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Ann Thorac Surg 1996;61:1194-1198
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Nitric Oxide in the Oxygenator Sweep Gas Reduces Platelet Activation During Experimental Perfusion

Department of Pediatric Surgery, Östra Hospital, Göteborg University, Göteborg, Sweden

Accepted for publication December 15, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Hemorrhage is a major complication experienced in 10% to 35% of neonates treated with extracorporeal life support (ECLS). The increased bleeding tendency is partly due to an ECLS-induced thrombocytopenia and impaired platelet function. In the present study, we evaluated the effect of nitric oxide on the ECLS-induced platelet consumption and activation.

Methods. Two identical in vitro ECLS circuits were primed with fresh, heparin-treated human blood and circulated for 24 hours. Nitric oxide (15, 40, or 75 ppm) was added to one of the oxygenators in each pair. Eight paired experiments were performed. Platelet count, plasma ß-thromboglobulin, platelet serotonin content, plasma nitrate, plasma cyclic guanosine monophosphate, and platelet membrane glycoprotein Ib were assayed before the start and at 0.5, 1, 3, 12, and 24 hours of perfusion.

Results. Plasma nitrate and plasma cyclic guanosine monophosphate levels were significantly higher in the nitric oxide circuits than in the control circuits (p < 0.01). Higher platelet counts (p < 0.01) and lower ß-thromboglobulin levels (p < 0.01) were observed in the nitric oxide circuits compared with the control circuits. However, no significant differences in platelet serotonin content or platelet membrane glycoprotein Ib density were noted between the circuits.

Conclusions. Nitric oxide probably reduces platelet consumption and platelet activation during ECLS.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Extracorporeal circulation is frequently used in clinical practice. In all systems where blood is brought into contact with biomaterial, activation of various cascade systems and blood cells occurs. Hemorrhage, in particular intracranial hemorrhage, is a complication experienced in 10% to 35% of neonates treated with extracorporeal life support (ECLS) [1, 2]. This increased bleeding tendency is due to a combination of various hemostatic disturbances, among which a platelet dysfunction is believed to be crucial. Indeed, different drugs have been used to prevent the ECLS-induced platelet lesions, such as dipyridamole [3], prostacyclin [4], or combinations of various drugs [5].

Nitric oxide (NO) donors, eg, nitroglycerin, are known to inhibit platelet aggregation [6] as well as platelet adhesion to endothelial cells [7]. Organic nitrates also have been used experimentally to decrease the platelet activation encountered during percutaneous transluminal coronary angioplasty [8] and to decrease platelet adhesion to the endothelium after balloon angioplasty [9]. Treatment with organic nitrates and inhalation of NO prolongs the bleeding time in animals [10] and humans [11], indicating that even inhaled NO has an important effect on the circulating platelet.

The aim of the present study was to evaluate the effect of NO on the ECLS-induced platelet activation and consumption. We assayed ß-thromboglobulin (BTG), a sensitive marker of platelet alpha-granule release, and platelet membrane glycoprotein Ib (GPIb), a receptor protein very sensitive to proteolytic degradation. Nitric oxide was administered to one of the oxygenators of paired in vitro ECLS circuits, and platelet activation markers were followed up for 24 hours. In vitro models only partially mirror the in vivo situation, in which activated platelets externalizing the P-selectin molecule are rapidly cleared from the circulation. The advantage of this in vitro system is that it permits well-controlled, paired experiments with human blood.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experimental Design
Two identical in vitro ECLS circuits were primed with fresh, heparin-treated human blood obtained from 5 different blood donors and were circulated for 24 hours. Nitric oxide in N₂ (1:1,000; AGA Gas AB, Lidingö, Sweden) was added to the oxygenator sweep gas through a Y-connector immediately before the oxygenator (Dideco D-901 hollow fiber oxygenator; Dideco, Mirandola, Italy) in one of the circuits. The other circuit served as a control. The sweep gas used in this experiment consisted of 5% CO₂ in air. Three different NO concentrations were used in the experiments: 15, 40, and 75 ppm. The NO concentration in the inlet tube was recorded by the fuel cell technique (City Technology, London, UK). The perfusion flow was maintained at 0.6 L/min using roller pumps (Sarns Inc, Ann Arbor, MI). The perfusate temperature was set at 37°C. Electrolytes, glucose, and hematocrit were kept constant during the experiment. An antibiotic (cefotaxime, 1 g/L blood) was added and cultures were performed at the end of the experiments. The circuits were used once and then discarded. In total, eight paired experiments were performed. Thirty-milliliter blood samples were withdrawn immediately before dividing the pooled blood between the paired circuits, and from each circuit at 0.5, 1, 3, 12, and 24 hours of perfusion.

Blood Cell Counting
Platelets were counted in a Bürker chamber.

Plasma Nitrate
Blood was collected in heparinized tubes and rapidly centrifuged to obtain plasma. Plasma nitrate (NO₃^-) was determined with a stable isotope (Na¹⁵NO₃) dilution assay, using positive ion/chemical ionization gas chromatography/mass spectrometry, after conversion of endogenous and radiolabeled nitrate in the samples to nitrotoluene. This method has been described in detail elsewhere [12].

Plasma Cyclic Guanosine Monophosphate
For determination of cyclic guanosine monophosphate (cGMP), 10 mL of blood was collected in tubes containing 0.12 mL 0.34 mol/L K₃–ethylenediamine tetraacetic acid and immediately placed on ice. Within 60 minutes after sampling, the blood was centrifuged at 2,000 g at 5°C for 10 minutes. Plasma was withdrawn, and the proteins were precipitated by adding an equal volume of 10% (wt/vol) trichloroacetic acid. The samples then were centrifuged at 4,000 g at 5°C for 15 minutes. The supernatants were stored at -70°C until assay. The samples were extracted with 4 x 3 mL of water-saturated diethyl ether. The aqueous phase was recovered and lyophilized, and the residue was dissolved in 50 mmol/L acetate buffer, pH 6.2. The cyclic nucleotide was measured by a radioimmunoassay. This technique and preparation of the antiserum used have been described in detail elsewhere [13].

Plasma Cyclic Adenosine Monophosphate
The blood was collected and prepared as described for cGMP. Cyclic adenosine monophosphate (cAMP) was measured by a radioimmunoassay similar to that described for cGMP [13].

Plasma ß-Thromboglobulin
Five milliliters of blood was collected in Diatube H collecting tubes (Diagnostica Stago, Leuven, Belgium) and incubated on ice for 15 minutes. The anticoagulated blood was then centrifuged at 10,000 g at 4°C for 30 minutes to obtain a platelet-poor plasma (PPP). The midportion of the PPP was removed and stored at -70°C. The plasma concentration of BTG was measured using a commercially available enzyme-linked immunosorbent assay (Asserachrom; Diagnostica Stago). Before assay, the PPP was diluted (1:400 to 1:800) with 0.01 mol/L phosphate-buffered saline solution containing 3% bovine serum albumin.

Platelet Serotonin Content
Five milliliters of blood was collected in tubes containing 0.5 mL of 3.8% sodium citrate and immediately placed on ice. One portion of the anticoagulated blood was centrifuged at 180 g at 4°C to obtain a platelet-rich plasma (PRP). The other portion of the anticoagulated whole blood was centrifuged at 10,000 g at 4°C for 30 minutes to obtain PPP. The PRP and PPP specimens were stored at -70°C until analyzed for serotonin concentrations using high-performance liquid chromatography, according to Kissinger and associates [14]. The results are expressed as nanograms of serotonin per 10³ platelets.

Platelet Membrane Glycoproteins
Five milliliters of blood was collected in Diatube H collecting tubes (Diagnostica Stago) containing a platelet inhibitor cocktail provided by the manufacturer (citrate, theophylline, and adenosine). The anticoagulated blood was centrifuged at 150 g for 10 minutes to obtain PRP. Twenty microliters of PRP was incubated with a saturating concentration of fluorescein-conjugated murine monoclonal antibodies specific for GPIb (clone AN51; Dakopatts, Glostrup, Denmark). After 1 hour incubation in the dark, the samples were diluted to 1 mL and fixed with 1% paraformaldehyde.

The specimens obtained at the different sampling points were analyzed simultaneously on a flow cytometer (FACScan; Becton Dickinson Immunocytometry Systems, Mountain View, CA) equipped with a 15-mW argon ion laser. The immunofluorescence was detected through a 530/30-nm band pass filter. A logarithmic amplifier was used for the fluorescence signal and the light scatter, and 10,000 ungated events were collected. The data were analyzed using Lysys II software (Becton Dickinson). Gating of the list mode files was first performed using forward and side scatter to identify platelets. The fluorescence intensity of fluorescein isothiocyanate–conjugated antibody binding was obtained on platelets within these gates, and the results were expressed as median fluorescence intensity and as percentage of phenotypically GPIb-negative platelets. An irrelevant fluorescein isothiocyanate–conjugated monoclonal antibody was used as a negative control.

Plasma Hemoglobin
Five milliliters of blood was collected in heparinized tubes and centrifuged at 2,000 g for 20 minutes to obtain plasma. The plasma samples were stored at -70°C until assay. For analysis, 0.2 mL of plasma was added to 0.4 mL of 32 mmol/L dicarboxidine (Kabi AB, Uppsala, Sweden), followed by the addition of 0.2 mL of 0.2 mol/L hydrogen peroxide solution (Merck, Darmstadt, Germany), and incubated for 40 minutes. Thereafter, 4.2 mL of 3.5 mol/L acetic acid (Analar; BDH Chemical Ltd, Poole, UK) was added; after 7 minutes' incubation, the absorbance was recorded in a spectrophotometer at 450 nm. Hemoglobin solutions (10 to 100 mg/L) were used to construct a standard curve [15].

Methemoglobin
The formation of methemoglobin was recorded at different times by means of an automated counter (Hemoximeter; Radiometer, Copenhagen, Denmark).

All variables studied were corrected for hemodilution.

Statistical Analysis
Standard statistical methods were used to calculate mean values and standard error of the mean. Unless otherwise stated, mean values ± standard error of the mean are reported. Between-group comparisons were performed by two-way analysis of variance and Student's t test for paired data; p less than 0.05 was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
No obvious dose-response relation was observed with respect to any of the variables recorded among the three different concentrations of NO administered. Therefore, the results are presented as a mean value of the eight experiments with different NO concentrations.

A marked decline in mean platelet count was observed in the control circuits. The mean platelet counts before the start of perfusion and at 30 minutes of perfusion were 193 ± 7 and 138 ± 11 x 10⁹/L, respectively (Fig 1). A similar decline in platelet count, but less pronounced, was seen in the NO circuits (193 ± 7 and 151 ± 8 x 10⁹/L, respectively). However, at all times studied, the mean platelet count was consistently higher in the NO circuits than in the control circuits, and the difference was statistically significant (p = 0.0045; analysis of variance, treatment effect).

View larger version (14K): [in this window] [in a new window]   Fig 1. . Platelet count (mean ± standard error of the mean) during the 24 hours of perfusion. (p = 0.0045; analysis of variance, treatment effect.) (NO = nitric oxide.)

View larger version (15K): [in this window] [in a new window]   Fig 2. . Plasma nitrate (NO3-) concentration (mean ± standard error of the mean) during the 24 hours of perfusion. (p = 0.001; analysis of variance, treatment effect.) (NO = nitric oxide.)

View larger version (16K): [in this window] [in a new window]   Fig 3. . Plasma cyclic guanosine monophosphate (cGMP) concentration (mean ± standard error of the mean) during the 24 hours of perfusion. (p = 0.0023; analysis of variance, treatment effect.) (NO = nitric oxide.)

View larger version (16K): [in this window] [in a new window]   Fig 4. . Plasma ß-thromboglobulin (BTG) concentration (mean ± standard error of the mean) during the 24 hours of perfusion. (p = 0.012; analysis of variance, treatment effect.) (NO = nitric oxide.)

View larger version (15K): [in this window] [in a new window]   Fig 5. . Platelet serotonin content (mean ± standard error of the mean) during the 24 hours of perfusion. (p = not significant; analysis of variance, treatment effect). (NO = nitric oxide.)

No statistically significant difference in the mean plasma hemoglobin concentration was noted between the NO and control circuits. The mean plasma hemoglobin concentrations at 24 hours of perfusion were 746 ± 190 and 642 ± 143 mg/L in the control and the NO circuits, respectively.

The methemoglobin concentration did not differ significantly between the circuits and did not exceed 1.5% at any of the times studied.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In the present experiments, we studied the platelet count and the biochemical indices of platelet activation in an in vitro ECLS system. During a 24-hour period of continued perfusion, the platelet count decreased and plasma BTG increased, suggesting platelet activation and consumption. Low concentrations of NO added to the oxygenator sweep gas decreased platelet activation and consumption. Addition of NO to the sweep gas did not, however, affect plasma serotonin levels or platelet membrane GPIb expression.

As mentioned above, postoperative bleeding may appear after cardiopulmonary bypass or other ECLS procedures. These events are thought to be caused by impairment of platelet function after adherence to artificial surfaces in the ECLS systems, leading to platelet activation and release. Accordingly, a large percentage of the circulating platelets, despite displaying a normal count, have lost important membrane receptors after no more than a few hours of perfusion [15–]. To overcome platelet activation and platelet loss, drugs such as prostacyclin and dipyridamole have been added during ECLS. These drugs increase platelet cAMP levels [3] by different mechanisms and thereby counteract platelet activation. The use of these drugs is limited, however, by the hypotension that results from systemic administration.

The current protocol, using an artificial ECLS system, recorded platelet count and platelet activation during 24 hours of perfusion. During this period, the platelet count displayed an initial drop followed by partial restitution. The initial decline in platelet count is a well-known phenomenon and is assumed to reflect adhesion of circulating platelets to the artificial surfaces of the perfusion system. Supporting this assumption, plasma BTG levels were found to increase progressively throughout the perfusion period. The restitution of platelet count has been proposed to indicate deadhesion and return of the activated and granule-depleted platelets to the circulating blood.

Nitric oxide is a powerful regulator of platelet adhesion and aggregation, operating by activation of soluble guanylate cyclase and thereby elevating platelet cGMP [19]. When added to the oxygenator sweep gas in the present experiments, NO elicited a progressive increase in plasma nitrate during the experiments. It has been demonstrated previously that inhaled NO is metabolized to nitrate in red blood cells in vivo [12]. The accumulation of nitrate observed in this study indicates that the NO added to the sweep gas in fact entered the blood through the oxygenator, and furthermore, that it was metabolized in the blood perfusing the ECLS system in the same way as in vivo [20].

Because NO elicits activation of guanylate cyclase in tissues, it was of particular interest to assess whether the plasma concentrations of cGMP in the NO-perfused ECLS circuits would differ from those in the control circuits. A decrease in plasma cGMP was observed in both the control and NO-added circuits; we interpret this decrease to be due to the action of plasma enzymes such as phosphodiesterases, as described previously [21]. In the NO-added circuits, a moderate increase in the plasma concentration of cGMP was observed during the first 3 hours of the experiments, as compared with the initial concentration. Furthermore, plasma cGMP levels in the NO circuits were consistently higher than in the control circuits. We assume that the observed difference in plasma cGMP between the NO and control circuits was due to increased guanylate cyclase activity in a fraction of the blood cells, presumably the platelets. If this is correct, then the lower decrease in platelet count in the NO circuits may be explained in terms of cGMP-mediated inhibition of platelet adhesion and aggregation in the ECLS system.

Supporting the concept of cGMP-mediated protection against platelet activation and release by NO, in the present experiments the plasma levels of BTG increased less in the NO circuits than in the control circuits. In contrast, plasma serotonin levels did not differ between the two types of circuits. Decreased release of BTG, but not of serotonin, may indicate that NO was efficient in protecting alpha-granules, but not dense granules, from releasing their content. This is in accordance with an earlier study, in which an action of NO on alpha-granule release was reported [22].

In the present experiments, we were unable to demonstrate an effect of NO on the expression of the platelet membrane receptor GPIb. This glycoprotein is necessary for platelet adhesion [16]. However, GPIb is most sensitive for degradation by endogenous proteases, and continuous degradation of GPIb has been reported during platelet storage [23], in extracorporeal bypass operations [18], and in the in vitro ECLS model used for these experiments [17]. Furthermore, the GPIb receptor is stored within the platelets [23], and GPIb from this intracellular pool is externalized on the platelet membrane after activation. This externalization of intraplatelet GPIb, replacing part of the glycoproteins lost by degradation, makes the assay somewhat insensible. We assume that these factors together may sufficiently explain the lack of observed effect of NO on platelet membrane GPIb density.

In this study, we attempted to use NO as a platelet-preserving agent during extracorporeal circulation. Because NO is a gas, it is easy to administer to an ECLS circuit. Its effect on platelets may be assumed to be rapid in both onset and disclosure, thereby offering good pharmacologic properties for use under these conditions. We therefore propose NO as a strong candidate drug for the prevention of platelet exhaustion, and hence for reduction of bleeding complications appearing after different ECLS procedures. Applied studies are still required, however, to assess whether the promising effects of NO noted in this study are applicable to its clinical use in patients requiring ECLS.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported by grants from the Swedish Heart and Lung Foundation, Barnhusfonden, Göteborg Medical Society, the Swedish Medical Research Council (project 4341), and Crown Princess Louisa's foundation. We thank Dr Johan Ahlner for skillful analysis of cGMP and cAMP, Dr Annika Lindholm for blood banking support, and Åke Järnås, MT, for expert technical assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Mellgren, Department of Pediatric Surgery, Östra Hospital, S-416 85 Göteborg, Sweden.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Zwischenberger JB, Nguyen TT, Upp JR, et al. Complications of neonatal extracorporeal membrane oxygenation. Collective experience from the Extracorporeal Life Support Organization. J Thorac Cardiovasc Surg 1994;107:838–48.[Abstract/Free Full Text]
2. Cilley RE, Zwischenberger JB, Andrews AF, Bowerman RA, Roloff DW, Bartlett RH. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics 1986;78:699–704.[Abstract/Free Full Text]
3. FitzGerald GA. Dipyridamole. N Engl J Med 1987;316: 1247–54.[Medline]
4. Arén C. Prostacyclin infusion during coronary bypass surgery. Effects on platelets, postoperative bleeding, and cerebral complications. Minab/Gotab, Kungälv.Thesis Göteborg,1984
5. Bernabei A, Gikakis N, Kowalska MA, Niewiarowski S, Edmunds LH Jr. Iloprost and echistatin protect platelets during simulated extracorporeal circulation. Ann Thorac Surg 1995;59:149–53.[Abstract/Free Full Text]
6. Weber AA, Strobach H, Schrör K. Direct inhibition of platelet function by organic nitrates via nitric oxide formation. Eur J Pharmacol 1993;247:29–37.[Medline]
7. Radomski MW, Vallance P, Whitley G, Foxwell N, Moncada S. Platelet adhesion to human vascular endothelium is modulated by constitutive and cytokine induced nitric oxide. Cardiovasc Res 1993;27:1380–2.[Abstract/Free Full Text]
8. Langford EJ, Brown AS, Wainwright RJ, et al. Inhibition of platelet activity by S-nitrosoglutathione during coronary angioplasty. Lancet 1994;344:1458–60.[Medline]
9. Groves PH, Penny WJ, Cheadle HA, Lewis MJ. Exogenous nitric oxide inhibits in vivo platelet adhesion following balloon angioplasty. Cardiovasc Res 1992;26:615–9.[Abstract/Free Full Text]
10. Högman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G. Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 1994;151:125–9.[Medline]
11. Högman M, Frostell C, Arnberg H, Hedenstierna G. Bleeding time prolongation and NO inhalation. Lancet 1993;341:1664–5.[Medline]
12. Wennmalm Å, Benthin G, Edlund A, et al. Metabolism and excretion of nitric oxide in humans-an experimental and clinical study. Circ Res 1993;73:1121–7.[Abstract/Free Full Text]
13. Steiner AL, Parker CW, Kipnis DM. Radioimmunoassay for cyclic nucleotides. J Biol Chem 1972;247:1106–13.[Abstract/Free Full Text]
14. Kissinger PT, Bruntlett CS, Davis GC, Felice LJ, Riggin RM, Shoup RE. Recent developments in the clinical assessment of the metabolism of aromatics by high-performance, reversed-phase chromatography with amperometric detection. Clin Chem 1977;23:1449–55.[Abstract/Free Full Text]
15. Swolin B, Roberts D, Waldenström J. Quantitative determination of plasma hemoglobin using dicarboxidine. Clin Chim Acta 1982;121:389–91.[Medline]
16. Plötz FB, van Oeveren W, Bartlett RH, Wildevuur CRH. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg 1993;105:823–32.[Abstract]
17. Mellgren K, Friberg LG, Hedner T, Mellgren G, Wadenvik H. Blood platelet activation and membrane glycoprotein changes during extracorporeal life support (ECLS)-in vitro studies. Int J Artif Organs 1995;18:315–21.[Medline]
18. George JN, Pickett EB, Saucerman S, et al. Platelet surface glycoproteins. Studies on resting and activated platelets and platelet membrane microparticles in normal subjects and observations in patients during adult respiratory distress syndrome and cardiac surgery. J Clin Invest 1986;78:340–8.[Medline]
19. Buechler WA, Ivanova K, Wolfram G, Drummer C, Heim JM, Gerzer R. Soluble guanylyl cyclase and platelet function. Ann NY Acad Sci 1994;714:151–7.[Medline]
20. Wennmalm Å, Benthin G, Petersson A-S. Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood on the oxygenation of its red cell haemoglobin. Br J Pharmacol 1992;106:507–8.[Medline]
21. Beltman J, Sonnenburg WK, Beavo JA. The role of protein phosphorylation in the regulation of cyclic nucleotide phosphodiesterases. Mol Cell Biochem 1993;127-128:239–53.[Medline]
22. Drummer C, Lüdke S, Spannagl M, Schramm W, Gerzer R. The nitric oxide donor SIN-1 is a potent inhibitor of plasminogen activator inhibitor release from stimulated platelets. Thromb Res 1991;63:553–6.[Medline]
23. Michelson AD, Adelman B, Barnard MR, Carroll E, Handin RI. Platelet storage results in a redistribution of glycoprotein Ib molecules. Evidence for a large intraplatelet pool of glycoprotein Ib. J Clin Invest 1988;81:1734–40.[Medline]

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