Ann Thorac Surg 2002;74:390-393
© 2002 The Society of Thoracic Surgeons
Original article: cardiovascular
Is the kaolin or celite activated clotting time affected by tranexamic acid?
J.F. Matthias Bechtel, MDa,
Joachim Prosch, CTPa,
Hans-Hinrich Sievers, MDa,
Claus Bartels, MD*a
a Department of Cardiac Surgery, University Hospital of Luebeck, Luebeck, Germany
Accepted for publication April 30, 2002.
* Address reprint requests to Dr Bartels, Klinik für Herzchirurgie, Universitaetsklinikum Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany
e-mail: bartels{at}medinf.mu-luebeck.de
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Abstract
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Background. During cardiopulmonary bypass, the activated clotting time is frequently used for determination of anticoagulation, and either Celite or kaolin are used as activators. If aprotinin is administered concomitantly, the Celite activated clotting time (C-ACT) becomes significantly higher than the kaolin activated clotting time (K-ACT). Therefore, insufficient anticoagulation using C-ACT in the presence of aprotinin is a major concern. Whether the application of tranexamic acid (TA), a pharmacologic alternative to aprotinin, has similar effects has not been studied before.
Methods. An in vitro study using the blood of healthy volunteers was performed. Both C-ACT and K-ACT were measured at baseline, after adding TA, and after adding TA and heparin. In addition, 30 patients undergoing primary cardiac operations had simultaneous measurements of C-ACT and K-ACT after skin-incision, 5 minutes after the application of heparin and TA, every 30 minutes during cardiopulmonary bypass, and 10 minutes after the application of protamine.
Results. In vitro, C-ACT and K-ACT correlated significantly at each measurement. Tranexamic acid had no influence on the activated clotting time. In vivo, C-ACT and K-ACT did not differ significantly, but at each time C-ACT tended to be greater than K-ACT (p = 0.086). The average difference between K-ACT and C-ACT was stable before and after the application of TA (p = 0.85) but the variability of the differences significantly increased during cardiopulmonary bypass (p < 0.001).
Conclusions. Application of TA does not seem to differentially affect the mean C-ACT and K-ACT. No recommendation seems warranted to prefer one activator over the other in patients receiving TA.
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Introduction
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The application of the antifibrinolytic drug tranexamic acid is emerging as an alternative pharmacologic strategy for reducing perioperative blood loss and the need for allogenic transfusions in cardiac operations. Potential advantages of using tranexamic acid include that it is synthetic, has a low allergic potential [1], and is cheaper than but seems to be equally effective as aprotinin [2–5].
Aprotinin is a naturally occurring serine protease inhibitor derived from bovine lung. Besides being antifibrinolytic, aprotinin has antiinflammatory and even mild anticoagulatory and antithrombotic properties [6, 7]. It therefore influences various clotting tests. Notably, the routinely used kaolin activated clotting time (K-ACT) and the Celite (Hemochrom 401; International Technidyne, Edison, NJ) activated clotting time (C-ACT) are differentially affected by the application of aprotinin: the C-ACT becomes significantly higher than the K-ACT [8]. Most likely, the anticoagulatory effect of aprotinin [9] cannot be measured using the K-ACT because kaolin tightly binds to and inactivates aprotinin within the test tube [10]. However, others found evidence that the C-ACT is artificially prolonged [11]. The manufacturer of aprotinin recommends measuring the activated clotting time (ACT) with kaolin to avoid inadequate heparinization. Whether tranexamic acid affects the ACT appears not to have been studied systematically. We therefore studied the effect of tranexamic acid on the ACT as measured with different activators.
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Patients and methods
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In vitro study
Six healthy volunteers who did not take any anticoagulatory medications consented to participate in an ex vivo study. Each volunteer donated three blood samples of 5 mL each. C-ACT (Hemochrom 401; International Technidyne) and K-ACT (HemoTec; Medtronic, Englewood, CO) were measured using the first blood sample. The second blood sample was mixed with 500 mg of tranexamic acid (Ugurol; Bayer, Leverkusen, Germany), and C-ACT and K-ACT were then determined. The third blood sample was mixed with 500 mg of tranexamic acid and 1000 IU heparin (Liquemin; Hoffmann-La Roche, Grenzach-Wyhlen, Germany); thereafter C-ACT and K-ACT were measured.
In vivo study
Thirty patients (20 men, 10 women; mean age, 66 ± 13 years) undergoing primary cardiac operations were studied after informed consent was obtained. All patients had normal results for international normalized ratio, partial thromboplastin time, and anti-thrombine III, but no further testing for clotting abnormalities was performed. A broad variety of cardiac surgical procedures was performed (isolated coronary artery bypass grafting, n = 23 [77%]; coronary artery bypass grafting plus aortic valve replacement, n = 3 [10%]; isolated aortic valve replacement, n = 3 [10%]; and pulmonary valve replacement, n = 1 [3%]). Duration of cardiopulmonary bypass was slightly skewed to the right (median, 97 minutes; range, 47 to 256 minutes) as was the lowest rectal temperature during cardiopulmonary bypass (median, 30.2°C; range, 24.3° to 32.9°C). The lowest hematocrit and the lowest hemoglobin measured 24.2% ± 3.5% and 7.9 ± 1.1 g/dL, respectively.
Anticoagulation with heparin consisted of a bolus dose of 400 IE/kg body weight. The K-ACT was aimed to be more than 400 seconds, and additional heparin was given, if indicated. After heparin administration, tranexamic acid was given as a bolus of 0.01 g/kg body-weight followed by a continuous infusion of 2 g of tranexamic acid at a rate of 0.001 g/kg body-weight per hour. Celite ACT and K-ACT were measured after skin incision, 5 minutes after the application of heparin and tranexamic acid, every 30 minutes until the discontinuation of cardiopulmonary bypass, and 10 minutes after the application of protamine (heparin to protamine ratio, 1:1).
Statistics
Nonparametric correlations were determined using Spearman’s rho. Data obtained from the volunteers were compared pairwise using the Wilcoxon test. To test whether the activator used for measurement of the ACT was of major importance, an analysis of variance was performed with fixed effects for time point of measurement, method of measurement, and patient, and an interaction between time point and method. In addition, the differences within pairs of K-ACT and C-ACT measurements obtained at the same time point were calculated and compared with the baseline difference using paired Student’s t tests. The variability of the measurements was tested by comparing the standard deviations of the differences between C-ACT and K-ACT using the F test. Linear regression analysis was performed to analyze the relation between lowest rectal temperature during cardiopulmonary bypass and ACT. All analyses were performed using SPSS for Windows, release 9.0 [SPSS Inc., Chicago, IL] or Minitab, release 12 [Minitab Inc., State College, PA].
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Results
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In vitro study
Figure 1
shows the result of the C-ACT and K-ACT measurements in healthy volunteers. The correlation between C-ACT and K-ACT was significant at baseline (r = 0.92; p = 0.026), after the application of tranexamic acid (r = 0.87; p = 0.019), and after the application of both tranexamic acid and heparin (r = 0.941; p = 0.005). Neither C-ACT nor K-ACT changed significantly after the application of tranexamic acid (p = 0.69 and 0.92, respectively). After the administration of heparin and tranexamic acid, C-ACT and K-ACT increased significantly (p = 0.028 both).
In vivo study
Measurement of ACT with the two different activators at baseline, at different time points during cardiopulmonary bypass, and after the application of protamine is depicted in Figure 2.
At baseline, the correlation between C-ACT and K-ACT was significant (r = 0.93; p < 0.001) and comparable to the correlations observed in the in vitro study. There was some nonsignificant evidence that at each time the mean C-ACT was greater than the mean K-ACT (p = 0.086; mean difference, 14 seconds; 95% confidence interval, -2 to 36 seconds). There was no evidence that the differences between K-ACT and C-ACT were themselves different at different times (p = 0.85) or that the average difference between K-ACT and C-ACT was affected by the application of tranexamic acid after the baseline measurement. Therefore, tranexamic acid was not found to have a differential effect on either mean C-ACT or K-ACT. However, the variability of the K-ACT and C-ACT measurements was significantly higher during cardiopulmonary bypass (p < 0.001 as compared with baseline) but not thereafter (p = 0.82). In addition, there was significant evidence that the mean ACT increased with decreasing temperature (p = 0.002).
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Comment
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The ACT can be measured with either kaolin or Celite as activators. We found that in the presence of tranexamic acid the activator used for measurement does not significantly influence the mean ACT. In addition, we found some evidence that the mean C-ACT was higher than the mean K-ACT, confirming an earlier study [8].
We also found that during cardiopulmonary bypass the variability of the results of the ACT measurements significantly increased. Therefore, while on average the application of tranexamic acid did not influence C-ACT or K-ACT, C-ACT and K-ACT may differ substantially in an individual patient during cardiopulmonary bypass. It should be noted that the variability of the ACT was not increased after application of protamine while tranexamic acid was still active. Therefore, whether the higher variability of the ACT during cardiopulmonary bypass is related to an unknown interaction of tranexamic acid with heparin or to the known sensitivity of the ACT to hypothermia, hemodilution, and its poor correlation with the heparin concentration [12, 13] cannot be concluded from our study. Our in vitro study provides some evidence that tranexamic acid has no effect on either C-ACT or K-ACT.
Tranexamic acid was developed as a pure antifibrinolytic drug that acts by competitively blocking lysine binding sites on plasminogen [1]. However, several small, unconfirmed studies recently suggested that tranexamic acid may have more complex pharmacologic properties [14–16]. In a study on 60 patients undergoing cardiac operations, an increased rate of thrombin generation in patients receiving tranexamic acid was observed as compared with control patients and patients receiving aprotinin [16]. These newer studies may ultimately challenge our view of tranexamic acid as a pure antifibrinolytic drug. It is in this regard that we decided to perform the reported study despite theoretical considerations that tranexamic acid is not expected to influence clotting tests. To our best knowledge it has not been systematically studied before whether or not tranexamic acid influences the ACT.
A more frequent use of tranexamic acid in cardiac operations can be anticipated because tranexamic acid is nonbovine and its use seems to be more cost-effective than the use of aprotinin [17]. However, tranexamic acid seems to be less well studied than aprotinin. In addition to the aforementioned, the most effective dosing regimen is unknown. No trial comparing the patency rate of coronary artery bypass grafts after tranexamic acid and placebo administration has been performed. On a large scale, no comparative safety and tolerability data between tranexamic acid and other blood-sparing drugs are available.
The HemoTec device used for measurement of the K-ACT uses smaller blood volumes and a different method of activation as compared with the Hemochrom device, which might have influenced our results. We believe that the high correlations between C-ACT and K-ACT observed at baseline provide evidence that both devices provide comparable results in the absence of tranexamic acid. The high variability of the results in the presence of tranexamic acid and heparin during cardiopulmonary bypass is more likely to result from hemodilution, hypothermia, and the poor correlation of the ACT with the heparin concentration, as discussed previously. The high correlation observed in the in vitro study provides some evidence that both devices provide comparable results also in the presence of tranexamic acid (with or without heparin). The sample points of our in vivo study are representative of routine cardiac surgical practice, but we did not measure ACT after tranexamic acid administration followed by another ACT after heparin administration. To overcome this weakness we included an in vitro study that provided no evidence that tranexamic acid itself influenced the ACT. The main limitation, of course, of our study is its size.
In conclusion, we found no evidence that the application of tranexamic acid affected the average C-ACT or K-ACT. If confirmed by other studies, no recommendation seems warranted to prefer one activator over the other in patients receiving tranexamic acid. Our finding that the variability of the ACT measurements during cardiopulmonary bypass is significantly increased corroborates the concern that measurement of the ACT may not be the best test for determination of adequate anticoagulation during cardiopulmonary bypass [18].
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Acknowledgments
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We are indebted to Derek R. Robinson, PhD, Center for Statistics and Stochastic Modeling, School of Mathematical Sciences, University of Sussex, Brighton, UK, for statistical analysis of the patient data, and to the patients and volunteers for participation in the study.
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Top
Abstract
Introduction
) and kaolin activated clotting time (
) at baseline, after the application of tranexamic acid (TA), and after the application of tranexamic acid and heparin to ex vivo blood samples of healthy volunteers. The application of tranexamic acid alone does not significantly change the baseline activated clotting time. Data are mean ± standard deviation.