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Anesth Analg 2001;93:635-640
© 2001 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Xenon Does Not Affect Human Platelet Function In Vitro

Lothar W. de Rossi, MD*, Nicola A. Horn, MD*, Jan H. Baumert, MD*, Kai Gutensohn, MD{dagger}, Gabriele Hutschenreuter, MD{ddagger}, and Rolf Rossaint, MD*

*Department of Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany; {dagger}Department of Transfusion Medicine/Transplantation Immunology, University Hospital Eppendorf, Hamburg, Germany; and {ddagger}Institute of Transfusion Medicine, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany

Address correspondence and reprint requests to Lothar W. de Rossi, MD, Department of Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstr. 30, D-52074 Aachen, Germany. Address e-mail to L.derossi{at}gmx.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We sought to determine whether xenon affects platelet glycoprotein expression and platelet-related hemostasis in vitro at a clinically relevant concentration. Human whole blood was stimulated with either adenosine diphosphate or the thrombin receptor agonist peptide (TRAP)-6 after incubation with 65% xenon. Halothane at 2 minimum alveolar anesthetic concentration was used as a positive control. Platelet function and activation were evaluated with two-color flow cytometry. The expression of the platelet glycoproteins GPIIb/IIIa, GPIb, and P selectin were detected with fluorochrome-conjugated monoclonal antibodies. In vitro measurement of platelet-related hemostasis under conditions of high shear stress was performed in citrated whole blood with a platelet function analyzer (PFA-100®) by using collagen/epinephrine and collagen/adenosine diphosphate cartridges. Xenon did not affect basal or agonist-induced expression of platelet membrane glycoproteins, activation-dependent conformational changes of the GPIIb/IIIa receptor, expression of P selectin, or PFA closure times. In contrast, halothane reduced TRAP-6-induced activation of the GPIIb/IIIa complex. Furthermore, collagen/epinephrine-induced PFA closure time was significantly prolonged. These results demonstrate that xenon does not affect the unstimulated or agonist-induced platelet glycoprotein expression, activation of GPIIb/IIIa, or platelet-related hemostasis.

IMPLICATIONS: Halothane and sevoflurane inhibit platelet aggregation. Xenon did not affect platelet glycoprotein expression or in vitro bleeding time. Because platelet glycoprotein expression is strongly related to platelet adhesion to sites of vascular injury and platelet aggregation, we suggest that xenon does not interfere with platelet function in vitro.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Platelets play an important role in primary hemostasis during the perioperative period. Therefore, all clinically used volatile anesthetics have been evaluated, whether or not they interfere with platelet function. Halothane inhibits platelet function in vivo (1,2) and in vitro (3,4). Isoflurane appears to have only minor or negligible effects on platelet aggregation in comparison with halothane (5,6). Sevoflurane has strong antiaggregatory effects on adenosine diphosphate (ADP)-induced platelet aggregation, even at subanesthetic concentrations (7), whereas thrombin-induced platelet aggregation was not affected (8).

There is a rapidly growing interest in the use of xenon as an anesthetic. Studies in animals and humans show a lack of organ toxicity (9) and display rapid recovery characteristics (10), as well as cardiovascular stability (11). However, the effect of xenon on platelet function is unknown.

In this study we used a whole blood assay to investigate whether xenon influences platelet function in vitro. This analysis was based on flow cytometric detection of changes in the expression of platelet surface glycoproteins, activation-dependent conformational changes of the glycoprotein (GP)IIb/IIIa receptor, and expression of P selectin. Furthermore, measurement of platelet-related hemostasis under conditions of high shear stress was performed with a platelet function analyzer (PFA-100®; Dade, Miami, FL).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and written informed consent, whole blood was collected from 20 healthy volunteers by venipuncture with a 21-gauge butterfly needle without a tourniquet. Subjects’ ages ranged from 25 to 42 yr, and subjects had not taken any medications within the last 14 days. Platelet counts of all volunteers were within normal ranges. Blood was aspirated directly into blood collection tubes (Sarstedt, Nümbrecht, Germany) containing a 1:10 volume of either 3.2% (for flow cytometric assay) or 3.8% trisodium citrate (for PFA analysis) after discarding the first 2 mL of blood. Before the incubation, blood samples allocated for flow cytometric analysis were diluted 1:1 with phosphate-buffered saline (PBS without Ca2+ or Mg2+; Sigma Chemical Co., St. Louis, MO). The blood samples used for PFA analysis were not diluted before incubation. One blood sample was processed within 10 min after blood withdrawal for flow cytometric analysis and PFA measurements to obtain baseline values. The remaining blood samples were incubated with either 65% xenon or 2 minimum alveolar anesthetic concentration (MAC) halothane for 60 min. The MAC value used for halothane in this study was 0.8%. Control samples were placed at the same time point in an incubator (BB 16; Heraeus, Hanau, Germany) with an atmosphere of 21% oxygen and 5% CO2 at 37°C. After incubation, blood samples were immediately processed for stimulation procedures, flow cytometric analysis, and PFA measurements.

Incubation of blood samples with either xenon or halothane was performed in a small chamber (volume 5.6 L). Inside the chamber we maintained an atmosphere of 21% oxygen and 5% CO2 at 37°C. Xenon was delivered as a gas/oxygen mixture by using a low-{Delta}P mass flowmeter with control unit (types F-201C-FA-22-V and E-7300-AAA; HI-TEC Bronkhorst, EC Veenendal, The Netherlands). Xenon gas concentrations were monitored with an Ecotec 500 Euro gas analyzer and measured with Masterquad V3.2MG software (both Leybold, Cologne, Germany).

Halothane was delivered as a volatile air mixture by using a commercially available anesthetic machine (Sulla 909; Dräger, Lübeck, Germany). Oxygen, CO2, and halothane concentrations within the chamber were continuously monitored with a multigas analyzer (Datex Compact; Datex, Helsinki, Finland).

Preparation of blood samples for stimulation procedures and flow cytometric analysis were performed as previously described (12), with minor modifications. Briefly, after incubation, whole blood samples were diluted to 20,000 platelets per microliter by using PBS containing 1 mg/mL bovine serum albumin (Sigma). Aliquots of 500 µL were stimulated with ADP (final concentration, 1 µM; Sigma) or thrombin receptor activating peptide

(TRAP)-6 (final concentration, 6 µM; Bachem, Heidelberg, Germany). After 5 min stimulation, platelets were finally incubated at room temperature for 15 min in the dark with saturating concentrations of fluorescein isothiocyanate, conjugated (FITC)- and phycoerythrin-conjugated monoclonal antibodies for flow cytometric two-color analysis. Activation and staining was stopped by the addition of 1.5 mL cold PBS containing 1 mg/mL bovine serum albumin and 1% paraformaldehyde, and cells were analyzed within 30 min without washing steps.

The following antibodies were used in this study: CD41a-PE (clone HIP8; Pharmingen, San Diego, CA) directed against an activation-independent epitope characteristic for the intact GPIIb/IIIa complex; CD42b-PE (clone HIP1; Pharmingen) directed against the {alpha} subunit of the GPIb complex; PAC-1-FITC (Becton-Dickinson, San Jose, CA) directed against neoepitopes generated by activation-dependent conformational changes in the GPIIb/IIIa complex; and CD62P-FITC (clone AK4; Pharmingen) directed against the activation-dependent expressed adhesion protein P selectin on the surface of platelets. Negative immunoglobulin G1 (IgG1)-FITC (clone MOPC-21) and IgM-FITC (clone G155–228; both from Pharmingen) were used as isotype controls.

Flow cytometric analysis was performed on a FACSCalibur flow cytometer and analyzed with CellQuest 3.1 software (Becton-Dickinson). Fluorescent microbeads (Calibrite Beads; Becton-Dickinson) were used daily for the calibration of the flow cytometer. Platelets were identified on the basis of the size in the forward scatter and side scatter as well as on the PE staining of the highly expressed GPIIb/IIIa and GPIb. The data of 10,000 platelets per sample were stored in list mode at a flow rate of 500 cells per second. For analysis, platelets were gated in the side scatter versus fluorescence 2 dot plot. The mean FITC- and PE-fluorescence intensities for all variables were calculated from fluorescence histograms for the gated platelet populations. Furthermore, for the activation-dependent variables PAC-1 and CD62P, the percentage of positive platelets was measured in the fluorescence 1 versus fluorescence 2 dot plot.

The PFA-100® system is a high shear stress system testing platelet-related hemostasis in vitro (13–15). The system comprises a microprocessor-controlled instrument with either collagen/epinephrine- or collagen/ADP-coated membrane test cartridges. The instrument aspirates anticoagulated whole blood under steady-flow conditions through a capillary and a microscopic aperture cut in the cartridge membrane. The platelet agonist on the cartridge membrane, in combination with the high shear rate generated by the steady-flow conditions, leads to platelet activation and aggregation. The time necessary for the occlusion of the aperture, defined as closure time, caused by platelet aggregation is indicative of platelet function in the blood sample.

Xenon and halothane gas concentrations in the aqueous phase were measured with a headspace injector system (Model 7050; Tekmar-Dohrmann, Cincinnati, OH) connected to a gas chromatograph/mass spectrometer (HP 6890/MSD 5973; Hewlett-Packard, Palo Alto, CA). The gas chromatograph was equipped with a 60-m x 320-µm chromatograph column coated with a 1.8-µm film of 6% cyanopropylphenyl- and 94% dimethylpolysiloxan (Rtx®-624; Restek, Bad Homburg, Germany). Helium was used as a carrier gas at a head pressure of 80 kPa. The area under the curve from gas chromatography measurement values and the concentrations of both gases in the samples were calculated by using the multiple headspace extraction method (Perkin Elmer, Boston, MA) and the technique of linear regression.

Data were tested for normal distribution by using the Kolmogorov-Smirnov test. Analysis of variance and the Scheffé test at a significance level of P < 0.05 were used to compare baseline, control, and drug-exposed blood samples. Data are expressed as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
To exclude artificial platelet activation during the incubation time, we compared baseline and control values of unstimulated and agonist-induced platelet activation markers. The 60-min treatment in the incubator had no influence on either basal or agonist-induced activation of the GPIIb/IIIa and GPIb receptor or P-selectin expression on the surface of platelets (Table 1, 2).


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  		Table 1. Effect of 65% Xenon on the Expression of Activated GPIIb/IIIa, GPIb, and P Selectin in Comparison with Control
 

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  		Table 2. Effect of 2 MAC Halothane on the Expression of Activated GPIIb/IIIa, GPIb, and P selectin in Comparison with Control
 
The percentage of PAC-1-positive platelets and the mean intensity of the PAC-1-FITC fluorescence was used to evaluate the effect of xenon and halothane on the activated GPIIb/IIIa receptor on platelets. Xenon had no effect on the basal and agonist-induced expression of the activated GPIIb/IIIa receptor (Table 1). After exposure to 2 MAC halothane, the percentage of PAC-1-positive platelets and the number of activated GPIIb/IIIa receptors per platelet in the TRAP-6-stimulated blood samples were significantly reduced in comparison with control (P < 0.05). ADP-induced activation of the GPIIb/IIIa receptor on the surface of platelets was not inhibited after halothane exposure (Table 2).

The mean intensity of the CD42b-PE fluorescence was used to evaluate the effect of xenon and halothane on GPIb expression on platelets. Neither xenon nor halothane altered the basal expression or agonist-induced redistribution of the GPIb receptor on the platelet surface membrane (Table 1, 2). In both groups, expression of the GPIb receptor was decreased by 25%–30% in association with the ADP or TRAP-6 stimulation.

The percentage of CD62P-positive platelets and the mean intensity of the CD62P-FITC fluorescence was recorded to evaluate the effect of both anesthetics on P-selectin degranulation. Xenon did not influence spontaneous or agonist-activated platelet degranulation and expression of P selectin (Table 1). In the unstimulated blood samples, 2 MAC halothane did not alter the expression of P selectin on the surface of platelets, whereas TRAP-6-induced P selectin expression was significantly reduced in comparison with control (P < 0.05, Table 2).

A comparison between baseline PFA closure time data and control closure time data showed no increase in platelet aggregation caused by incubation time or incubation conditions (Fig. 1, 2). Incubation of the blood samples with xenon had no effect on either collagen/epinephrine- or collagen/ADP-induced in vitro bleeding time (Fig. 1). In contrast, after 2 MAC halothane, collagen/epinephrine closure time was significantly prolonged compared with control values (P < 0.01, Fig. 2).



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  		Figure 1. Effect of 65% xenon on PFA-100® closure time in comparison with control values. Data are expressed as mean ± SD of 10 independent experiments.

 


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  		Figure 2. Effect of 2 minimum alveolar anesthetic concentration halothane on PFA-100® closure time in comparison with control values. Data are expressed as mean ± SD of 10 independent experiments. * P < 0.01 vs 60-min control values.

 
The mean concentration of xenon in the anticoagulated diluted blood samples at 37°C was 2.96 ± 0.05 mM, and the mean partition coefficient was 0.102 ± 0.05. Corresponding halothane values were 1.44 ± 0.06 mM and 2.008 ± 0.04. Equilibration of the gas/aqueous distribution was complete after 15 min for both anesthetics.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we showed that xenon in clinical concentrations does not alter unstimulated or agonist-induced platelet glycoprotein expression, activation of the fibrinogen binding receptor GPIIb/IIIa, or platelet-related hemostasis in human whole blood. Platelet adhesion at sites of vascular injury is mediated via the platelet glycoprotein GPIb receptor (16), which initiates thrombus formation through an interaction with the adhesive ligand von Willebrand factor. In a second step, the ability of the glycoprotein receptor GPIIb/IIIa to bind fibrinogen, von Willebrand factor, fibronectin, and thrombospondin leads to platelet spreading onto the exposed vascular surface, platelet aggregation, and development of a platelet plug (17–20). Flow cytometry is increasingly used for the analysis of platelet function and allows the evaluation of the in vitro response of platelets at the glycoprotein receptor level to different stimuli (21). Therefore, we investigated the effect of xenon in a clinically used concentration on platelet function in a whole blood assay with two-color flow cytometry. Furthermore, in vitro platelet-related hemostasis under conditions of high shear stress was measured with a platelet function analyzer, PFA-100®.

The importance of the glycoprotein GPIb in normal hemostasis has been shown in patients with Bernard-Soulier syndrome (22). In these patients, surface expression of GPIb on platelets is either absent or decreased because of a genetic defect, and prolonged bleeding from trauma or surgery is reported (23). Activation with either weak or strong agonists in vitro is associated with a decrease in the number of GPIb receptors on the platelet surface; these are redistributed into the platelet open canalicular system (24). In our study, incubation of whole blood with 65% xenon over 60 min did not affect expression of GPIb or the agonist-induced physiologic redistribution of the receptor from the platelet surface. Thus, we conclude that xenon may not alter platelet adhesion at sites of vascular injury. Data on the effects of other volatile anesthetics on GPIb are controversial. Kohro and Yamakage (6) and our own results showed that halothane did not interfere with the expression and redistribution of GPIb on the surface of platelets. In contrast, Fröhlich et al. (25) reported a dose-dependent decrease in the surface expression of GPIb in the presence of halothane, isoflurane, sevoflurane, and desflurane, and this decrease suggests platelet activation.

Fibrinogen binding to the activated glycoprotein receptor GPIIb/IIIa is an important step in the development of thrombus formation, because this process leads to platelet aggregation (17–20). Inhibition of fibrinogen binding to GPIIb/IIIa contributes to hemorrhagic complications, as seen in patients with uremia (26,27) or after treatment with GPIIb/IIIa antagonists in the acute coronary syndrome (28). The effect of xenon and halothane on the activated GPIIb/IIIa complex was tested by using the antibody PAC-1, which appears to be specific for the recognition of the fibrinogen binding site exposed by conformational changes in the GPIIb/IIIa complex (29,30). Our results show that the exposure of platelets to xenon does not influence the activation of the GPIIb/IIIa complex, which transforms the complex to a fibrinogen-binding conformation and subsequent platelet aggregation. Furthermore, the lack of effect of xenon on PFA closure time indicates that xenon does not interfere with platelet function in vitro.

Halothane, in concentrations used clinically, inhibits platelet aggregation in vivo (1,2) and in vitro (3,4,6). The mechanism of the inhibition of thrombin-induced platelet aggregation is caused by a decrease in the intracellular concentration of free Ca2+ and production of inositol 1,4,5-triphosphate (IP3), whereas the expression of GPIb is not altered (6). With these results we show that halothane reduces the percentage of platelets with activated GPIIb/IIIa and the number of activated GPIIb/IIIa receptors on single platelets in TRAP-6-stimulated whole blood. Because platelet aggregation results from the binding of fibrinogen to its activated receptor, this finding provides a further explanation for the inhibiting effect of halothane on thrombin-induced platelet aggregation. Furthermore, this finding might also explain the prolonged collagen/epinephrine-induced PFA closure time. A direct inhibitory mechanism of halothane on the GPIIb/IIIa receptor can be eliminated, because ADP-induced activation of GPIIb/IIIa was not affected by halothane.

Thrombin-induced activation of the GPIIb/IIIa receptor is mediated via the specific thrombin receptors PAR1 and PAR4 in the membrane of platelets (31). However, the signaling pathways that deliver messages from these receptors to the GPIIb/IIIa complex remain incompletely characterized. There is evidence that there is an important link between the G protein-coupled thrombin receptors PAR1 and PAR4 and the GPIIb/IIIa receptor, involving phospholipase Cß, IP3, and protein kinase C (32). Therefore, inhibition of the thrombin-induced increase in IP3 by halothane might be responsible for the observed effect of halothane on the activation-dependent conformational changes in the GPIIb/IIIa receptor in our study.

Platelet activation is characterized not only by the expression of glycoproteins involved in platelet adhesion and aggregation, but also by secretion of lysosomal proteins. P selectin is a glycoprotein located in the membranes of {alpha} granules, which become externalized on the surface membrane upon activation of platelets (33). P selectin plays a prominent role in mediating cellular interactions among platelets, leukocytes (34), and endothelial cells (35). In this study, xenon did not alter the expression of P selectin on unstimulated or stimulated platelets. Furthermore, basal P-selectin expression was also unaffected after exposure to halothane. This is in contrast with a previous study that showed an increase of P-selectin expression with the presence of halothane, isoflurane, sevoflurane, and desflurane (25). ADP-induced P-selectin expression was not affected by these volatile anesthetics.

It is interesting to note that halothane significantly decreased P-selectin expression associated with TRAP-6 stimulation. Therefore, we speculate that halothane might modulate cellular interactions among platelets, leukocytes, and endothelial cells. However, further studies are required to define the physiologic consequences of this finding.

In summary, xenon in clinical concentrations does not alter unstimulated or agonist-induced platelet glycoprotein expression, activation of the fibrinogen receptor GPIIb/IIIa, or platelet-related hemostasis. Furthermore, our study indicates that the inhibitory effect of halothane on thrombin-induced platelet aggregation is mediated by a decreased activation of the fibrinogen binding receptor GPIIb/IIIa. We suggest that halothane reduces activation of the GPIIb/IIIa receptor by decreasing IP3, which is involved in the intracellular signaling pathway.


   Acknowledgments
 
This study was supported in parts by START, a research grant of the Rheinisch-Westfälische Technische Hochschule Aachen, and the Department of Anesthesiology, University Hospital, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany. Xenon was donated from Messer GmbH, Krefeld, Germany.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 18, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press