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Anesth Analg 2008; 107:391-397
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31817b7732
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CARDIOVASCULAR ANESTHESIOLOGY

The Influence of Aprotinin and Tranexamic Acid on Platelet Function and Postoperative Blood Loss in Cardiac Surgery

Andinet M. Mengistu, MD, Kerstin D. Röhm, MD, Joachim Boldt, MD, PhD, Jochen Mayer, MD, Stefan W. Suttner, MD, and Swen N. Piper, MD

From the Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Ludwigshafen, Germany.

Address correspondence and reprint requests to Andinet M. Mengistu, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Bremserstrasse 79, D-67063 Ludwigshafen, Germany. Address e-mail to a.mengistu{at}gmx.de.

Abstract

BACKGROUND: Antifibrinolytic drugs including aprotinin and tranexamic acid are currently used in cardiac surgery to reduce postoperative bleeding and transfusion requirements, and may have different effects on platelets. We therefore evaluated platelet function after cardiopulmonary bypass (CPB) and cardiac surgery to determine the effect of either aprotinin or tranexamic acid.

METHODS: In a prospective, randomized study, 50 patients scheduled for elective cardiac surgery with CPB were evaluated. Patients received high-dose aprotinin (n = 25) or tranexamic acid (n = 25) as antifibrinolytic drugs. Coagulation and platelet function were assessed preoperatively, after CPB, 3 and 24 h after surgery using modified thrombelastography and whole blood aggregometry.

RESULTS: Impaired coagulation after CPB occurred in both groups compared with preoperative data (P < 0.01). In contrast to modified thrombelastography, thrombin receptor-mediated aggregometry after CPB was significantly decreased only in those patients receiving tranexamic acid until the end of the study period in comparison to the aprotinin group (P < 0.05). Aprotinin-treated patients showed significantly less chest tube drainage (575 mL ± 228 vs 1033 mL ± 647, P < 0.05) and need for postoperative transfusion requirements (P < 0.01) compared with the tranexamic acid group.

CONCLUSIONS: Platelet function measured by whole blood aggregometry is better preserved by aprotinin than tranexamic acid and may be responsible for producing less bleeding within the first 24 h after CPB.

Excessive bleeding after cardiac surgery contributes to postoperative morbidity and mortality.1 Platelet dysfunction is considered to be a major cause of bleeding after cardiac surgery following cardiopulmonary bypass (CPB), resulting in an increased need for transfusions.2 CPB results in a systemic inflammatory response produced by the kinin-kallikrein, the fibrinolytic coagulation and the complement system that generate proinflammatory mediators through a series of consecutive proteolytic cleavages.3,4 Increased plasma concentrations of plasmin and thrombin lead to platelet dysfunction after CPB.5

Antifibrinolytic drugs reduce bleeding and postoperative transfusion requirements.6,7 Two different classes have been developed, the lysine analogous, including {epsilon}-aminocaproic acid and tranexamic acid (TA), and serine protease inhibitors, namely aprotinin. Lysine analogous inhibit fibrinolysis by attachment to the lysine binding sites on plasminogen and plasmin and prevent fibrinolysis by blocking engagement of these fibrinolytic proteins with fibrinogen and fibrin.8 A broader action is described for aprotinin that inhibits many inflammatory mechanisms, including activation of plasmin, thrombin, kallikrein, and protein C. Previous studies suggest a platelet-preserving effect as a mechanism for reduced bleeding by aprotinin.9,10 Because of recent reports regarding aprotinin,11 drug safety has to be balanced against efficacy when choosing an antifibrinolytic drug.

In the present study, we investigated the effects of aprotinin and TA in patients undergoing primary cardiac surgery with CPB on hemostatic outcome, using modified thrombelastography and a new point-of-care (POC) whole blood function analyzer. We hypothesized that platelet function would be better preserved by the use of aprotinin in comparison with TA.

METHODS

After approval by the Institutional Review Board (IRB) and written informed consent, 50 patients undergoing primary coronary bypass surgery using CPB were studied. Exclusion criteria were determined as history of bleeding diasthesis, abnormal coagulation test (activated partial thromboplastin time [aPTT] >40 s, international normalized ratio [INR] >1.25), thrombocytopenia (platelet count <150/nL), previous cardiac surgery, or oral therapy with antiplatelet drugs within the last 10 days preoperatively.

Patient Management
Patients were randomized into two groups. One group received aprotinin (Trasylol®, Bayer HealthCare AG, Leverkusen, Germany; n = 25), the other one TA (Cyclokapron®, Pharamcia GmbH, Karlsruhe, Germany; n = 25) as the antifibrinolytic drug perioperatively. Patients treated with aprotinin received high-dose aprotinin (Hammersmith) with a bolus of 2 x 106 KIU after induction of anesthesia, followed by continuous infusion of 5 x 105 KIU/h aprotinin until arrival at the intensive care unit (ICU). The extracorporeal circuit was primed with 2 x 106 KIU of aprotinin. In the other group, 2 g TA was administered after induction of anesthesia and 6 mg · kg–1 · h–1 TA was continuously given until arrival at the ICU. The CPB-circuit was primed with 1 g TA.

After premedication with flunitrazepam (0.02 mg/kg) 60 min before surgery, anesthesia was induced by midazolam (0.1 mg/kg), sufentanil (1.5 µg/kg), and pancuronium (0.1 mg/kg). Anesthesia was sustained by continuous administration of sufentanil (0.15 µg · kg–1 · h–1), sevoflurane (0.2–0.7 Vol % end-tidal), and intermittent administration of pancuronium (15 µg/kg). After endotracheal intubation, lungs were ventilated with 50% oxygen in air with a tidal volume of 8–10 mL/kg and a positive end-expiratory pressure of 5 mm Hg. The ventilation rate was adjusted to normal end-expiratory carbon dioxide concentration (32–42 mm Hg).

Surgery was performed in a single surgery unit with standard surgical techniques. In all patients, a Sarns 9000 CPB machine and a hollow fiber membrane oxygenator was used which was primed with 1000 mL lactated Ringer's solution and 500 mL hydroxyethyl starch 6% 130/0.4 (Voluven®). During CPB, a nonpulsative flow rate of 2.4 L · min–1 · m–2 was performed and body temperature was kept at mild hypothermia (bladder temperature >34°C). Patients received heparin (300 U/kg) before cannulation for CPB and it was repeated (in steps of 5000 U), if necessary, to achieve an activated clotting time (ACT) of >400 s. At the end of surgery, heparin was reversed by protamine sulfate (3 mg/kg) by the same regime to reach an ACT <125 s. Packed red blood cells (PRBC) were added in the CPB if hematocrit was <20%. The residual blood remaining in the extracorporeal circuit was concentrated using a cell saving device and retransfused at the end of surgery.

Volume replacement in the ICU was administered as deemed necessary by the attending physician using hydroxyethyl starch 6% 130/0.4 and lactated Ringer's solution. PRBC were transfused if the hemoglobin level was <8 g/dL. Fresh frozen plasma (FFP) was administered if the INR was >1.5 or in case of excessive bleeding (>200 mL/h for 2 h). Platelet concentrates were given if the platelet count was <60/nL and bleeding occurred (>200 mL/h for 2 h). Intraoperative and postoperative need of PRBC, FFP, and platelet concentrates was recorded until 24 h after surgery as well as the cumulative blood loss from chest drainage and closed pleural drainage over the same time period.

Blood samples were obtained before induction of anesthesia (T0), after administration of protamine at the end of CPB (T1) controlled by ACT (<125 s), 3 h (T2), and 24 h after surgery (T3). All specimens were drawn through a 1.2 mm (18-gauge) Teflon catheter positioned in the radial artery.

Measurements
Whole Blood Aggregometry
Whole blood aggregometry (WBA) was assessed using a new platelet function analyzer (multiplate® analyzer, Dynabyte GmbH, Munich, Germany). This new bedside POC monitoring system uses the technique of multiple electrode platelet aggregometry and quantifies platelet function by attachment of activated platelets onto metal electrodes leading to an increase of electrical impedance.12 300 µL of whole blood mixed with a thrombin inhibitor (hirudin 25 µg/mL) was stirred with 300 µL prewarmed isotonic saline solution in a measuring cell and incubated for 3 min at 37°C. Adenosine diphosphate (ADP, ADPTest®: 0.2 mM/mL; 20 µL, final concentration 6.5 µM/mL, Instrumentation Laboratory, Munich, Germany), collagen (ColTest®: 100 µg/mL; 20 µL, final concentration 3.2 µg/mL, Instrumentation Laboratory), and thrombin receptor-activating-protein-6 (TRAP-6, TRAPTest®: 1 mM/mL; 20 µL, final concentration 32 µM/mL, Instrumentation Laboratory) were used for platelet activation. Changes in electrical impedance ({Omega}; arbitrary aggregation units, AU) were continuously recorded for 6 min after activation. The area under the curve (AUC) was analyzed automatically by an integrated computer system plotting AU against time. Every measurement was performed by the same person blinded to the study as a double determination due to the functional design of the test cell, using a semiautomatic pipetting system. Aggregation studies were not used for guiding transfusion therapy and the attending physician was blinded to measurement values.

A power analysis revealed that a sample size of 25 would provide a power of 80% in detecting a difference in TRAP-mediated WBA of at least 25% between patients treated with aprotinin or TA.

Thrombelastometry (ROTEM®)
For rotation thrombelastometry, a four-channel analyzer (ROTEM; NobisDiagnostics, Endingen, Germany) was used to measure onset of coagulation (coagulation time [CT]; standard TEG: reaction time r), kinetic of clot formation (clot formation time [CFT]; standard TEG: coagulation time k), maximum clot firmness (MCF; standard TEG: MA), and alpha-angle ({alpha}-angle). Compared with standard thrombelastography, reagent and mechanically modified thrombelastometry uses standardized reagents with the aim of accelerating test time and getting differential information of coagulation disturbances. Thrombelastometry was performed as described previously.13 In brief, to assess intrinsic activity 300 µL citrated whole blood was recalcified with 20 µL 0.2 M calcium chloride (StartTEM®) in a prewarmed cup and added by a surface activator (InTEM®, ellagic acid with partial thromboplastin phospholipid; 20 µL). Intrinsic thrombelastometry resembles an aPTT in whole blood. The contact activator is ellagic acid, an organic contact activator which, unlike kaolin or celite, has a much smaller tendency to sediment. Thromboplastin is coagulation-activating tissue extract, e.g., made of rabbit brain, and contains both phospholipids and tissue factor. In the same way, blood samples were processed for measurement of extrinsic activity using tissue thromboplastin (ExTEM®: rabbit brain extract, 20 µL). All reagents were taken from the manufacturer of the ROTEM system, and tests were performed using a semiautomatic pipetting system by the same person who was blinded to the study design. Thrombelastometry was not used for guiding transfusion therapy, and the attending physician was blinded to measurement values.

Statistics
Statistical analysis was performed using SPSS 11.0 (Windows Software Package, SPSS Inc., Chicago, IL). Data concerning blood loss and standard clinical laboratory values are expressed as mean (±sd). Paired Student's t-test for comparison of effects inside the groups and two way analysis for repeated measures for intergroups effects as well as Pearson's coefficient were used for statistical analysis. ROTEM and WBA data are presented as Box-and-Whisker plots showing median as well as 5, 25, 75, and 95% percentile (median [5th-percentile; 95th-percentile]). Statistics were performed by Wilcoxon signed-ranked test, Kruskal–Wallis one-way analysis of variance and Spearmann's correlation coefficient. For invariable characters, like transfusion requirements, the {chi}2 test was applied. A P < 0.05 was considered as criterion of statistical significance.

RESULTS

There were no differences in age, weight, and gender, or need for reoperation between groups. No statistical differences were observed in preoperative laboratory values: hemoglobin, platelet count, and coagulation tests (aPTT, INR) as well as fibrinogen concentration (Table 1). Intraoperative transfusion requirements of PRBC and FFP did not differ between groups and there were no differences in total doses of heparin and protamine (Tables 2 and 3).


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  		Table 1. Routine Coagulation Data

 

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  		Table 2. Demographic Data and CPB Variables

 


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  		Table 3. Postoperative Blood Loss and Transfusion Requirements

 
Whole Blood Aggregometry
WBA did not differ at baseline (T0) between groups. After CPB, there was a significant decrease in ADP-mediated aggregometry (T1) (aprotinin: 611 [172,720] vs 277, [74,707] P < 0.05; TA: 525 [186,806] vs 235, [96,885] P < 0.05). Platelet aggregometry returned to preoperative levels 24 h after surgery for all groups (Fig. 1). Collagen-mediated aggregometry was significantly increased in patients treated with aprotinin compared with the TA group at the end of the study period (604 [148;1356] vs 359 [73;1376], P < 0.05). TRAP-mediated aggregometry after CPB was significantly higher in aprotinin-treated patients compared with the TA group (934 [366;1730] vs 690 [61;1516], P < 0.05) until the end of the study period (Fig. 1). Postoperative platelet aggregation mediated by TRAP correlated with postoperative blood loss (Spearman r = –0.421, P < 0.01).


Figure 19
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  		Figure 1. Changes of platelet function measured by whole blood aggregometry over time; Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; - median). T0 preoperative, T1 after cardiopulmonary bypass (CPB), T2 3 h after surgery, T3 24 h after surgery; AUC = area under the curve (AUC = {Omega} · min); normal ranges: adenosine diphosphate (ADP): 369–1180, collagen: 546–1134, TRAP: 927–1565; *P < 0.05 in comparison to preoperative measurement, #P < 0.05 in comparison to tranexamic acid (TA).

 

Thrombelastometry (ROTEM®)
MCF and {alpha}-angle decreased significantly after CPB with return to preoperative levels at the end of the study (Fig. 2). Three hours after surgery, {alpha}-angle was increased in the aprotinin group in contrast to TA-treated patients (70 [60;78] vs 65 [40,79] P < 0.05). Neither MCF nor {alpha}-angle were correlated with postoperative blood loss and transfusion requirements at any time (Fig. 3).


Figure 29
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  		Figure 2. Changes of platelet function measured by thrombelastography, maximal clot firmness (MCF); Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; - median). T0 preoperative, T1 after cardiopulmonary bypass (CPB), T2 3 h after surgery, T3 24 h after surgery; Normal ranges: InTEM, ExTEM: 53–74 mm; *P < 0.05 in comparison to preoperative measurement, #P < 0.05 in comparison to tranexamic acid (TA).

 

Figure 39
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  		Figure 3. Changes of platelet function measured by thrombelastography, {alpha}-angle; Data are presented as Box-and-Whisker plots (25% and 75% percentile; 5% and 95% percentile; - median). T0 preoperative, T1 after cardiopulmonary bypass (CPB), T2 3 h after surgery, T3 24 h after surgery; Normal ranges: InTEM, ExTEM: 66°–89°. *P < 0.05 in comparison to preoperative measurement, #P < 0.05 in comparison to tranexamic acid (TA).

 

Postoperative Routine Coagulation Laboratory
On ICU arrival, the hemoglobin, INR, aPTT and platelet count significantly decreased in comparison to preoperative values in both groups (Table 1). Platelet count was significantly higher in the aprotinin group compared with TA-treated patients (175 ± 73 per nL vs 141 ± 45 per nL, P < 0.05) 24 h after surgery. Correlation studies of routine coagulation laboratory values are presented in Table 4.


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  		Table 4. Correlation to Postoperative Blood Loss

 

Blood Loss and Transfusion Requirements
In the TA group, significant increased chest tube drainage over 24 h (1033 ± 647 mL vs 575 ± 228 mL, P < 0.01) and transfusion requirements (1.8 ± 2.4 U of PRBC vs 0.8 ± 1.1 U of PRBC, P < 0.05) were observed in comparison to aprotinin-treated patients (Table 2). The transfusion ratio was significantly higher in patients treated with TA when compared with aprotinin (Table 2).

DISCUSSION

We demonstrated that platelet function in response to the agonist TRAP is preserved by aprotinin in patients undergoing CPB surgery as assessed by a new POC whole blood function analyzer. In comparison to TA, aprotinin significantly decreased postoperative chest tube drainage and transfusion requirements. Previous reports noted that glycoprotein (GP) expression on platelets decreases after CPB such as the loss of adhesion molecules including GP Ib receptors and fibrinogen receptors (GP IIb/IIIa).14,15 Platelet dysfunction after CPB is caused in part by thrombin generation.4 Thrombin initiates its cellular effects by activation of protease-activated receptors (PAR-1 to PAR-4).16 In contrast, ADP and collagen (e.g., via GP Ib) induce platelet aggregation by protease-independent receptors.17 Regardless of the agent, platelet activation finally results in expression of the GP IIb/IIIa receptor in a ligand-receptive state for fibrinogen.18

In a recent study, Kuitunen et al.19 indicated thrombin formation as well as fibrinolytic activity to be better preserved by the use of aprotinin when compared with TA. Poullis et al.16 demonstrated that aprotinin inhibits platelet aggregation in vitro through prevention of thrombin-induced platelet activation by preserving proteolysis of the PAR-1 receptor without any effect of nonprotease-depending mechanisms including ADP and collagen. As supported by our in vivo study, there were no differences between aprotinin and TA patients in platelet aggregation activated by ADP.20 Thus, aprotinin protects platelets from activation by thrombin generation during CPB while maintaining hemostatic activity of platelets in surgical wounds, sites where ADP and collagen are likely to be generated.21,22 Day et al.23 showed in a placebo-controlled trial PAR-1-mediated platelet activation to be preserved in vivo by aprotinin, considering this effect most likely attributed to the protection against PAR-1 cleavage. Ferraris et al.24 found thrombin-mediated platelet aggregation to correlate with post-CPB bleeding that was only present at the end of this study and do not explain the differences in clinical outcome between groups. These reports support our findings that aprotinin preserves platelet function after CPB. In an in vitro study,25 platelet exposure to aprotinin decreased availability of activated GP IIb/IIIa receptors after activation by TRAP-6, whereas the total number of GP IIb/IIIa receptors remained unchanged. The authors hypothesized that aprotinin may inhibit a conformation change of exposed GP IIb/IIIa receptors to a fibrinogen receptive state. After cessation, aprotinin is rapidly redistributed from the plasma through binding to the endothelium and renal clearance suggesting this effect is transient.26 Preservation of fibrinogen binding sites after exposure to aprotinin may contribute to preserved platelet function in the time after CPB with the consequence of reduced postoperative bleeding. These results are supported by a study of van Oeveren et al.27 who compared platelet activation by CPB in aprotinin and placebo-treated patients and noted GP IIb/IIIa receptor exposure not to differ between groups in the time after CPB whereas fibrinogen binding of platelets was significantly increased in aprotinin-treated patients. While these properties were not shown for TA, this might explain the decrease of TRAP-6 mediated platelet aggregation after CPB which was not present in the aprotinin group.

Plasmin is presumed to be responsible for the release of GP Ib from the platelet surface that is important for contact activation mediated by collagen.15,17 GP Ib was shown to be preserved by aprotinin and TA, whereas aprotinin has the most antifibrinolytic potency.19,27 These findings support our results of no differences in collagen-mediated platelet aggregation after CPB in either group. At the end of the study period, collagen and TRAP-6-mediated aggregometry was significantly increased compared with baseline measurements and TA group. However, platelet hyper-reactivity 24 h after surgery was reported that was present only in aprotinin-treated patients, but this issue does not explain the difference between bleeding and transfusion requirements when compared with tranexamic acid.28

Thrombelastography is used as a global test of the coagulation cascade, and to guide therapeutic interventions in a bleeding patient.29,30 MCF is mostly influenced by platelet function and fibrinogen, but primary hemostasis is not specifically considered. In a recent study, MCF was found to be correlated with postoperative bleeding.31 These results are confirmed by Cammerer et al.32 who reported risk stratification using MCF and {alpha}-angle. In a placebo-controlled trial, Mongan et al.6 did not observe any differences in TEG parameters, postoperative blood loss or transfusion requirements between aprotinin and TA treatment. Comparative studies failed to find an impact on MA or {alpha}-angle compared with placebo, challenging ROTEM as a suitable device to assess platelet function.33,34 Coagulation activation by tissue factor, in contrast to other mediators like celite, minimize prolonged clot formation by aprotinin, a potential limitation of our study.35 Our in vitro studies using thrombelastometry did not reflect a platelet-preserving effect of aprotinin as seen in WBA because TEG does not provide a comprehensive or sensitive reflection of impaired platelet function compared with other methods of platelet function assessment.36

A limitation of our current study is the lack of a control group but the use of antifibrinolytic drugs has become a clinical standard to decrease bleeding. FibTEM® analysis as a platelet-indicative test of the ROTEM system, representing fibrin polymerization to delineate it from platelet dysfunction, was not performed. Due to the fact of normal ranged fibrinogen levels without any diffrences between the groups, it does not seem to be a factor affecting our results. Platelet function was investigated by a more sensitive technique as compared with thrombelastometry and supports the outcome in this clinical setting. A further limitation was the lack of blinding of the attending physician to antifibrinolytic treatment. However, intraoperative and postoperative treatment, particularly transfusion therapy, was standardized by a study algorithm and aggregation studies were performed outside the operating room without being used for clinical treatment. Despite the reduction of postoperative bleeding by aprotinin in our study, these results remain controversial and do not show the superiority of one drug.7

In summary, we demonstrated that aprotinin preserves platelet function measured by a new whole blood function analyzer. Increased thrombin-mediated platelet aggregation after CPB may explain the decrease of postoperative blood loss and transfusion requirements in aprotinin-treated patients in comparison to TA, suggesting that aprotinin is more effective in patients undergoing primary CPB surgery. Despite these findings, in cooperation with the German Federal Institute for Drugs and Medical Devices and the United States Food and Drug Administration, aprotinin was temporarily suspended by the manufacturer in November 2007 from the worldwide market as preliminary findings of the Canadian Blood Conservation Using Antifibrinolytics Trial, a randomized, controlled trial being conducted in high-risk cardiac surgery patients, have shown reduced bleeding but increased all-cause mortality in the aprotinin treatment arm as compared with TA and {epsilon}-aminocaproic acid.

Footnotes

Accepted for publication April 1, 2008.

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