect ◽

Ion Concentration ◽

Inhibitory Effects ◽

Fat Emulsion ◽

Intracellular Calcium Ion

Background The inhibitory effects of propofol on platelet aggregation are controversial because the fat emulsion used as the solvent for propofol may affect platelet function. The effects of propofol on platelet intracellular calcium ion concentration and on aggregation were investigated. Methods Platelet aggregation was measured in 10 patients who received an intravenous infusion of propofol. Intralipos, the propofol solvent, was infused in 10 healthy volunteers and platelet aggregation were measured. The in vitro effects of propofol and Intralipos on platelets were also investigated. The inhibitory effects of various concentrations of propofol were studied. The effects of propofol on the changes in intracellular calcium level using a fluorescent dye, fura-2, were also observed. Template bleeding time was measured to determine the effect of propofol in clinical use. Results Platelet aggregation was significantly inhibited by infusion of propofol, although bleeding time was not prolonged. Intralipos did not inhibit platelets either in vivo or in vitro. Propofol significantly inhibited platelet aggregation in vitro and at 5.81 +/- 2.73 microg/ml but not at 2.08 +/- 1.14 microg/ml. The increase of intracellular calcium concentration was inhibited both in influx and discharge of calcium. Conclusions Propofol inhibited platelet aggregation both in vivo and in vitro. Inhibition of platelet aggregation appeared to be caused by propofol itself and not by the fat emulsion. This inhibitory effect was also supported by the suppressed influx and discharge of calcium. No change in the bleeding time suggests that this inhibitory effect does not impair hemostasis clinically.

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Enhancement by Ticlopidine of the Inhibitory Effect on In Vitro Platelet Aggregation of the Glycoprotein IIb/IIIa Inhibitor Tirofiban

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665415 ◽

1997 ◽

Vol 78 (05) ◽

pp. 1381-1384 ◽

Cited By ~ 13

Author(s):

K Umemura ◽

K Kondo ◽

Y Ikeda ◽

M Nakashima

Keyword(s):

Platelet Aggregation ◽

Bleeding Time ◽

Inhibitory Effect ◽

Clinical Effects ◽

Percent Inhibition ◽

Inhibition Of Platelet Aggregation ◽

Prolonged Bleeding Time ◽

Period 2 ◽

Aggregation Inhibition

SummaryWe determined the effects of combining the glycoprotein IIb/IIIa inhibitor tirofiban (MK-383, Aggrastat) and ticlopidine on inhibition of ADP-induced platelet aggregation, inhibition of collagen-induced platelet aggregation, and prolongation of bleeding time in 5 healthy male volunteers. The study consisted of 2 periods. In period 1, tirofiban was administered intravenously as a bolus injection at a dose of 5.0 µg/kg for 5 min, then as a continuous infusion at a rate of 0.05 µg/kg/min for 5 h 55 min. In period 2, ticlopidine was given orally at a dose of 200 mg once daily for 4 days, after which tirofiban was administered in the same manner as in period 1, starting 2 h after the last dose of ticlopidine. The percent inhibition of platelet aggregation induced by ADP 5 µM at the end of tirofiban infusion in periods 1 and 2 was 73.6 ± 2.6 and 87.1 ± 5.7% (mean ± SD), respectively. The corresponding values for inhibition of platelet aggregation induced by collagen 2 µg/ml were 45.4 ± 36.1 and 82.8 ± 27.0%, respectively. In contrast, the percent inhibition of platelet aggregation induced by ADP and collagen after treatment with ticlopidine alone was 15.8 ± 20.2 and p ± 4.8%, respectively. Compared with tirofiban alone, the combination of tirofiban and ticlopidine significantly enhanced inhibition of platelet aggregation induced by both ADP and collagen (p <0.02 and p <0.012, respectively). The inhibitory effects of ticlopidine alone were not statistically significant. Tirofiban prolonged bleeding time both in period 1 and in period 2. However, tirofiban and ticlopidine combined did not affect bleeding time. Ticlopidine administration did not alter the pharmacokinetics of tirofiban. In conclusion, at the doses of tirofiban and ticlopidine used in this study, the combination of the two drugs enhanced inhibition of platelet aggregation but did not prolong bleeding time, suggesting that appropriate doses of tirofiban can be used concomitantly with ticlopidine with no further safety concerns but with potential additional clinical effects.

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