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Anesth Analg 2003;96:713-719
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Effect of Propofol on the Interaction of Platelets with Leukocytes and Erythrocytes in Surgical Patients

D. Mendez, PhD*, J.P. De La Cruz, PhD{dagger}, M.M. Arrebola, PhD{dagger}, A. Guerrero, PhD{dagger}, J.A. González-Correa, PhD{dagger}, E. García-Temboury, MD*, and F. Sánchez de la Cuesta, PhD{dagger}

*Anesthesiology and Resuscitation Unit, Carlos Haya University Hospital, Málaga; and {dagger}Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, Spain

Address correspondence and reprint requests to J.P. De La Cruz, PhD, Department of Pharmacology and Therapeutics, School of Medicine, University of Málaga, 29071 Málaga, Spain. Address e-mail to jpcruz{at}uma.es


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the antiplatelet effect described for propofol in vitro in surgical patients. Platelet aggregation induced by adenosine diphosphate, collagen, and arachidonic acid was tested in samples of whole blood, platelet-rich plasma (PRP), PRP with red blood cells, and PRP with leukocytes. Also measured were platelet production of thromboxane (Tx)B2 and leukocyte production of 6-keto-prostaglandin F1{alpha} (a stable metabolite of prostacyclin) and plasma levels of nitrites + nitrates (indicator of nitric oxide production). Anesthesia was induced with a bolus IV injection of sodium thiopental 4 mg/kg (n = 10), with a bolus dose of 2.5 mg/kg of propofol (n = 20), or with propofol total IV anesthesia (n = 20). Sodium thiopental did not modify any of the analytical values. In patients who received a bolus injection of propofol, platelet aggregation was significantly reduced in whole blood and in PRP + leukocytes. Platelet production of TxB2 was reduced by 35%; the inhibition of 6-keto-prostaglandin F1{alpha} was not statistically significant. Plasma levels of nitrites + nitrates increased by 37%; this change correlated significantly with the decrease in systolic and diastolic blood pressure (both P < 0.05). Similar changes, albeit of larger magnitude, were seen in patients who were given total IV anesthesia with propofol. In conclusion, propofol inhibited platelet aggregation in surgical patients mainly as a result of the inhibition of Tx synthesis and the increase in nitric oxide production. These effects are thought to be related to the hypotensive effect of this anesthetic.

IMPLICATIONS: In vitro experiments have shown that propofol inhibits platelet aggregation and increases nitric oxide production. This study shows that doses habitually used to induce or maintain anesthesia also have these effects. These findings have potential applications for patients at increased risk for bleeding and may partly explain the hypotensive effect of propofol.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
One of the effects of propofol in surgical patients is a decrease in blood pressure. Several theories have been proposed to elucidate the mechanisms involved in the vasoactive property of propofol; one such theory is based on a possible increase in nitric oxide (NO) production. In this connection, propofol has been shown to interfere with endothelial NO synthesis in experiments that quantified cyclic guanosine monophosphate (cGMP) production in endothelial cell cultures. The production of cGMP was increased in the presence of propofol and inhibited by incubation with hemoglobin (1). In an earlier study, it was demonstrated that propofol interfered with the platelet-leukocyte interaction by increasing NO production in white blood cells (2). The solvent Intralipid did not influence this effect.

NO is a cell mediator produced mainly by endothelial cells but also synthesized and released by polymorphonuclear leukocytes (PMNL) (3). Once released, it binds to guanyl-cyclase and increases intracellular levels of cGMP. Two consequences of NO release are relaxation of the vascular smooth muscle fibers (vasodilation) and inhibition of platelet functioning (antiplatelet aggregant effect). Several reports from our group have shown that propofol has an antiplatelet aggregant effect in whole blood (2,4); this effect is not seen in platelet-enriched plasma (PRP) but is potentiated in the presence of leukocytes or red blood cells (RBC). This effect has been related to two basic mechanisms: the inhibition of platelet thromboxane (Tx) A2 synthesis and the increased synthesis of leukocyte NO. Both effects may, in turn, be related to the antioxidant effect of propofol (5–7).

However, all reported experiments have been performed in vitro. The aim of the present study was to determine whether the antiplatelet effects also occurred in patients when propofol was given at doses habitually used in clinical practice to induce or maintain anesthesia.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study protocol was approved by the Ethics Committee of the Hospital. Each participant was informed as to the purpose of the study and gave his or her verbal consent in the presence of a relative.

The study was performed in 50 patients who underwent surgery (29 men and 21 women; mean age, 43.4 ± 9.2 yr) (Table 1). The selection criteria were scheduled for surgery with general anesthesia and ASA physical status I or II (8). Patients with any of the following were excluded from the study: diabetes mellitus, hypertension, use of nonsteroidal antiinflammatory drugs or antiplatelet drugs during the 7 days before inclusion, age younger than 18 yr and older than 65 yr, or open abdominal surgery. This last criterion was used to exclude excessive alterations of platelet function that might have masked the effects of the anesthesia.


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  		Table 1. Main Characteristics of Patients
 
The patients were divided into three groups according to the type of anesthesia used. In Group I, anesthesia was induced with an IV bolus dose of thiopental 4 mg/kg. In Group II, an IV bolus dose of propofol 2.5 mg/kg was administered. In Group III, total IV anesthesia (TIVA) was used for operations expected to last at least 1 h; an IV bolus dose of propofol 2.5 mg/kg was followed by an IV infusion of propofol at a dose of 4 mg · kg-1 · h-1. Assignment of patients to Group I and II was randomized; assignment to Group III was according to the foreseeable duration of surgery (>1 h). In the period between the induction and the first sample at 5 min, anesthesia was maintained in all cases with an inhaled mixture of N2O:O2 (67%:33%).

Surgical patients received oral premedication with 5 mg of chlorazepate 12 h before and 125 mg of ranitidine 2 h before the operation. After an arm vein was cannulated, physiological saline solution was infused, and 2 µg/kg of fentanyl was given IV. Then anesthetic was induced as described above. Atracurium 0.5 mg/kg was given as a muscle relaxant.

In all groups, blood was collected before thiopental or propofol was administered and 5 min after the induction of anesthesia. In Group III, a third blood sample was obtained 45 min after the first bolus dose of propofol. At each blood sample, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were recorded.

Sodium citrate at 3.8% was used at a proportion of 1:10 as an anticoagulant. Each blood sample was separated into several fractions (apart from the portion reserved as whole blood). PRP was obtained by centrifugation of whole blood at 190g for 10 min at 20°C. RBC from the pellet produced by centrifugation for PRP were washed in 0.1 M of phosphate-buffered saline at a pH value of 7.4 and centrifuged at 1000g for 10 min at 20°C. Leukocytes were obtained by centrifugation of whole blood on a Ficoll gradient (progressive densities 1077 and 1119) and washing in phosphate-buffered saline (pH value of 7.4), followed by centrifugation at 1000g for 15 min at 20°C. After centrifugation, two cellular zones were defined: mononuclear leukocytes (MNL) and PMNL.

Platelet aggregation was measured by the electric impedance method described by Cardinal and Flower (9) with a Chrono-Log 540 aggregometer (Chrono-Log Corp, Haverton, PA) using adenosine diphosphate (ADP), collagen, or arachidonic acid (Menarini Diagnóstica, Barcelona, Spain) to induce platelet aggregation. Maximum intensity of aggregation was quantified as the maximum change in electric impedance 10 min after the inducer was added.

Aggregation was tested in whole blood, PRP, PRP with RBC, and PRP with MNL or PMNL at a proportion similar to that found in cell counts of whole blood (226 ± 48 x 109 platelets/L, 4.3 ± 0.5 x 1012 RBC/L, 6.6 ± 0.8 leukocytes/L, and 63.5% ± 3.2% for PMNL and ± 35.8% for MNL). In these experiments, collagen (2 µg/mL) was used as a standard inducer of platelet aggregation because it is the main component of subendothelium, which activates platelet function in flow conditions into vessels.

TxB2 was measured as the stable metabolite of TxA2. Samples of PRP were stimulated with 2 µg/mL of collagen for 5 min at 37°C, and then 100 µM of indomethacin was added to stop the reaction. The sample was centrifuged at 10,000g for 5 min, and the amount of TxB2 in the supernatant was determined by enzyme immunoassay (Amersham International plc, Little Chalfont, Buckinghamshire, United Kingdom).

6-keto-prostaglandin F1{alpha} (6-keto-PGF1{alpha}) was mea-sured as the stable metabolite of prostacyclin. Samples leukocytes (MNL + PMNL, 7.01 ± 0.4 x 109 leukocytes/L) were stimulated with 1 µM of calcium ionophore A 23187 for 3 min at 37°C, and then 100 µM of indomethacin was added to stop the reaction. The sample was centrifuged at 10,000g, and the amount of 6-keto-PGF1{alpha} in the supernatant was determined with an enzyme immunoassay (Amersham International).

To determine plasma nitrite + nitrate concentration (NOx), platelet-depleted plasma was obtained by centrifuging a sample of whole blood with sodium citrate as the anticoagulant at 2000g for 15 min. Samples of plasma were filtered through Ultrafree-MC microcentrifuge filters (Millipore, Gif-sur-Yvette, France) to remove hemoglobin from cell lysis. The nitrate:nitrite ratio was determined with a commercial kit (Cayman Chemical, Ann Arbor, MI) based on the Griess reaction after nitrates were converted to nitrites via nitrate reductase. The NOx content was spectrophotometrically measured at 540 nm and compared against a standard curve prepared with sodium nitrite.

All data are reported as the mean ± SE of the mean (SEM). The results were subjected to analysis of variance with the Bonferroni post hoc test. Linear correlations were also calculated. All data were processed with the Statistical Package for the Social Sciences, version 10.0 for Windows (SPSS, Chicago, IL). A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The administration of a bolus dose of sodium thiopental (4 mg/kg) did not significantly modify any of the biochemical or functional variables (Table 2).


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  		Table 2. Variables Determined in Patients Treated with a Bolus of Sodium Thiopental (4 mg/kg IV) or Propofol (2.5 mg/kg IV)
 
The administration of a single bolus dose of propofol (2.5 mg/kg) significantly inhibited the maximum intensity of platelet aggregation induced by collagen or arachidonic acid in whole blood. The effect was much smaller when ADP was used to induce aggregation in whole blood (Table 2).

In experiments that studied platelet aggregation induced by collagen in the absence (PRP alone) or in the presence of RBC, and in the presence of MNL or PMNL, a single bolus dose of propofol (2.5 mg/kg) did not modify the maximum intensity of aggregation in PRP alone or PRP + RBC but significantly inhibited aggregation in samples that contained PRP + MNL or PRP + PMNL (Table 2).

After a bolus injection of propofol, platelet production of TxB2 was significantly reduced by 34.4% ± 3.3% in comparison to the preinduction value. The effect on leukocyte 6-keto-PGF1a synthesis (12.6% ± 1.97% inhibition) did not reach statistical significance. However, plasma concentrations of NOx increased significantly by 35% ± 2.9% in comparison to the preinduction value (Table 2).

SBP and DBP were significantly reduced after a bolus dose of propofol (SBP, 24.6% ± 1.5%; DBP, 24.4% ± 1.5%). Heart rate was not significantly affected (Table 2).

After 45 min of propofol infusion (TIVA), the values of all variables studied were increased (Figs. 1–3). Moreover, there was a significant effect on ADP-induced platelet aggregation in whole blood, platelet aggregation in samples with PRP + RBC, in the plasma levels of NOx, and in heart rate.



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  		Figure 1. Maximum intensity (Imax) of platelet aggregation in whole blood induced by adenosine diphosphate (ADP), collagen, or arachidonic acid, and Imax of platelet aggregation induced by 2 µg/mL of collagen in platelet-rich plasma (PRP), PRP plus red blood cells (RBC), PRP plus mononuclear leukocytes (MNL), or PRP plus polymorphonuclear leukocytes (PMNL) before (preinduction) or 45 min after (postinduction) the administration of an IV infusion (4 mg · kg-1 · h-1) of propofol (n = 20). *P < 0.05 with respect to the preinduction value.

 


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  		Figure 2. Platelet thromboxane B2 (TxB2) production induced by 2 µg/mL collagen, leukocyte 6-keto-prostaglandin F1{alpha} (6-keto-PGF1{alpha}) production induced by 1 µM of calcium ionophore A 23187, and plasma levels of nitrites + nitrates (NO-2 + NO-3) before (preinduction) or 45 min after (postinduction) the administration of an IV infusion (4 mg · kg-1 · h-1) of propofol (n = 20). *P < 0.05 with respect to the preinduction value.

 


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  		Figure 3. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate before (preinduction) or 45 min after (postinduction) the administration of an IV infusion (4 mg · kg-1 · h-1) of propofol (n = 20). *P < 0.05 with respect to the preinduction value.

 
When the results for all patients were considered globally, a significant linear correlation between plasma levels of NOx and both SBP and DBP was found (Fig. 4).



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  		Figure 4. Linear correlations between plasma levels of nitrites + nitrates (NO-2 + NO-3) and systolic blood pressure (SBP) (upper panel) or diastolic blood pressure (DBP) (lower panel) in all patients who were receiving propofol.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In general, propofol inhibited platelet aggregation in whole blood from surgical patients who were given the anesthetic IV. That the effects were caused by propofol is further supported by the fact that the administration of sodium thiopental did not modify platelet function at any time. Our results were thus attributable to propofol and not to any other factor related to surgery or pharmacological treatment in these patients.

These findings confirm earlier results from in vitro studies (2,4) that showed that propofol inhibited platelet aggregation in a concentration-dependent manner. In experiments using samples of whole blood, propofol inhibited platelet activation. However, no such effect was seen in PRP. A similar study by Türkan et al. (10) used PRP and reported no antiplatelet aggregant effect of propofol in patients for whom this anesthetic was used.

The results of our analyses with whole blood show that when aggregation was induced with collagen or arachidonic acid, the effect was more than with ADP. The results of the present study show that the induction of aggregation with ADP in whole blood is not significantly inhibited by propofol. This is probably because of the larger concentrations of propofol required in vitro to demonstrated this effect in ADP-induced aggregation, which is not reached after an IV bolus of propofol in patients. In other words, aside from its other possible effects, propofol seems to act on the platelet cyclooxygenase pathway. In this connection, propofol indeed inhibited platelet TxB2 production. Moreover, earlier in vitro studies showed a significant linear correlation between the degree of inhibition of platelet aggregation induced by arachidonic acid and the percent inhibition of TxB2 synthesis (2). This finding is evidence that propofol inhibits the platelet arachidonic acid pathway.

In general, the antiplatelet effect of propofol was enhanced in the presence of leukocytes (both MNL and PMNL); in proportional terms, the greatest effect was that exerted by neutrophils. Only RBC seemed to potentiate the effect of propofol in TIVA but not when the anesthetic was given as a single bolus injection. In addition, a bolus injection of sodium thiopental did not significantly modify platelet aggregation under any of the conditions we studied.

The fact that the greatest effects were seen in samples that contained neutrophils points to an important role for NO in the relationship between propofol and the leukocyte-platelet interaction (3). However, we cannot eliminate the participation of monocytes, which may exert their effect through prostaglandin synthesis (11). The inhibitory effect of propofol on prostacyclin was weaker than its inhibition of Tx production. This may reflect the inhibition by propofol of the Tx synthase enzyme or the fact that propofol behaves like a small dose of aspirin, i.e., it tends to inhibit Tx synthesis to a greater extent than prostacyclin synthesis (12). This latter explanation is supported by the similarity in chemical structure between these two compounds.

With regard to the enhanced NO production, our results corroborate the earlier findings of in vitro experiments (2). Studies about the production of NO in leukocytes and its relation to platelet-leukocyte interactions are performed in in vitro and ex vivo conditions; however, these mechanisms might play a role in vivo, as demonstrated by several authors (13–15). This effect, along with the inhibition of Tx synthesis, may account for the antiaggregant effect of propofol in whole blood. At first, it seems logical that the propofol-induced increase in NO production should have repercussions on functional variables in the patient. One possible hypothesis to account for such repercussions is the relationship between NO production and blood pressure, both of which are altered by propofol.

When we searched for possible linear correlations between blood pressure and the biochemical variables that propofol influenced, these changes in both SBP and DBP significantly correlated with changes in the plasma concentration of NOx. The more propofol increased NO production, the larger the reduction in blood pressure in our surgical patients. In this connection, Petros et al. (1) showed that propofol increased cGMP concentrations in cultures of endothelial cells, and this effect was inhibited by NO synthesis inhibitors. From a functional standpoint, part of the vasodilating effect of propofol may be mediated by endothelial NO production (16–18). However, the vasodilation produced by propofol seems to involve multiple factors including, in addition to a possible effect via NO, blockage of the calcium entry pathway to the interior of the smooth muscle fibers (19–21).

In an earlier study of surgical patients who received propofol (5), the drug decreased the production of lipid peroxides, i.e., free radicals. These radicals are one of the main reactants of NO with which they form peroxynitrites compounds with neither vasodilating nor antiplatelet aggregant effects (22). If propofol is an antioxidant molecule, it would be expected to prevent free radicals from reacting with NO, thus increasing the half-life of the vasodilating mediator.

In conclusion, our findings confirm the antiplatelet action of propofol when the anesthetic is given at doses habitually used in clinical practice for surgical patients. The results are further evidence of the importance of NO in this effect. These effects do not support the conclusion of a high risk of bleeding, as demonstrated by Aoki et al. (23) who described a lack of change in bleeding time; however, a possible association with other drugs that affect platelet function, such as nonsteroidal antiinflammatory drugs and Antithrombotics (heparin, small dose aspirin, or clopidogrel), could increase the bleeding risk.


   Acknowledgments
 
We thank Antonio Pino Blanes for his excellent technical assistance and K. Shashok for translating significant parts of the manuscript into English.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  19. Robinson FP, Ebert TJ, O‘Brien TJ, et al. Mechanisms whereby propofol mediates peripheral vasodilation in humans: sympathoinhibition or direct vascular relaxation? Anesthesiology 1997; 86: 64–72.[Web of Science][Medline]
  20. Xuan YT, Glass P. Propofol regulation of calcium entry pathway in cultured A10 and rat aortic smooth muscle cells. Br J Pharmacol 1996; 117: 5–12.[Web of Science][Medline]
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Accepted for publication November 15, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press