Anesth Analg 2001;93:1240-1245
© 2001 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Local Anesthetic Actions on Thromboxane-Induced Platelet Aggregation
Bernard Lo, MD*,
Christian W. Hönemann, MD*
,
Rainer Kohrs, MD*,
Markus W. Hollmann, MD*
,
Renate K. Polanowska-Grabowska, PhD
,
Adrian R. L. Gear, PhD, and
Marcel E. Durieux, MD PhD*||
University of Virginia Health System, Departments of *Anesthesiology and Biochemistry & Molecular Genetics, Charlottesville, Virginia; ||Department of Anesthesiology, University Hospital Maastricht, The Netherlands; Department of Anesthesiology, University of Heidelberg, Germany; and Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Münster, Germany
Address correspondence and reprint requests to Christian W. Hönemann, MD, Department of Anesthesiology, Universitätsklinikum Münster, Albert-Schweitzer-Straße 33, 48129 Germany. Address e-mail to honemac{at}uni-muenster.de
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Abstract
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Some local anesthetics (LA), in concentrations present in blood during IV or epidural infusion, inhibit thrombus formation in the postoperative period. Studies on thromboxane A2 (TXA2) signaling in a recombinant model suggest that interference with TXA2-induced platelet aggregation may explain, in part, the antithrombotic actions of epidural analgesia and IV LA infusion. In this study we investigated the effects of clinically used LAs (lidocaine, ropivacaine, and bupivacaine) on TXA2-induced early platelet aggregation (1–5 s) by using quenched-flow and optical aggregometry. Our findings demonstrate that the LAs tested seem to have only a limited ability to inhibit TXA2-induced platelet aggregation assessed at early times (1–5 s). Therefore, the clinical effects of LAs on thrombi formation are unlikely to be explained by this manner alone. At large LA concentrations, moderate effects were obtained. Prolonged incubation with LA did not significantly increase effectiveness, and the lack of an effect could not be explained by generation of secondary mediators. The results were independent of the anesthetic studied. Local anesthetic effects on TXA2-induced early platelet aggregation (1–5 s) are unlikely to play a major role in the clinically observed antithrombotic effects of local anesthetics.
IMPLICATIONS: Local anesthetic effects on thromboxane A2-induced early platelet aggregation (1–5 s) are unlikely to play a major role in the clinically observed antithrombotic effects of local anesthetics. Thus, other potential targets need to be explored.
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Introduction
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The trauma of surgery induces a systemic inflammatory response and an associated hypercoagulable state. The magnitude of both is related to the traumatic insult. After surgery with significant tissue trauma, the combination of this state with postoperative immobilization leads to a frequent incidence of postoperative deep venous thrombosis (PODVT). Although anticoagulants (such as low-molecular-weight heparin) can prevent PODVT effectively, these compounds are not without risk in the postoperative patient, and therapies that would prevent the hypercoagulable state would be preferred. However, the mechanisms underlying the hypercoagulable state are still unclear. Several inflammatory mediators are also potent platelet aggregators, and increased blood levels of such compounds have been determined after surgery. Thromboxane A2 (TXA2) is one of these compounds, and its levels are increased after various types of surgery, such as invasive orthopedic (1), cardiac (2), abdominal (3), vascular (4), or obstetric surgery (5). In addition, TXA2 has been proposed as a mediator of myocardial ischemia and coronary vasoconstriction (6,7), as well as thrombosis (8).
The use of epidural analgesia is associated with a significant reduction in the incidence of PODVT and pulmonary emboli (9–11), and similar reductions are obtained when local anesthetics (LAs) are infused IV (12). We have shown previously that LAs, in concentrations as present in blood during IV or epidural infusion (1–10 µM), inhibit TXA2 signaling in a recombinant model (13). We hypothesized that LA interference with TXA2-induced platelet aggregation may explain, in part, the antithrombotic actions of epidural analgesia and IV LA infusion. Therefore, we studied the effects of several LAs on TXA2-induced platelet aggregation in an in vitro model.
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Methods
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The study protocol was approved by the University of Virginia IRB. Venous blood was obtained by antecubital venipuncture from 10 nonsmoking volunteers who had not ingested a fatty meal for 6–8 h before blood donation or any drugs within 10 days. The anticoagulant acid citrate dextrose (ACD) (6.6 mM glucose, 115 mM trisodium citrate, and 10 mM citric acid) was added in a 10:1 (vol/vol) ratio (apparent citrate concentration 11.5 mM). Platelet-rich plasma (PRP) was prepared by slow-speed centrifugation (2 x 3 min and 1 x 5 min at 350 g) (14). To inhibit endogenous TXA2 production, indomethacin (1 µg/mL) was added. PRP was prepared in plastic tubes, which were capped in an atmosphere of 5% CO2 and 95% air to help preserve pH and platelet quality. The PRP was stored at room temperature until use (within 4 h unless indicated otherwise).
Figure 1A shows the basic principle of the method (14). PRP is placed in one plastic syringe and the agonist (in this case, the metabolically stable TXA2 analog U-46619) in another syringe. A dual-drive syringe pump forces these solutions through 0.8-mm inner diameter Teflon tubing before entering a common reaction tube of 0.25 mm inner diameter, which mimics shear stress forces found in the arterial circulation (10–50 dynes/cm2). Reaction time is determined by tubing length and pump rate, and the reaction is stopped by quenching with glutaraldehyde. Single platelet counts are then evaluated in the effluent by a resistive particle counter.
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Figure 1. (A) Schematic of the quenched-flow system to study platelet aggregation. (B) Concentration-response curves for U-46619 (1 µM)-induced platelet aggregation after 2, 3, 4, and 5 s. The most effective aggregation was obtained after 5 s. The half-maximal effect concentration for the longest time point (5 s) was 8.7 ± 3.9 x 10-7 M. (C) U-46619 (1 µM)-induced platelet aggregation was nearly completely prevented (96% ± 4% of control) by SQ29548 (10 µM, P < 0.05, t-test), a TXA2 antagonist. (D) U-46619-induced platelet aggregation was found to be approximately fivefold more potent than adenosine diphosphate (ADP). U-46619 (1 µM) reduced single platelet count to 37% ± 8% of control; ADP (5 µM) reduced it to 41% ± 6% (n = 3, P < 0.05 at 2 and 3 s, t-test).
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LAs were diluted in Tyrode’s solution (in mM: 150 NaCl, 5 KCl, 1 MgCl2, 16 H2O, 2 CaCl2/H2O, 10 dextrose, 10 HEPES) and added to the PRP at the appropriate concentration and incubated for 10 min (37°C), unless otherwise indicated. The same amount of Tyrode’s solution without anesthetic was added to a control sample. Experiments were performed at 37°C. Quenched-flow aggregometry was used for the majority of experiments, because it detects early platelet aggregation events (<5 s) and mimics conditions in the microcirculation better than optical aggregometry (14).
Optical aggregometry is a widely used method whereby light transmission through PRP is continuously recorded. The aggregometer (Lumi aggregometer; Chronolog Corp., Havertown, PA) used a stirring rate of 1000 rpm at 37°C. Each aliquot contained 400 µL of the platelet suspension with approximately 4 x 105 platelets per microliter. Baseline was monitored for 1–5 min to ensure that baseline was stable. After adding the aggregation-inducing reagent (U-46619; 1 µM), light transmission increased progressively as aggregation began and reached a plateau when aggregation was maximal. Maximum aggregation occurred within 2–3 min. The magnitude of aggregation was assessed by measuring the maximum rate of aggregation (the tangent to the curve measure in millimeters per unit time, reported as slope value). Mean values of samples of control PRP (with buffer solution Tyrode) were compared with those incubated for 30, 60, and 120 min in Tyrode’s solution containing 1, 10, or 100 µM bupivacaine. Platelet count was the same for control and the treatment groups.
U-46619 was obtained from Cayman Chemical (Ann Arbor, MI). Ropivacaine was a kind gift from Astra Pharmaceuticals, L.P. (Westborough, MA), and other chemicals were obtained from Sigma (St. Louis, MO).
Results are reported as mean ± SEM (n = 7, unless otherwise stated). Statistical tests used are indicated in Results. P < 0.05 was considered significant. Concentration-response curves were fit to the following logistic function, derived from the Hill equation: y = ymin + (ymax - ymin) [1- xn/(x50n + xn)], where ymax and ymin are the maximum and minimum response obtained, n is the Hill coefficient, and x50 is the half-maximal effect concentration (EC50 for agonist) or half-inhibitory effect concentration (IC50 for antagonist).
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Results
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U-46619 effectively aggregated platelets as determined by single-particle counting and quenched-flow aggregometry (Fig. 1D). To assess the best time to study aggregation, concentration-response relationships were determined after 2-, 3-, 4-, and 5-s reaction times (Table 1, Fig. 1B). The reaction was very fast, because no appreciable differences in the concentration-response relationship were noted when reaction time was varied between 2 and 5 s. The EC50 determined from the longest time point (5 s) was 8.7 ± 3.9 x 10-7 M (Table 1). On the basis of these experiments, we selected a U-46619 concentration of 1 µM and a reaction duration of 5 s for subsequent studies. U-46619 (1 µM) reduced single platelet count to 34% ± 7% of control. This effect was inhibited nearly completely (96% ± 5% of control, Fig. 1C) by the TXA2-antagonist SQ29549, indicating that the response was indeed caused by TXA2 signaling.
We compared the effectiveness of U-46619 (1 µM) with the aggregating effect of adenosine diphosphate (ADP) (5 µM), an agonist frequently used for platelet aggregation studies. We found U-46619 to be approximately fivefold more potent than ADP (Fig. 1D). U-46619 (1 µM) reduced single platelet count to 37% ± 8% of control; ADP (5 µM) reduced it to 41% ± 6% (n = 3).
After confirming that Tyrode’s solution did not induce platelet aggregation by itself (Fig. 2A), we tested the effects of lidocaine, bupivacaine, and ropivacaine on platelet aggregation. All three anesthetics inhibited U-46619-induced platelet aggregation in a concentration-dependent manner. However, the concentrations required were 5- to 10-fold higher than those found to inhibit TXA2 signaling in our previous study (13) (Fig. 2B–D).
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Figure 2. (A) Tyrode’s solution did not induce platelet aggregation. (B–D) All three local anesthetics inhibited U-46619 (1 µM)-induced platelet aggregation in a concentration-dependent manner. Lidocaine (B) inhibited platelet aggregation at 10-1 (P < 0.05 at 2, 3, 4, and 5 s, t-test) and 10-2 M and ropivacaine (C) at 10-3 (P < 0.05 at 3 and 4 s, t-test) and 10-4 M, whereas bupivacaine (D) was more potent then the two other local anesthetics, inhibiting platelet aggregation at concentrations of 10-3 (P < 0.05 at 2, 3, 4, and 5 s, t-test), 10-4 (P < 0.05 at 3, 4, and 5 s, t-test), and 10-5 M.
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We have shown previously that prolonged exposure of TXA2 receptors to LAs increases sensitivity to the compounds (15). Because prolonged exposure might also mimic the clinical situation of epidural analgesia more closely, we studied the effect of 4 h incubation in 1 µM bupivacaine or in 1 µM ropivacaine on TXA2-induced platelet aggregation; the effect of both compounds was not time dependent (Fig. 3, A and B).
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Figure 3. (A and B) The effect of 4 h incubation in 1 µM bupivacaine (A) or ropivacaine (B) on 1 µM U-46619-induced platelet aggregation. The effect of the compounds was not significantly time dependent: even after 4 h incubation, only minor effects on platelet aggregation were observed.
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Platelet aggregation can be associated with the release of intracellular platelet granule contents (containing ADP, serotonin, nitric oxide, and other factors), and this may amplify platelet aggregation (16). If so, even significant inhibition by LAs of TXA2 signaling might have little effect on aggregation, because the effect may be overwhelmed by subsequent secondary mediator release. To test this hypothesis, we investigated how much of the effect of U-46619 is caused by secondary mediator release. We incubated platelets for 10 min in 1 µM U-46619 and then removed platelets by centrifugation. The supernatant (which would contain secreted mediators), mixed with excess SQ29549 to block any effect of remaining U-46619, was then used as agonist for a subsequent aggregation study. The supernatant had little aggregating ability (Fig. 4A). Thus, induced release of secondary mediators does not play an important role in this aggregation model, and the lack of LA effect cannot be explained on the basis of massive release of secondary mediators.
Finally, the duration of agonist exposure in quenched flow aggregometry (5 s) was much shorter than that in our previous study (1 min). Although we demonstrated (as shown previously) that the effect of U-46619 was very rapid, it is conceivable that the difference in exposure time might influence the result. Therefore, we determined the effect of three different concentrations of bupivacaine (1, 10, and 100 µM) on U-46619 (1 µM)-induced platelet aggregation in an optical aggregometer, where platelets can be exposed to agonist for minutes. The results were very similar to those obtained with quenched-flow aggregometry: only bupivacaine concentrations 
100 µM and incubation times 60 min significantly (P < 0.05, one-way analysis of variance with Bonferroni’s correction) reduced the U-46619-induced increase in light transmission corresponding to an impaired platelet aggregation (Fig. 4 B, Table 2). Therefore, concentrations of bupivacaine that produced TXA2 signaling blockade in our previous study (13) did not induce significant inhibition of early platelet aggregation in this model.
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Discussion
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Our findings demonstrate that the clinically used LAs lidocaine, ropivacaine, and bupivacaine seem to have only a limited ability to inhibit TXA2-induced platelet aggregation assessed at early times. The results were independent of the anesthetic studied, and even at large concentrations only modest effects were obtained. Prolonged incubation with the LA did not increase effectiveness, and the lack of effect could not be explained by generation of secondary mediators. Similar results were obtained with a different model of aggregation (optical aggregometry). Therefore, clinically relevant LA concentrations on TXA2-induced early platelet aggregation are unlikely to play a major role in the clinically observed antithrombotic effects of LA.
We studied the effects of LAs on TXA2-mediated platelet aggregation because TXA2 has been implicated in the hypercoagulable state that develops after various types of surgery and because we previously observed significant inhibition of TXA2 receptor function by clinically relevant concentrations of LAs in several cell models (13).
Thromboembolic complications are common after surgery and seem to result from hypercoagulation and hypoperfusion (the latter often induced by vasoconstriction). After major orthopedic or urologic surgery, PODVT occurs in 30%–80% of patients (12,17). Similarly, myocardial ischemia induced by microthrombosis, coronary vasoconstriction, or both is frequent (18,19). The mechanisms for these adverse events are poorly understood, but inflammatory mediators—released in response to surgical trauma and inducing thrombosis and vasoconstriction—are likely to be pivotal. TXA2 is a potent platelet aggregator and vasoconstrictor. It is one of the major mediators released during orthopedic (1), cardiac (2), abdominal (3), vascular (4), or obstetric surgery (5). TXA2 has been proposed as a mediator of myocardial ischemia and coronary vasoconstriction (6,7), as well as thrombosis (8). Thus, TXA2 is likely to play an important role in perioperative thrombosis, and the beneficial actions of epidural (10,11,20) and IV (12) LAs on postoperative hypercoagulation could be explained by interference with TXA2 signaling.
We previously expressed human TXA2 receptors in Xenopus oocytes and studied LA effects on Ca-activated Cl currents induced by U-46619 (13,15). Bupivacaine, at micromolar concentrations, blocked TXA2 signaling effectively. Lidocaine was significantly less potent. We obtained similar results in K562 cells, a human erythroid leukemia tumor line that endogenously expresses TXA2 receptors (13). We measured intracellular Ca release by fluorometry and observed inhibition by bupivacaine, lidocaine, and ropivacaine. Because we found similar effects both in a recombinant system and a native system, we proceeded with this study and evaluated the effects of LAs on TXA2-mediated platelet aggregation.
We chose the quenched-flow model of platelet aggregation for several reasons (14,21). First, it mimics the conditions within the vasculature much more closely than do other aggregation systems. In particular, shear stress is very important for platelet behavior and is usually close to zero in other platelet aggregation models. In the quenched-flow system, however, it is maintained at relevant values throughout the activation process (14). Second, quenched-flow aggregometry allows one to study early platelet aggregation (within 1–5 s), because reaction times are precisely controlled. TXA2 is an early activator in aggregation (16,22), and we therefore wished to determine LA effects on its action during the first several seconds of aggregation. However, because significant effects of the LAs were observed at large concentrations only, we repeated some of our experiments in a more conventional transmission aggregometry system and obtained similar results. These results are in contrast to earlier studies that used thromboelastography and activated clotting time (23). In this study, bupivacaine inhibited platelet aggregation in both models at clinically relevant concentrations. The difference in results between our previous and present studies are unlikely to be explained by differences in TXA2 receptor types. Despite the fact that the recombinant TXA2 receptors used in Xenopus oocytes were from the rat, in all other instances human receptors were used. However, there is only a single TXA2 receptor subtype in humans, and there are only minor differences between rat and human TXA2 receptors.
Because in all models studied, LAs and agonists were applied to cells in solution, it is unlikely that access to the cells explains the different results. However, in contrast to the oocytes and K562 cells (which were studied in electrolyte solutions), platelets were studied in serum. LA binding to 
1-acid glycoprotein may therefore explain part of the different results. This is particularly true for highly protein-bound compounds such as bupivacaine. Lidocaine is less protein bound but was also much less potent in our previous studies. Therefore, even a modest decrease in availability would have caused concentrations required for inhibition to be outside the range studied. To test this hypothesis, a study of LA effects on platelet aggregation in a solution with known free drug concentrations would be required. A second potential explanation for the difference in results is the complexity of the pathway studied. In both oocytes and K562 cells, our end point was intracellular Ca release (determined as Ca-activated Cl current in oocytes and fluorescence changes in K562 cells). This event happens proximal in the signaling pathway. The cellular changes leading to platelet aggregation are much more complex, and it is conceivable that amplification steps within the aggregation pathway obscure a modest effect of LAs. To test this hypothesis, the effects of LAs on intracellular Ca release in TXA2 activated platelets will be required.
Whatever the mechanism, it seems unlikely that the clinically observed antithrombotic effects of clinically relevant concentrations of LAs can be explained by interference with TXA2 induced platelet aggregation, and other potential targets need to be explored.
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Acknowledgments
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This work was supported by "Ben Covino Award 1998" of the International Anaesthesia Research Society sponsored by Astra Pain Control, Inc. (CWH) and in part by National Institute of Health Grant GMS 52387 (MED), Bethesda, MD, and an American Heart Association grant (Mid-Atlantic Affiliation) VHA 9920345 U (MWH), Baltimore, MD. Dr. Hönemann is supported by Innovative Medizinische Forschung Grant IMF I-6-II/96-8 and IMF I-6-II/97-27, Münster, Germany, and in part by the Carman Trust, Richmond VA (ARLG). Dr. Hollmann is supported in part by a grant of the German Research Society (DFG HO 2199/1-1), Bonn, Germany.
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Footnotes
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Presented in part at the 4th Congress on Eicosanoids and Bioactive Lipids in Cancer, Inflammation and Radiation Injury, San Diego, CA, 1997 (meeting report published in Advances in Medicine and Biological Research 1999;469:269–76) and at the annual meeting of the American Society of Anesthesiologists in Orlando, FL, October, 1998.
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Accepted for publication June 6, 2001.
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Abstract
Introduction
