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J Thorac Cardiovasc Surg 1994;108:1083-1091
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Linz, Austria, and Berne, Switzerland
Received for publication Feb. 9, 1994. Accepted for publication May 25, 1994. Address for reprints: Barbara Blauhut, MD, Blutspendedienst des Roten Kreuzes für Oberösterreich, Krankenhausstrasse 9, A-4020 Linz, Austria.
Abstract
Aprotinin reduces blood loss after cardiopulmonary bypass, but may sensitize recipients and is expensive. Tranexamic acid, a synthetic antifibrinolytic, has less disadvantages, but opinions differ regarding its efficacy. We studied three groups of patients undergoing cardiopulmonary bypass for coronary disease: recipients of aprotinin (total dose 4.2 x 106kallikreininhibiting units, n= 14), recipients of tranexamic acid (total dose 20 mg/kg body weight, n= 15), and nonmedicated controls (n= 14) during 24 hours after cardiopulmonary bypass. Compared with controls, aprotinin reduced blood loss, the number of patients requiring transfusions, and the mean number of transfused red cell units (all with p< 0.05), whereas the recipients of tranexamic acid did not differ either from aprotinin recipients or from controls. Aprotinin and tranexamic acid both mitigated the early postoperative reduction of adenosine diphosphate–induced platelet aggregation seen in the controls (p< 0.05). Postoperative increases of plasma concentrations of the prothrombin activation fragment F1+2and the thrombin-antithrombin III complex showed an activation of intravascular coagulation, without any intergroup differences. The balance between concentrations of tissue plasminogen activator and the type 1 plasminogen activator inhibitor disclosed an activation of fibrinolysis, without differences between the groups. The concentrations of D-dimer, a breakdown product of cross-linked fibrin, remained at baseline in the recipients of aprotinin and tranexamic acid but tripled in the controls (p< 0.05). By contrast, the plasma antiplasmin activity was equally depressed in the tranexamic acid and the control groups but decreased less in the recipients of aprotinin (p< 0.05). This discrepancy may reflect the different modes of action of the two agents, which may make aprotinin more efficacious than tranexamic acid in the "nonfibrinolytic" act of protecting platelet function against attack by plasmin during cardiopulmonary bypass. (J THORACCARDIOVASCSURG1994;108:1083-91)
With few exceptions, 
1-4 the significant reduction of blood loss and needs for homologous red cell transfusions brought about by aprotinin after coronary bypass procedures 5 has now been confirmed by numerous studies. 6-12 Aprotinin is a broad-spectrum antiprotease isolated from bovine tissues and has a molecular weight of approximately 6500 d. Anaphylactic reactions possibly associated with an activation of the complement system are rare (<1%) in patients on first-time exposure. 6,8,13,14 Subsequent exposures may, however, cause severe incidents in 5% to 6% of patients undergoing surgery of the thoracic aorta. 15 In many centers, the cost of aprotinin moreover restricts its use to patients at particularly high risks of postoperative bleeding, which means that most patients are denied the potential benefits of a reduced exposure to homologous transfusions. For these reasons, other agents capable of decreasing blood loss and transfusion requirements after cardiopulmonary bypass (CPB) continue to be of interest.
One group of such agents includes the synthetic, low-molecular antifibrinolytic drugs, which seem to carry less risk of sensitization, 16 and which are much less expensive thanaprotinin. The first of these compounds was 
-aminocaproic acid (EACA), which was tested without 17 or with effect (usually modest) 18-20 in patients undergoing CPB. Its successor tranexamic acid (AMCA; trans-4-(aminomethyl)-cyclohexane-carbonic acid) is 5 to 10 times more potent than EACA. 16 However, positive reports 21-23 aswell as negative findings 24 relative to nonmedicated controls have been published. In one study comparing aprotinin and -aminocaproic acid, both agents were equally effective, 25 but the study did not include a nonmedicated control group. We therefore undertook a comparison of the effects of aprotinin, tranexamic acid, and no treatment on blood loss and related variables during the first 24 hours after CPB.
PATIENTS AND METHODS
The study protocol was approved by the institutional ethics committee, and informed consent of participants was obtained. Criteria for nonadmission to the study were intake of aspirin, other nonsteroidal antirheumatics, or beta-lactam antibiotics; treatment with heparin, fibrinolytic agents, or oral anticoagulants; a condition requiring emergency surgery or reoperation; and liver or kidney disease. Forty-five patients (37 male and 8 female) were allocated at random to three treatment groups intended to comprise 15 patients each: aprotinin (n = 15; two female), tranexamic acid (n = 16; three female) and nonmedicated controls (n = 14; three female). One male patient each in the aprotinin and the tranexamic acid groups was subsequently excluded because of postoperative bleeding of surgical origin necessitating immediate revision. All patients were cared for by the same team, and no other differences existed in their management, which, as a basic principle, was open and determined by the clinical condition of the individual patients. 8 The only therapeutic decision directly pertinent to the study— whether to transfuse homologous red cells—was based on a hematocrit value of less than 30% versus 30% or greater determined after 1 hour in the recovery area of the intensive care unit.
CPB.
The details of premedication, anesthesia, and CPB including cardioplegia as well as administration of heparin and its neutralization with protamine were as previously specified, 8 except that a Bard HF-5000 membrane oxygenator (Bard Inc, Billeria, Mass.) with a priming volume of 560 ml was used in the present study.
Aprotinin (Trasylol; Bayer AG, Leverkusen, Germany) was administered as recommended by Royston and associates, 5 that is a loading dose of 2 x 10 6 kallikrein inhibiting units (KIU) plus a maintenance dose of 0.5 x 10 6 KIU/hr until the patient was transferred to the recovery area of the intensive care unit. In addition, 10 6 KIU was added to the oxygenator priming fluid, giving an average total dose of 4.2 x 10 6 KIU as previously reported. 8
Tranexamic acid (Cyklokapron; Kabi AB, Stockholm, Sweden) was administered intravenously at a dose of 10 mg/kg body weight, beginning 30 minutes before incision of the skin and followed by 1 mg/kg per hour for 10 hours after the beginning of the surgical procedures. 21,22 Measurements of samples for the study were obtained at four times: 1 = baseline, immediately after induction of anesthesia; 2 = end of bypass, before administration of protamine; 3 = 1 hour after the patient's transfer to the intensive care unit; and 4 = next morning in the intensive care unit (approximately 7 AM). Blood loss was quantitated by the volume of drainage fluid accumulating during the first 24 postoperative hours.
Laboratory methods.
We specify only those methods that are not routine in every clinical chemistry or hematology laboratory. Reference ranges (mean ± 2 standard deviations) in percentage of standard (100%) or as direct units of measurement are given in parentheses and are those stated by the manufacturers of the equipment or test reagents used. Platelet aggregation induced by adenosine diphosphate (ADP) 26 was measured with Cluster ADP reagent (Baxter Healthcare Corp., Dade Division, Miami, Fla.) in a final ADP test concentration of 2 µmol/L. The change of the transmission of light in percentage of the attainable maximum was read with an Aggrecorder II PA 3220 aggregometer (DIC, Kyoto, Japan). The normal range is 77% to 94%. Fibrinogen (1 to 4 gm/L) was measured according to Clauss. 27 Factor V (70% to 130%) was assayed with a thromboplastin reagent (Thromborel; Behringwerke, Marburg, Germany) and factor V–deficient plasma. Chromogenic peptide substrates and test specifications from Kabi AB, Mölndal, Sweden, were used for the following assays: factor VII (CPS S-2765; 80% to 130%); factor VIII:c (S-2222; 50% to 120%); factor X (S-2337; 60% to 120%); antithrombin III (S-2238; 80% to 120%); Protein C (S-2366; 70% to 140%); plasminogen (S-2251; 75% to 125%), and antiplasmin (S-2251; 80% to 120%). Enzyme-linked immunosorbent assay (ELISA) methods (Asserachrom) from Boehringer, Mannheim, Germany were used to measure von Willebrand Factor–related antigen (60% to 150%), factor IX antigen (60% to 150%), and D-dimers (<500 ng/ml). Similarly, ELISA methods (Enzygnost) from Behringwerke were used for the assays of prothrombin activation fragment ("F1+2micro", 0.4 to 1.1 nmol/L) and the thrombin-antithrombin III complex ("TAT micro", 1 to 4.1µg/L). Finally, ELISA kits (Coaliza) from Chromogenix/ Kabi were used to measure tissue plasminogen activator (tPA) (1 to 12 ng/ml) and the type 1 plasminogen activator inhibitor (10 to 70 ng/ml).
Statistical analysis.
Differences among the three patient groups with respect to patient characteristics, time on bypass, intervals between measurements and drainage losses, as well as transfusion requirements, were assessed by analysis of variance, with the use of Duncan's multiple range statistic to determine significant differences. A repeated-measures multivariate analysis of variance procedure was used to screen for differences of other parameters between groups and sampling time points, as well as interactions. Differences between groups at specific times were then inspected by a one-way analysis of variance with Duncan's multiple range test. For some variables, the statistical analysis was performed with nonparametric statistic procedures; differences between individual groups were then determined with the Mann-Whitney U test. For those variables where means were calculated, means ± standard error of the mean (SEM) are provided in the text. In all cases, a two-tailed p < 0.05 is considered significant.
RESULTS
Patient characteristics.
The patient characteristics and the intervals between the measuring or sampling points 1, 2, 3, and 4 are specified in Table I. No differences in patient characteristics were found among the three treatment groups.
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Blood loss, hematocrit levels, and red cell transfusions.
The drainage losses during the first 24 postoperative hours are depicted in Fig. 1. Analysis of variance showed significant differences between the groups (p = 0.03). Drainage in the aprotinin recipients (269 ± 38 ml) and the control group (453 ± 52 ml) was significantly different (p < 0.05 by Duncan's range test), whereas the tranexamic acid group (403 ± 52 ml) was not significantly different from either the aprotinin group or the nonmedicated controls.
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The indication for red cell transfusions during the first 24 hours after surgical procedures was a hematocrit level of less than 30% at time point 3, that is, after 1 hour in the intensive care unit. By this criterion, 19 of 43 (44%) of the patients with a mean hematocrit level of 28.5% ± 0.5% (standard error of the mean) received 1 or more red cell units. The remaining 24 patients with a mean hematocrit level of 33.8% ± 0.5% were not transfused. The proportions of patients with versus those without transfusions in the three treatment groups during the period of study were 3 versus 11 aprotinin recipients, 7 versus 8 recipients of tranexamic acid, and 9 versus 5 in the control group. These proportions differed significantly with p = 0.024. Expressed differently, the three groups required statistically different, mean numbers of red cell units to be transfused within 24 hours of surgical procedures (analysis of variance, p = 0.026). The means of the aprotinin and the control groups (0.36 ± 0.20 and 1.57 ± 0.40 red cell units, respectively) differed with p < 0.05 by Duncan's range test, whereas the tranexamic acid group, with 0.80 ± 0.28 red cell units, did not differ from either aprotinin recipients or controls. The numbers of patients requiring between 0 and 4 red cell units are summarized in Table II.
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Table II, the distributions of patients in the aprotinin and the control groups differ with p = 0.015 by the Mann-Whitney U test, whereas the recipients of tranexamic acid can not be distinguished from either of the other groups. From Table II, it is also seen that the total numbers of transfused red cell units were 5, 12, and 22, respectively, in the groups receiving aprotinin, tranexamic acid, and no medication. In addition to 3 and 4 red cell units, respectively, two control patients required one pooled, 6-donor platelet concentrate each. The mean hematocrit levels of the treatment groups at the four measurement points are shown in Table III.
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Table IV.
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Plasmatic coagulation system.
The overall averages of fibrinogen levels in grams per liter at the time points 1, 2, 3, and 4 were, respectively, 3.29 ± 0.12 (SEM), 1.90 ± 0.08, 2.39 ± 0.12, and 3.36 ± 0.12 (i.e., within the normal range of 1 to 4 gm/L). Similarly, the mean activities of the von Willebrand factor were 106% ± 9%, 72% ± 5%, 107% ± 7%, and 168% ± 10% of standard (i.e., they remained within the reference range (60% to 150%). Factor V, VII, VIIIc, IX, and X were not depleted to a critical degree after CPB (data not shown), and none of these variables differed significantly between the three treatment groups. The variables reflecting activation and inhibition of intravascular coagulation are shown in Table V.
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Table V differed between treatments.
Fibrinolytic system.
The data reflecting tissue-derived activation and inhibition of the fibrinolytic system are summarized in Table VI. At the end of CPB and after 1 hour in the intensive care unit (time points 2 and 3), the activity increase of the activator tPA and the simultaneous activity decrease of the type 1 plasminogen activator inhibitor shifted the balance expressed by the ratio of type 1 plasminogen activator inhibitor/tPA toward a stimulation of fibrinolysis.
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As previously noted, 8 plasminogen cannot be assayed in plasma samples containing aprotinin. No differences of plasminogen were found between the tranexamic acid and the control group, the means of both groups at time points 1 to 4, respectively, being 125% ± 2%, 71% ± 3%, 88% ± 4%, and 95% ± 3% (reference range 75% to 125%) of standard.
The variables illustrating the effects of the tissue factors plus the antifibrinolytic agents administered in this study are shown in Table VII. Here, a difference between the two antifibrinolytic agents was apparent.
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By contrast, the antiplasmin activities decreased to essentially the same extent in the tranexamic acid and the control groups, remaining significantly higher in the recipients of aprotinin. This finding may be partly due to the antiplasmin activity of aprotinin because the assay used in our study (see Patients and methods) is not specific for the natural inhibitor 
2-antiplasmin in the presence of an exogenous antiplasmin.
DISCUSSION
The dose of aprotinin that we used was the same as that used in the pioneering study, 5 and our results agreed with those subsequently reported on the effects of high-dose aprotinin therapy during CPB. 6-12 With tranexamic acid, we used the same dose as that recommended by Horrow and associates 21,22—a loading dose of 10 mg/kg body weight after induction of anesthesia but preceding incision of the skin, plus 1 mg/kg per hour for 10 hours—yet we failed to reproduce the positive results communicated by that author.
The question arises if this discrepancy may be due to an insufficient number of patients in our study. Power analysis shows that to have an 80% chance of attaining a significance level of p = 0.05 for the difference of the observed means of the tranexamic acid and the control group, as depicted in Fig. 1, a study would need to comprise 180 patients in each treatment arm. In other words, our data on postoperative blood loss are suggestive but not strong enough to prove definitively that tranexamic acid is without effects.
In any event, tranexamic acid is less effective if its administration starts only after the neutralization of heparin by protamine. 23 In this case, a single intravenous dose of 40 mg/kg body weight did not sustain postoperative hemoglobin levels any better than a consistently implemented, nonpharmacologic blood conservation protocol. 24 In the study comparing high-doseaprotinin with -aminocaproic acid, 25 neither postoperative blood losses nor transfusion requirements differed significantly between the groups. Without inclusion of a nonmedicated control group, the authors concluded that both agents were equally effective. Altogether, however, the effects of tranexamic acid on postoperative blood loss and transfusion requirements after CPB seem to be less clear-cut than those of aprotinin.
The data summarized in Table IV and showing that the impact of CPB on platelet function 28,29 is mitigated by aprotinin as well as tranexamic acid essentially agree with published reports. Apart from its effect on ADP = and epinephrine-induced aggregation, 2 aprotinin is protective with respect to platelet aggregation on extracellular matrix, 30,31 ristocetin-induced agglutination, 32 and the membrane glycoproteins Ib and IIa/IIIb. 33 Similarly, tranexamic acid has been reported to mitigate plasmin-induced platelet activation and to sustain the ADP content of dense granules, 23 whereas -aminocaproic acid counteracts the reduction of ristocetin-induced agglutination. 34 These positive in vitro findings do not, however, provide a quantitative relationship between platelet function and postoperative blood losses and transfusion requirements, nor do they define the relative in vivo efficacy of aprotinin and tranexamic acid. Nonuniformity of in vitro methods, as well as variations of in vivo perfusion techniques, complicate the interpretation of such in vitro data.
In agreement with recent studies, 35,36 the time profiles of the prothrombin activation fragment and the thrombin-antithrombin complex, summarized in Table V, show a significant activation of intravascular coagulation at the end of CPB (time point 2), that is, when the patients were still fully heparinized. Next morning in the intensive care unit (time point 4), this activation had not disappeared completely. The means of prothrombin activation fragment and thrombin-antithrombin complex in Table V are comparable with those reported in conditions as diverse as acute leukemia, fulminant hepatic failure, postoperative thrombosis, shock, sepsis, and investigate infusion of tumor necrosis factor in human beings 37-41; however, the accompanying activities of antithrombin III and protein C do not suggest the presence of disseminated intravascular coagulation in the sense of a consumptive coagulopathy with manifestly abnormal bleeding. Apart from contact activation of the coagulation cascade by foreign surfaces in the extracorporeal circuit, the mean antithrombin activity at time point 2 (57% ± 2%) is sufficiently low to activate intravascular coagulation, as reflected by a significant increase of prothrombin activation fragment levels in individuals with a hereditary deficiency and plasma activities of the inhibitor below 70%. 42 At any given time point, the individual thrombin-antithrombin complex concentrations in our patients did not correlate with total antithrombin activities. This finding makes sense when the molar concentrations of prothrombin, antithrombin, and the complex in plasma are considered: thrombin-antithrombin complex concentrations as high as 200 µg/L are equivalent to no more than 0.1% to 0.2% of the constituents of the complex, and variations of this magnitude cannot be picked up by total activity assays. 43
The concentrations of prothrombin activation fragment and thrombin-antithrombin complex in our patients did not differ among the three treatment groups. We thus cannot confirm the observation 44 that aprotinin lowered thrombin-antithrombin complex concentrations relative to untreated controls during and after CPB, but the concentrations were not higher. This finding is of some interest in view of recent concerns that the use of antifibrinolytic agents might promote occlusions of coronary bypass grafts and other vessels of similar or smaller caliber. 45-50 In the patient who died of a cerebral infarction on the third postoperative day (see Patient characteristics), the concentrations of prothrombin activation fragment and thrombin-antithrombin complex were somewhat above average but by no means the highest recorded during the study period. The autopsy findings were equally inconclusive with respect to a possible role of aprotinin in the fatal sequence of thromboembolic events.
Our data on the activities of tPA and type 1 plasminogen activator inhibitor, both of which are released by vascular endothelium, were displayed in Table VI. The transient activity increase of tPA in our patients has also been noted by other authors after CPB and especially during the anhepatic stage of orthotopic liver transplantation. 10,51-55 Some authors have found that the use of aprotinin blunted this increase of tPA activity. 51,52,54 Our data agree with those of other studies, 12,56 showing no such effects of aprotinin (or tranexamic acid). In fact, the activity of tPA was higher in the aprotinin group than in the control group at time point 4.
The time profile of the type 1 plasminogen activator inhibitor mirrored that of tPA, showing a nadir at the end of CPB and a secondary increase comparable with that observed during the post-anhepatic stage of liver transplantation. 53 Like tPA, type 1 plasminogen activator inhibitor was higher in the recipients of aprotinin than in the controls next morning in the intensive care unit, but no other differences were found between the groups. As a result of these variations with time, the mean activity ratio of type 1 plasminogen activator inhibitor/tPA, calculated from individual values and giving an impression of the fibrinolytic inhibitor/activator balance, pointed to an acceleration of fibrinolysis at time point 2 and 3. The baseline conditions were restored next morning in the intensive care unit. In the balance, however, neither aprotinin nor tranexamic acid modified the release of the tissue factors affecting fibrinolysis as compared with nonmedicated controls.
By contrast, the variables shown in Table VII and illustrating the effects of the tissue factors plus the agents administered in this study showed a discrepancy between aprotinin and tranexamic acid. The time profiles of D-dimers in our patients fully agree with published reports on the effects of aprotinin versus nonmedicated controls. 8,12,33,44,57 As judged by this variable, the antifibrinolytic effect of tranexamic acid is just as good as that of aprotinin. However, the pattern of antiplasmin activities in plasma conveys a different impression, in that the tranexamic acid and the control groups are virtually indistinguishable, whereas antiplasmin activity is significantly better sustained in the recipients of aprotinin.
It is tempting to speculate that this discrepancy is related to the different modes of action of these two antifibrinolytic agents. Aprotinin inactivates plasmin by the rapid and virtually irreversible formation of an antiprotease-protease complex. By contrast, tranexamic acid inhibits fibrinolysis specifically by blocking the access of plasmin to its binding sites on fibrinogen and fibrin monomers. 16 Before it can be definitively neutralized by the relatively low potential of its natural plasmatic antagonist 2-antiplasmin, which is consumed in the process, plasmin might still be able to damage the platelet membrane Ib glycoproteins, that is, it might interfere with platelet adhesion, which is probably at least as important for hemostasis as the platelet aggregation which we were able to measure. 33,58-60 A study comparing the interaction of aprotinin and tranexamic acid with the platelet membrane Ib glycoproteins might contribute to the evaluation of the relative hemostatic efficacy of aprotinin and tranexamic acid under the conditions of CPB.
In summary, our study reconfirmed the efficacy of aprotinin in reducing blood loss and transfusion requirements after CPB but failed to show a significant effect of tranexamic acid. Both agents protected platelet aggregation induced by ADP; neither modified post-CPB activation of intravascular coagulation or the release of plasminogen activator tPA and its type 1 plasminogen activator inhibitor as compared with nonmedicated controls. Plasma concentrations of D-dimer, a breakdown product of cross-linked fibrin, remained at baseline in the recipients of both agents but tripled in the controls. By contrast, plasma antiplasmin activities decreased to the same extent in the tranexamic acid and the control groups, remaining significantly higher in the recipients of aprotinin. We submit that this discrepancy reflects the different modes of action of the two agents, which may make aprotinin more effective than tranexamic acid in the "nonfibrinolytic" act of protecting the membrane glycoproteins mediating platelet adhesion against an attack by plasmin generated during and after CPB.
We sincerely appreciate the expert technical assistance of F. Etzlsdorfer and the preparation of the manuscript by S. Büssard and Y. Mermod.
Footnotes
From the Red Cross Blood Transfusion Service, a the Department of Surgery, b and the Central Laboratory, c General Hospital, Linz, Austria; the Central Laboratory of the Swiss Red Cross Blood Transfusion Service, d and the University Department of Experimental Surgery, e Berne, Switzerland. 
References
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B. Eberle, E. Mayer, G. Hafner, J. Heinermann, M. Dahm, W. Prellwitz, W. Dick, and H. Oelert High-Dose {epsilon}-Aminocaproic Acid Versus Aprotinin: Antifibrinolytic Efficacy in First-Time Coronary Operations Ann. Thorac. Surg., March 1, 1998; 65(3): 667 - 673. [Abstract] [Full Text] [PDF]
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B. J. Hunt, R. N. Parratt, H. C. Segal, S. Sheikh, P. Kallis, and M. Yacoub Activation of Coagulation and Fibrinolysis During Cardiothoracic Operations Ann. Thorac. Surg., March 1, 1998; 65(3): 712 - 718. [Abstract] [Full Text] [PDF]
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S. Westaby Aprotinin Fifteen Years Later Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 1997; 1(4): 366 - 375. [Abstract] [PDF]
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D. Royston Hemostatic Drugs in Prothrombotic or Hypercoagulable States Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 1997; 1(4): 376 - 394. [Abstract] [PDF]
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O. Shigeta, H. Kojima, T. Jikuya, Y. Terada, N. Atsumi, Y. Sakakibara, T. Nagasawa, and T. Mitsui Aprotinin Inhibits Plasmin-Induced Platelet Activation During Cardiopulmonary Bypass Circulation, July 15, 1997; 96(2): 569 - 574. [Abstract] [Full Text]
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S. Cicek, U. Demirkilic, E. Ozal, E. Kuralay, H. Bingol, H. Tatar, and O. Y. Ozturk POSTOPERATIVE USE OF APROTININ IN CARDIAC OPERATIONS: AN ALTERNATIVE TO ITS PROPHYLACTIC USE J. Thorac. Cardiovasc. Surg., December 1, 1996; 112(6): 1462 - 1467. [Abstract] [Full Text]
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S. Cicek, U. Demirkilic, E. Kuralay, E. Ozal, and H. Tatar Postoperative Aprotinin: Effect on Blood Loss and Transfusion Requirements in Cardiac Operations Ann. Thorac. Surg., May 1, 1996; 61(5): 1372 - 1376. [Abstract] [Full Text]
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