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Ann Thorac Surg 1998;66:792-799
© 1998 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations

^a Department of Cardiac Surgery, Anesthesiology, Medical University of Lübeck, Lübeck, Germany
^b Department of Internal Medicine, Medical University of Lübeck, Lübeck, Germany

Accepted for publication April 30, 1998.

Address reprint requests to Dr Sievers, Department of Cardiac Surgery, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
e-mail: (herzchir{at}medinf.mu-luebeck.de)

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Postoperative bleeding still remains a serious problem in bypass surgery. This study evaluated fibrinolysis and perioperative low-dose antifibrinolytic regimens adjusted to the time course of fibrinolysis.

Methods. In a prospective, randomized study of 42 patients undergoing bypass grafting, patients received low-dose aprotinin (group A; n = 14) or low-dose tranexamic acid (group TA; n = 14) intraoperatively and postoperatively, respectively, with no antifibrinolytics for comparison (group C; n = 14). Parameters of procoagulation, fibrinolysis, and activated factor VII were measured preoperatively, intraoperatively, and postoperatively. Blood loss was determined up to 24 hours.

Results. The level of thrombin–antithrombin III complex was significantly decreased postoperatively in the treatment groups (group A and TA versus C: 25 ± 14 and 19 ± 10 µg/L, respectively, versus 40 ± 21 µg/L; p < 0.05). Levels of plasmin–antiplasmin complexes were significantly decreased postoperatively in group A (607 ± 231 µg/L) versus group C (825 ± 225 µg/L) (p < 0.05) but were increased in group TA (1,145 ± 394 µg/L) versus group C (p < 0.05). At all times intraoperatively and postoperatively, levels of D-dimers were significantly decreased in group A and group TA versus control (p < 0.001), indicating that fibrinolysis persists after the operation. Intraoperatively, the factor VIIa level decreased significantly in group A (20 ± 8 mU/mL) versus group C (31 ± 15 mU/mL) (p < 0.05), but not in group TA (32 ± 15 mU/mL). Blood loss was significantly lower in group A (135 ± 37 mL) and group TA (155 ± 71 mL) versus group C (354 ± 170 mL) (p < 0.001).

Conclusions. This low-dose aprotinin regimen adjusted to perioperative fibrinolysis reduces blood loss significantly in coronary bypass grafting. For further progress in this subject, clinical investigations of individual fibrinolysis-adjusted antifibrinolytic treatment seems warranted.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patients undergoing coronary artery bypass grafting have an increased risk for perioperative bleeding complications owing to fibrinolysis [1]. Antifibrinolytic agents such as aprotinin and tranexamic acid have been administered in various dosages within the scope of bypass surgery in recent years to effectively reduce postoperative blood loss [2–6]. Royston and associates [7] demonstrated a significant reduction of blood loss under a high-dose aprotinin regimen. At present, a consensus has not been reached on the basic necessity of applying antifibrinolytic substances on their optimal dose. Some reports suppose an increased potential of thrombembolic events under antifibrinolytic medication [8], as well as the risk of renal damage [9] which could in theory be higher under high-dose aprotinin regimens. Liu and associates [10] used low doses of aprotinin and demonstrated that these regimens are as effective as high-dose applications in reducing postoperative bleeding. In this context it appears to be essential for optimal efficiency of this treatment to find a scheme for dosing antifibrinolytic agents such as aprotinin as well as tranexamic acid by taking into consideration the time course of fibrinolysis [8, 9].

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patients
After approval by the institutional ethical committee (Reference No. 103/95) and written informed consent from the patients a prospective, randomized, open study was conducted. Patients were randomized into three groups: aprotinin (group A; n = 14), tranexamic acid (group TA; n = 14), and control (group C; n = 14). Inclusion criteria were primary bypass grafting, age 75 years or less, ejection fraction 0.45 or more, body weight 100 kg or less, no intravenous heparin infusion before the operation, no administration of acetylsalicylic acid in the last 5 days before operation, and bypass grafting with a venous graft in addition to an internal mammary artery. Exclusion criteria were renal insufficiency stages II to IV, a known coagulopathy as assessed by routine coagulation parameters (activated partial thromboplastin time, thrombin time, antithrombin III, and fibrinogen) and patient history, a platelet count less than 150,000/µL of blood, a known hypersensitivity against aprotinin, and redo or emergency operations. Patient characteristics and operative data did not differ among the groups (Table 1).

To counteract a possible allergic reaction all patients received a test dose of 30,000 KIU aprotinin at anesthesia induction. One million KIU was added to the pump prime. After protaminization further aprotinin was administered in a dose of 200,000 KIU/h for another 5 hours.

Tranexamic acid (Ugurol; Bayer AG) is a synthetic antifibrinolytic substance derived from -aminocaproic acid. In contrast to aprotinin, tranexamic acid inhibits the fibrinolytic system at an earlier stage, ie, the precursor of plasmin—plasminogen—at the lysin binding site [12]. The following dosage scheme was applied: 10 mg/kg body wt as a bolus after heparinization followed by a continuous intravenous infusion of 1 mg/kg body wt/hour over 10 hours.

Operative patient management
The surgeon was not informed about randomization. Anesthesia was standardized in all patients (central venous catheter, arterial catheter, oral intubation, and intermittent positive-pressure ventilation with nitrous oxide in oxygen supplemented by a narcotic analgesic and a relaxant). Routine cardiopulmonary bypass grafting was performed in moderate hypothermia (28°C nasopharyngeal) with a membrane oxygenator (Baxter; Bentley Spiral Gold, Unterschleißheim, Germany) and a roller pump (Stöckert, München, Germany). The pump was primed with 1,000 mL of Ringer’s solution, 250 mL of 20% mannitol, and 250 mL of 5% human albumin. Patients were heparinized fully according to body weight in a dose of 300 IE/kg body wt. The activated clotting time (ACT) was measured every 30 minutes and kept at 450 seconds. Kaolin was used as an activation agent. A total of 2,500 IE of heparin was added when the ACT was less than 450 seconds and 5,000 IE was added when the ACT was less than 400 seconds.

Patients received 7,500 IE of heparin subcutaneously immediately when they arrived at the intensive care unit. St Thomas solution was used for antegrade cardioplegia (500 mL initially and 200 mL after every 20 minutes of cross-clamp time). After antegrade discontinuation of cardiopulmonary bypass grading, heparin was reversed with protamine chloride in a ratio of 1:1.

Blood sampling
Blood samples were taken at the following times: in the morning of the operation day (baseline value), intraoperatively immediately after heparin reversal with protamine, and 2, 6, and 24 hours postoperatively.

Laboratory measurements
Routine parameters
Levels of hemoglobin (Hb), hematocrit (Hct) and platelet count (Tc), global clotting parameters such as activated partial thromboplastin time (aPTT), thrombin time (TT), antithrombin III (ATIII), and fibrinogen were determined by standard methods. Prothrombin time (PT) was measured with prothrombin Innovin (Baxter) (International Sensitivity Index: 1.01; charge: TFS278). Normal values are between 70% and 130% (1.25 to 0.85, international Normalized Ratio); therapeutical values are between 15% and 27% (4.5 to 2.5, international Normalized Ratio).

Procoagulation parameters
Levels of thrombin–antithrombin III complex (TAT complex) and prothrombin fragment F1+2 (F1+2) were measured by enzyme immunoassay (Enzygnost TAT micro and Enzygnost F1+2 micro; Behringwerke AG, Marburg, Germany).

Parameters of fibrinolysis
Apart from plasminogen and ₂-antiplasmin levels (measured by Berichrom plasminogen-₂-antiplasmin test and Berichrom-₂-antiplasmin test (Behringwerke AG), the concentrations of plasmin-₂–antiplasmin complex (PAP) (measured by Enzygnost PAP micro, Behringwerke AG) and of D-dimers (measured by enzyme immunoassay Asserachrom D-dimer test; Boehringer Mannheim, Mannheim, Germany) were determined.

Extrinsic clotting system
Factor VII plays a key role in the extrinsic clotting system. Recently, a method for the determination of the concentration of the active form of factor VII (FVIIa) was developed (Staclot VIIa-rTF test; Diagnostica Stago, Asnieres-Sur-Seine, France). Tissue factor is a special cofactor of factor VIIa. With factor VIIa, it induces phospholipides and calcium coagulation. The time for blood coagulation is directly related to the amount of factor VIIa. The shorter the clotting time is, the higher is the amount of factor VIIa. We analyzed FVIIa levels in 14 healthy men aged 21 to 35 years, to compare these data with our preoperative values from the three groups.

Postoperative blood loss, blood transfusion, and fresh-frozen plasma administration
Blood loss was recorded after 2, 6, 12, and 24 hours postoperatively. Up to the third postoperative day blood transfusions and fresh-frozen plasma administration was determinated. Indication for blood transfusion was decided individually for every patient with respect to the patient’s age, Hct, Hb, hemodynamic parameters (heart rate, blood pressure, and cardiac output), and actual catecholamine dosages. There was a general agreement to transfuse blood with an Hb of less than 80 g/L. In one patient with an Hb of 68 g/L no blood was transfused because of age and stable hemodynamic condition (group C). In another patient (group C) with an Hb of 97 g/L blood transfusion was indicated because of unstable hemodynamic conditions. Administration of fresh-frozen plasma was not related to bleeding. Fresh-frozen plasma was administered mainly in combination with blood transfusions.

Statistical analysis
Unless stated otherwise, values are expressed as mean ± standard deviation. The independent nonparametric Mann–Whitney U Wilcoxon Test was applied for comparison of the different groups. Individual comparisons of pairs were evaluated with the Wilcoxon Test. Differences were considered to be significant at a level of p less than 0.05.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Routine parameters
In all groups, lowest values of Hb, Hct, and platelet count were measured intraoperatively. Values were lower in group C than in groups A and TA at all times after the operation. These differences, however, did not reach statistical significance (Table 2).

View larger version (32K): [in this window] [in a new window]   Fig 1. Course of prothrombin F1+2 level. Prothrombin F1+2 levels showed no significant differences among groups. group C = control; group A = aprotinin group; group TA = tranexamic acid group. (NS = not significant versus control.)

View larger version (28K): [in this window] [in a new window]   Fig 2. Course of the concentration of thrombin–antithrombin III complexes. At 2 and 24 hours after protaminazation, levels of these complexes are significantly reduced in the tranexamic acid group (TA group) (TA) and aprotinin group (group A) compared with controls (group C). (NS = not significant versus control; *p < 0.01; **p < 0.001; °p < 0.05.)

View larger version (32K): [in this window] [in a new window]   Fig 3. Course of plasminogen level. Preoperatively and at 24 hours postoperatively the plasminogen level was significant higher in the aprotinin group (group A) versus the control group (group C). (group TA = tranexamic acid group; NS = not significant versus control; *p < 0.01 versus control.)

View larger version (34K): [in this window] [in a new window]   Fig 4. Course of 2-antiplasmin level. The 2-antiplasmin values are in normal range preoperatively with significant differences between the tranexamic acid group (group TA) versus the control group (group C) and group TA versus the aprotinin group (group A). There was a decrease of 2-antiplasmin in all groups intraoperatively followed by an increase in group TA and group C up to 24 hours postoperatively. After an initially mild increase at 2 hours, group A showed a decrease up to 24 hours postoperatively. (NS = not significant versus control; *p < 0.01; **p < 0.001; ***p < 0.0001; °°p < 0.005 [versus control].)

View larger version (32K): [in this window] [in a new window]   Fig 5. Course of plasmin-2–antiplasmin complex level. There is an intraoperative increase in the aprotinin group (group A) and the tranexamic acid group (group TA) followed by a decrease in the postoperative course. In group TA the increase in plasmin-2–antiplasmin complex lasted until 6 hours postoperatively, followed by a decrease at 24 hours. (group C = control group; NS = not significant versus control; °p < 0.05; **p < 0.001.)

View larger version (29K): [in this window] [in a new window]   Fig 6. Course of levels of D-dimers. At all times postoperatively levels of D-dimers were significantly decreased in the tranexamic acid group (group TA) and the aprotinin group (group A) compared with control (group C) (**p < 0.001; ***p < 0.0001; °°°p < 0.0005.)

View larger version (37K): [in this window] [in a new window]   Fig 7. Course of factor VIIa level. The factor VIIa level showed a significant decrease in the aprotinin group (group A) versus the control group (group C) and the tranexamic acid group (group TA) intraoperatively. (NS = not significant versus control; °p < 0.05.)

View larger version (25K): [in this window] [in a new window]   Fig 8. Postoperative blood loss. In the tranexamic acid group (group TA) and the aprotinin group (group A), postoperative blood loss was significantly reduced versus controls (group C) at all times up to 24 hours. At 24 hours postoperatively blood loss was also significantly reduced in group TA versus group A. (**p < 0.001; ***p < 0.0001; °p < 0.05; °°p < 0.005; °°°p < 0.0005.)

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Antifibrinolytic therapy in patients undergoing elective coronary artery bypass grafting appears to be efficient in reducing postoperative blood loss [2, 4–6]. Liu and co-workers [10] and Landymore and colleagues [5] illustrated that low-dose regimens of antifibrinolytic agents have the same effect as the high-dose applications introduced into cardiac surgery in the mid-1980s by Royston and associates [7]. Although low-dose regimens of aprotinin such as the regimen of 2,000,000 KIU of aprotinin used in this study reduce costs to nearly one third of the costs of high-dose regimens of 5,000,000 to 6,000,000 KIU, each administration of an antifibrinolytic agent bears the risk of thrombembolic complications [8, 13]. Hence, it seems all the more important to adjust the antifibrinolytic medication to the time course of fibrinolysis. Concerning this matter, procoagulatory [14, 15] and fibrinolytic factors [10, 14–16] were investigated preoperatively, intraoperatively, and postoperatively in this study in patients undergoing primary bypass grafting. For this reason a perioperative low-dose aprotinin regimen was evaluated. It differs from other schemes published in that aprotinin was administered continuously beyond the cardiopulmonary bypass time. In comparison, a continuous dosage previously described by Horrow and co-workers [17] was used for tranexamic acid, which was also administered beyond cardiopulmonary bypass grafting and far into the postoperative phase. Analyzing Hb, Hct, and platelet count, no significant differences were noted among groups in this study. We thus confirm the results published in the literature [1, 18].

Global clotting parameters (aPTT, PT, TT, fibrinogen, and ATIII) were partly immeasurable during extracorporal circulation owing to systemic heparinization. With regard to aPTT, these findings support those of Hendrice and colleagues [3], who documented a significant difference between a patient population treated with high-dose aprotinin and a control group immediately after heparin antagonization with protamine.

These results further agree with the aPTT time course under tranexamic acid as described by Katsaros and associates [4]. Evaluating TT, our data are in congruence with those of other authors with reference to aprotinin treatment [18] and to treatment with tranexamic acid [4, 17]. De Smet and co-workers [19] analyzed—among other parameters—the concentrations of ATIII under a high-dose regimen of aprotinin. They found a decrease in ATIII level in the postoperative time course, which is in accordance with the data in this study.

With reference to procoagulation data, different statements are made in the literature regarding TAT complexes [14, 20]. In this context, Kawasuji and associates [15] observed no difference under low-dose aprotinin medication in comparison with a control group. In contrast to those findings, we were able to document a reduction of TAT complexes up to the first postoperative day with our new perioperative aprotinin regimen. Procoagulation as a reaction to fibrinolysis hence appears to be less pronounced in patient groups treated with antifibrinolytic agents than in group C. This could be an expression of adequate antifibrinolytic therapy. Prothrombin fragments F1+2 were investigated by Blauhut and associates [14]. In agreement with those authors, differences (although not significant) were substantiated in the various groups of our study, indicating a reduced fibrinolysis with antifibrinolytic drugs.

Regarding plasminogen as a fibrinolytic factor, we noted no differences among the three groups except in group C compared with group A preoperatively and 24 hours after heparin reversal with protamine. These results conflict with the findings of Liu and co-workers [10], who described a decline of plasminogen levels under low-dose aprotinin.

However, significant differences were found preoperatively between groups A and C. Referring to tranexamic acid, no data have been published to date. Evaluating ₂-antiplasmin levels, our observations also correspond to the findings of other authors [10, 14–16]. Apparently there is no difference between high-dose and low-dose aprotinin application concerning effective inhibition of plasmin by ₂-antiplasmin.

Our dosage regimen seems to be as efficient with regard to the fibrinolytic parameter ₂-antiplasmin as the dosage schemes used so far.

Plasmin-₂–antiplasmin complexes were investigated under low-dose aprotinin administration in the studies of Kawasuji and associates [15] and Mastroroberto and associates [16]. Even during cardiopulmonary bypass grafting, a significant reduction of PAP complexes were observed by both groups of authors. On the other hand, we were able to verify a decrease in PAP complexes not before 6 hours after heparin reversal with protame. When fibrinolysis takes place, fibrinogen cleavage products are detectable. We verified a decrease of D-dimer levels as a cleavage product of fibrinogen at all times in the perioperative and postoperative course of this study. In the tranexamic acid group the levels of D-dimers were within the reference range. These results also indicate adequate inhibition of fibrinolysis by the antifibrinolytic regimen applied in this investigation. By analyzing the levels of D-dimers it was proven that fibrinolysis occurs far into the postoperative phase and is not terminated with the administration of protamine. In contrast to the dosage regimen applied by Kawasuji and associates [15], which led to a significant decrease in fibrinogen cleavage products only for 1 hour after heparin reversal, the regimen used in this study seemed to be more efficient.

Preoperatively all of our patients had similar baseline values of activated factor VII. In the postoperative sequel a significant increase in factor VII activity was substantiated in all patient groups, especially 2 and 6 hours after protamine administration. This is in favor of extrinsic clotting system activation. On the first postoperative day, the activity of factor VII was—with the exception of group TA—impaired to such an extent that postoperative values fell below preoperative levels. Krück [21] and Petersen and colleagues [22] discussed an increased activity of factor VII as an additional risk factor in patients with coronary artery disease. This could result in a misinterpretation of preoperative values.

In contrast to the 14 healthy men, however, we were unable to find a difference in the preoperative FVIIa values of all patient groups. Further studies are needed to clarify whether the activated form of factor VII is to be considered as a cardiovascular risk factor.

Blood loss was significantly reduced in groups A and TA compared with control. Furthermore, blood loss was significantly reduced in group A compared with group TA at 24 hours after heparin reversal with protamine. The reason for this remains unclear. A possible explanation may be the relatively small population in each group.

This study provides insights into fibrinolytic processes related to coronary bypass grafting inasmuch as fibrinolysis persists after the end of operation. A perioperative low-dose regimen of aprotinin adjusted to the persistence of postoperative fibrinolysis reduces blood loss significantly. The next step could be individual antifibrinolytic treatment by analyzing the indicators of fibrinolysis to get an optimal dosage of antifibrinolytic agents.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Dr Hans-Jürgen Friedrich (Institute of Biomedical Statistics, Medical University of Lübeck, Germany) for help in statistical analysis, and Alexandra Jurat for excellent technical assistance in determining the data.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Martin Misfeld Hans-Hinrich Sievers Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Misfeld, M. Articles by Sievers, H.-H. Search for Related Content PubMed PubMed Citation Articles by Misfeld, M. Articles by Sievers, H.-H.