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Anesth Analg 2004;99:1121-1126
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000130620.79832.23

ANESTHETIC PHARMACOLOGY

Sevoflurane Anesthesia Attenuates Adenosine Diphosphate-Induced P-Selectin Expression and Platelet-Leukocyte Conjugate Formation

Go-Shine Huang, MD*, Chi-Yuan Li, MD MS*, Ping-Ching Hsu, MS{dagger}, Chien-Sung Tsai, MD{dagger}, Tso-Chou Lin, MD*, and Chih-Shung Wong, MD PhD*

*Department of Anesthesiology and {dagger}Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, National Defense University, Taipei, Taiwan, Republic of China

Address correspondence and reprint requests to Dr. Chi-Yuan Li, Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, 325 Cheng-Kung Rd., Section 2, Taipei, Taiwan, ROC. Address e-mail to cyli{at}ndmctsgh.edu.tw


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The expression of P-selectin on the surface of platelets and platelet-leukocyte conjugate formation are considered to be an indicator of platelet activation and are important in thrombotic and inflammatory disease. Previous studies have reported the inhibitory effects of sevoflurane on platelet aggregation. We investigated whether sevoflurane alters the expression of P-selectin on platelets and the formation of platelet-leukocyte conjugates. Twenty-five patients undergoing minor extremity surgery received sevoflurane-based general anesthesia, with mask induction and laryngeal mask airway anesthesia maintenance. Whole blood was obtained before and 40 min after sevoflurane anesthesia. Unstimulated and adenosine diphosphate-stimulated samples of whole blood and platelet rich plasma were stained with fluorochrome-conjugated antibodies. The expression of P-selectin on platelets and the formation of platelet-leukocyte conjugates were measured using flow cytometry. Sevoflurane inhibited platelet P-selectin expression. It also reduced the formation of platelet-leukocyte conjugates, both in unstimulated and adenosine diphosphate-stimulated blood samples at 3%–4% end-expiratory sevoflurane concentrations used to maintain anesthesia.

IMPLICATIONS: Sevoflurane inhibited P-selectin expression of platelets in platelet rich plasma and whole blood, and reduced platelet-leukocyte conjugate formation ex vivo via flow cytometry analysis, which suggests modulation of platelet activation and platelet-leukocyte interaction.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Platelet surface P-selectin, considered to be one of the major laboratory markers of platelet activation (1), is present in the {alpha}-granules of platelets (1) and translocates rapidly to the cell surface after platelet activation (2). Activated platelets may bind to leukocytes in vivo and form platelet-leukocyte aggregates, mainly via binding of platelet P-selectin to leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) (3,4). P-selectin surface expression on platelets and platelet-leukocyte conjugate formation have been reported as potential markers of life-threatening thrombotic diseases such as stroke and thrombosis (5–8).

Several investigations have shown that sevoflurane inhibits platelet function (9–11). Nonetheless, the details of the sevoflurane inhibitory mechanism are contradictory, and its direct effects on platelet surface antigens, such as P-selectin, and on early platelet activation have not been studied. The aim of this study was to evaluate the effects of sevoflurane on platelet activation. After exposure to sevoflurane, the expression of P-selectin on the surface of platelets and platelet-leukocyte conjugation were assessed in an ex vivo manner using flow cytometry.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After institutional approval, 25 young male patients, ASA patient classification I, scheduled for minor surgery of the extremities, were enrolled in the study. Informed consent was obtained from each patient before enrollment. All patients denied a history of recent trauma, coagulation disorders, systemic inflammatory diseases, and none had taken nonsteroidal antiinflammatory drugs or heparin therapy for at least 2 wk before the study. General anesthesia was induced with sevoflurane 6% with oxygen flow of 6 L for 15 min. After induction, a laryngeal mask airway was inserted. The end-expiratory sevoflurane concentrations had stabilized at 3%–4% for anesthesia maintenance. No additional medications were given to any patient during the anesthesia.

Whole blood 10 mL was collected from each patient 1 h before induction of anesthesia for control purposes, and again 40 min after induction. Blood was collected, without a tourniquet, from the antecubital vein of one arm via a 19-gauge needle, using the two-syringe technique. The first 3 mL of blood was discarded, whereas the second sample of 10 mL was used for flow cytometric analyses. Blood samples were anticoagulated with 1:9 volume of 3.8% sodium citrate solution. All blood samples were then immediately processed for stimulation procedures and flow cytometric analyses.

The blood samples were divided into 2 parts: 1 part was centrifuged at 100g for 10 min to obtain platelet rich plasma (PRP), and the other part was used for whole blood assays. PRP was used for detection of P-selectin expression on platelets, and whole blood was used to measure P-selectin expression on platelets and platelet-leukocyte conjugate formation.

PRP samples were prepared to a total volume of 300 µL each, with or without 8 µM final concentration of adenosine diphosphate (ADP) (Sigma-Aldrich, St. Louis, MO). PRP samples were then stained with phycoerythrin-conjugated CD62P antibody (clone AC1.2; Becton Dickinson, San Jose, CA), a monoclonal antibody directed against P-selectin expressed on the platelet surface, then incubated at 37°C for 5 min, and later fixed with 0.5 mL of FACS (Fluorescence-Activated Cell Sorter) lysing solution (Becton Dickinson) for 10 min. Samples were centrifuged at 1500g for 10 min to collect the platelet pellet; the pellet was then resuspended with 0.5 mL of phosphate buffered saline for flow cytometric analyses.

For the whole blood assay, within 10 min of blood collection, aliquots of blood samples were preincubated in the absence (unstimulated) or presence (stimulated) of ADP 20 µM at 37°C for 5 min. After 5 min, stimulated or unstimulated whole blood was added to saturating concentrations of anti-CD62P-PE and anti-CD41a-fluorescein-isothiocyanate (FITC) (clone HIP8; Becton Dickinson), a monoclonal antibody-recognizing platelet GPIIb/IIIa complex independent of activation or anti-CD45-FITC (clone 2D1; Becton Dickinson), a monoclonal antibody for the leukocyte common antigen; the samples were then allowed to stain for 20 min at 22°C in the dark. The whole blood samples were then fixed with 0.5 mL of FACS lysing solution (Becton Dickinson) for 10 min to lyse the erythrocytes. The samples were then centrifuged at 1500g for 10 min to collect the platelet pellet; the pellet was then resuspended in 0.5 mL of phosphate buffered saline for flow cytometric analyses.

To determine the CD62P expression in the PRP, the platelet population was defined by size using logarithmic scaling. For determination of CD62P expression on platelet surfaces in whole blood, the platelet population was defined by size and CD41a-FITC immunofluorescence. From each sample, 10,000 platelets were measured. The mean fluorescence intensities of CD62P were histographed from the gated platelet populations. To determine platelet-leukocyte conjugate formation, leukocyte subpopulations (neutrophils, monocytes, and lymphocytes) were differentiated by cell size (forward scatter), granularity (side scatter), and binding of anti-CD45-FITC, which recognizes all human leukocytes using linear scaling. The conjugation of platelets and leukocytes occurred through the interaction of P-selectin on platelets and PSGL-1 on leukocytes. The platelet-leukocyte conjugates were visualized as CD62P/CD45 double positive clusters by FACS analysis. For each sample, 10,000 leukocytes were counted. The mean fluorescence intensity (MFI) of CD62P per bound leukocyte was determined (Fig. 1). Flow cytometric analyses were performed using a FACScan cytometer and CellQuest software (Becton Dickinson), which detected the emitted fluorescence and light-scattering properties of each cell to electronically separate them into specific cell types (platelets, neutrophils, monocytes, and lymphocytes).


Figure 1
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  		Figure 1. Whole blood flow cytometric analysis of platelet-leukocyte conjugate formation. a, Leukocytes were gated as neutrophils, monocytes, and lymphocytes via sideward scatter (SSC) as well as their specific binding characteristics of anti-CD45-fluorescein isothiocyanate (FITC) (FL 1). b and c, Representative results of the binding of unstimulated and adenosine diphosphate-activated platelets to leukocytes. Total platelet-leukocyte and leukocyte subpopulation conjugates were visualized as anti-CD62P-PE (FL 2)/anti-CD45-FITC (FL 1) double positive clusters. The events in the leukocytes gate above the horizontal line in the right upper quadrant were considered to represent platelet-leukocyte conjugates and those below the line were considered to be platelet-free leukocytes, as determined by isotype controls.

 
Data were presented as the mean ± SD of all values for each experiment. A paired-Student’s t-test was used for comparisons before sevoflurane and after sevoflurane treatment in unstimulated and stimulated samples, separately. A value of P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The effect of sevoflurane anesthesia on P-selectin-positive platelets and platelet-leukocyte conjugate formation is summarized in Table 1. Before sevoflurane anesthesia, the unstimulated CD62P-positive platelet MFI was 12 ± 1.68 in PRP and 41.7 ± 3.33 in whole blood. With ADP stimulation, P-selectin increased approximately 4-fold in PRP and 1.5-fold in whole blood. After 40 min of sevoflurane anesthesia, the CD62P-positive platelets had significantly decreased in ADP-stimulated and in unstimulated PRP (Fig. 2a) and whole blood (Fig. 2b).


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  		Table 1. Effects of Sevoflurane Anesthesia (3%–4%) on P-Selectin-Positive Platelets and Platelet-Leukocyte Conjugate Formation
 

Figure 2
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  		Figure 2. Effect of sevoflurane on CD62P expression in platelet rich plasma (PRP) and whole blood unstimulated and stimulated by adenosine diphosphate (ADP). Platelet surface P-selectin expressed before and 40 min after exposure to sevoflurane anesthesia. The data show that platelet CD62P expression was inhibited significantly in PRP (a) and whole blood (b) after 40 min of exposure to sevoflurane anesthesia. Data are presented as mean ± SD.*P < 0.05 versus pre-sevoflurane; **P < 0.01 versus pre-sevoflurane. MFI = mean fluorescence intensity.

 
For determination of platelet-leukocyte conjugate formation in whole blood, CD62P-positive leukocytes were considered as conjugated to platelets. Figure 1a shows the dot plot of leukocytes by gating subpopulations as neutrophils, monocytes, and lymphocytes. Before sevoflurane anesthesia, the MFI of CD62P-positive leukocytes was 46.1 ± 11.54 in unstimulated blood, and increased to 127.3 ± 24.07 after ADP (20 µM) stimulation. This conjugation mainly occurred between platelets and monocytes. After 40 min of anesthesia, sevoflurane significantly reduced platelet binding to total leukocytes, monocytes, and lymphocytes in the unstimulated samples. Sevoflurane also slightly, but significantly, reduced platelet-neutrophil conjugate formation (Fig. 3a). Furthermore, sevoflurane significantly suppressed platelet binding to total leukocytes, neutrophils, and monocytes in the ADP-stimulated samples (Fig. 3b). The MFI of platelets bound to lymphocytes tended to be lower, but not significantly, than in the control samples.


Figure 3
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  		Figure 3. Effect of sevoflurane on CD62P-positive leukocytes in whole blood, unstimulated and stimulated by adenosine diphosphate (ADP). CD62P expressed on leukocytes (P-Leu), lymphocytes (P-Lym), neutrophils (P-Neu), and monocytes (P-Mon) conjugated before and 40 min after exposure to sevoflurane anesthesia. The results show that sevoflurane reduced CD62P-conjugated leukocytes in total and in leukocyte subpopulations, especially in monocytes. Data are presented as mean ± SD.*P < 0.05 versus pre-sevoflurane; **P < 0.01 versus pre-sevoflurane. MFI = mean fluorescence intensity.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Increased levels of P-selectin have been found in patients with stroke (7), peripheral artery disease (8), and acute coronary syndromes treated with angioplasty or thrombolysis (12). These findings suggest an important role for P-selectin in thrombotic disease. In the present study, we first demonstrated that P-selectin surface expression decreased on both ADP-stimulated and unstimulated platelets in PRP and whole blood after sevoflurane anesthesia, suggesting that sevoflurane may inhibit platelet activation.

Platelets and leukocytes form platelet-leukocyte conjugates, mainly via P-selectin and PSGL-1, or via bridging with fibrinogen, or thrombospondin (3,4,13), thus playing an important role in many inflammatory and hemostatic reactions (14). PSGL-1, the primary ligand for P-selectin, is constitutively expressed on the surface of circulating leukocytes (4,15). P-selectin and PSGL-1 cellular adhesives contribute to coagulation and inflammation. Platelet P-selectin was first thought to contribute uniquely to either coagulation or inflammation and is now known to contribute to both processes (16). Increased platelet-neutrophil and platelet-monocyte conjugate formation have been shown during cardiopulmonary bypass (6), myocardial infarction (5), and thrombosis (17). Binding of activated platelets to leukocytes induces inflammation and hemostatic processes (14,18). We found that sevoflurane inhibited both ADP-stimulated and unstimulated platelet-leukocyte conjugate formation, which was particularly true for the monocyte subpopulation. Because adhesion of activated platelets to leukocytes mainly depends on the interaction of leukocyte PSGL-1 with platelet P-selectin, decreased P-selectin expression on platelets may provide an explanation for the inhibitory effect of sevoflurane on the formation of platelet-leukocyte conjugates. Because our data do not eliminate the possibility of additional effects of sevoflurane on platelet-leukocyte conjugation events, further studies are necessary to confirm these potential interactions.

Hirakata et al. (10,11) and Dogan et al. (9) established that platelet aggregation was impaired during anesthesia with sevoflurane (11), which was consistent with our reports. However, there are still some differences in study design between our report and that of the Hirakata et al. (10,11) study. One difference is that endotracheal intubation is a stressful procedure during anesthetic induction. Another difference is that using an aggregometer could not disclose the effect of sevoflurane on P-selectin expression on platelets and formation of platelet-leukocyte conjugates. The third difference is that using induction drugs such as thiopental may affect platelet function (19). Hirakata et al. (10) concluded that the proposed mechanism of platelet aggregation inhibition was the suppression of thromboxane A2 formation caused by suppression of cyclooxygenase activity. Kohro and Yamakage (20) investigated the effect of halothane on platelet function and proposed a decrease in intracellular free Ca2+ and production of inositol 1,4,5-triphosphate as the possible inhibitory mechanism. A similar mechanism is possible for the effects of sevoflurane on platelet activation.

Horn et al. (21,22) found that sevoflurane had no effect or increased the expression of P-selectin on platelets, especially in in vitro samples stimulated by ADP and thrombin receptor agonist peptide-6. In one study, sevoflurane also enhanced binding of platelets to lymphocytes, neutrophils, and monocytes (22). These different results may be partly explained by the different methods. In contrast to the previous studies, we analyzed platelets ex vivo instead of in vitro. Clinically, platelet aggregation is thought to be induced by combined activation of multiple pathways in vivo involving strong agonists and weak agonists separately. Therefore, any effect of platelet aggregation by sevoflurane under in vitro laboratory conditions might not result in the net effect of clinical platelet aggregation.

Formerly, studies concerning the effect of volatile anesthetics on platelet function, using stimulus-dependent platelet aggregation as the main variable (10), have mostly been performed in vitro (9–12,23) and have neglected the possible important influences of red blood cells and plasma components. In this study, we investigated platelet activation under conditions designed to mimic physiological conditions; studies were conducted ex vivo. We also sought to minimize the nonsevoflurane effects of platelet activation as much as possible, thus simplifying the link between sevoflurane and platelet activation. All patients were healthy young males, effectively excluding coagulation disorders, drug, and gender-specific effects (hormone or contraceptive). Mask anesthetic induction and laryngeal mask airway maintenance were used to avoid catecholamine release caused by endotracheal intubation (24). Furthermore, compared with a previous ex vivo study (11), we also avoided potential interference by other induction drugs. Minor extremity elective surgery was chosen to keep surgical trauma, tissue damage, and blood loss to a minimum (24).

Knowledge of the effects of sevoflurane on platelet activation may be important, not only to understand the interactions between inhaled anesthetics and hemostasis, but also because, potentially, sevoflurane may be beneficial in thrombotic diseases. Sevoflurane is frequently used as a general inhaled anesthetic. The use of sevoflurane in vitro in whole blood reduces platelet aggregation (10). Our study is the first to demonstrate that sevoflurane attenuated platelet activation induced by ADP ex vivo by flow cytometry. These results suggest that the effects of sevoflurane on platelet function may act, at least in part, by modulating platelet P-selectin expression and platelet-leukocyte conjugation. Sevoflurane must be further evaluated to determine its effects on patients with hypercoagulability, such as severe venous and arterial thromboembolism.

In conclusion, we demonstrated that sevoflurane inhibited P-selectin expression of platelets in PRP and whole blood. Moreover, sevoflurane suppressed platelet-leukocyte conjugate formation, particularly in monocytes. Further understanding of the mechanisms by which sevoflurane inhibited platelet activation and platelet-leukocyte interaction may help identify and provide insight into therapies that might limit the development of thrombotic and inflammatory disease.


   Acknowledgments
 
This work was supported by grants from Tri-Service General Hospital (TSGH-C92-42) and the National Science Council (NSC 92-2314-B-016-056), Taiwan, ROC.


   References
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 Introduction
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 Discussion
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Accepted for publication April 14, 2004.




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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