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Ann Thorac Surg 2000;69:541-547
© 2000 The Society of Thoracic Surgeons

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Original Articles

Amelioration of the bleeding tendency of preoperative aspirin after aortocoronary bypass grafting

^a Wellington Hospital, London, England, United Kingdom

Address reprint requests to Dr Bidstrup, Department of Surgery, University of Queensland, North Queensland Clinical School, PO Box 1805, Townsville, QLD 4810 Australia
e-mail: b.bidstrup{at}mailbox.uq.edu.au

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Aspirin therapy is widely used in the treatment of cardiac disease. It has been recognized as a causative factor for increased bleeding and blood loss after open heart operations.

Methods. To determine whether high-dose aprotinin maintained its efficacy in reducing blood loss in the presence of aspirin pretreatment in patients undergoing aortocoronary bypass, we performed a double blind study on 60 adult patients. Half received high-dose aprotinin (Trasylol) and half placebo.

Results. Total hemoglobin loss, the primary efficacy variable was reduced from 36.1 ± 31.4 g (mean ± SD) to 14.1 ± 16.0 g (p = 0.002). Blood loss was reduced intraoperatively and total loss was reduced from 837.3 mL ± 404.9 mL to 368.7 mL ± 164.3 mL (p < 0.001). The number of patients who did not receive any donor blood products was significantly higher in the aprotinin-treated patients (56.7% versus 23.3%, p = 0.008). Activation of the clotting cascade was significantly less in the treated patients toward the end of cardiopulmonary bypass both by measurement of thrombin–antithrombin III complex (p < 0.0001) and prothrombin fragment 1 + 2 (p < 0.0001). D-Dimer generation was significantly less from the onset of bypass and after reversal of heparin in the aprotinin-treated patients (p < 0.0001).

Conclusions. High-dose aprotinin was highly effective in reducing bleeding in this high-risk group of patients. Biochemical analyses suggest the mechanism by which aspirin increases blood loss after cardiopulmonary bypass is different from the blood-preserving effects of aprotinin, which is acting as an antifibrinolytic agent.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The ability of aspirin to acetylate irreversibly cyclo-oxygenase, and thereby inhibit platelet function is responsible for its wide use in the treatment of cardiovascular disease. Aspirin has been shown both alone and in conjunction with other drugs to reduce mortality after myocardial infarction [1], to improve aortocoronary bypass graft (ACBG) patency [2, 3] and is beneficial in the treatment of unstable angina [4]. It has been shown to reduce cerebrovascular events in patients with carotid artery disease and may enhance long-term survival after ACBG [5, 6].

By inhibiting cyclo-oxygenase, the synthesis of thromboxane A₂ is reduced, decreasing the ability of platelets to aggregate when stimulated. The initial adherence of platelets to an area of damaged endothelium or exposed subendothelium is not inhibited. The anuclear platelet is unable to resynthesize cyclo-oxygenase. For recovery, a new population of platelets must be generated, a process that takes approximately 10 days [7].

Because of its beneficial effects in cardiovascular disease, the majority of patients who present for coronary artery bypass grafting are taking aspirin. Aspirin ingestion results in a prolonged skin bleeding time, and an increased tendency for surgical bleeding. Prospective studies have shown that preoperative exposure to aspirin results in increased bleeding, increased exposure to blood products, increased time in the intensive care unit, prolonged hospital stay, and increased incidence of reexploration for bleeding [8–10].

To decrease bleeding related to aspirin exposure, patients requiring operation involving cardiopulmonary bypass (CPB) are often deferred and aspirin stopped until the platelet population has regenerated. This may increase the risk of cardiac events before operation.

Aprotinin, a broad spectrum serine protease inhibitor, has been shown previously to reduce bleeding after all forms of open heart operations, and is relatively free of side effects [11, 12]. Many of the earlier studies excluded patients who had been taking platelet inhibitory drugs such as aspirin [13].

The purpose of this study was to determine whether high-dose aprotinin maintained its effectiveness in the presence of aspirin pretreatment in patients undergoing ACBG. Evaluation of markers of hemostatic activation was carried out to study the possible mechanisms of action of aprotinin. Should aprotinin be effective in reducing bleeding in these patients, conclusions may be drawn about the mechanisms of bleeding after CPB, and possibly the effect of aspirin.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Sixty adult patients undergoing first time ACBG with two or more grafts planned, were admitted to a placebo-controlled double blind study at the Wellington Hospital, London. All patients continued to take aspirin until less than 24 hours before operation, and had been taking more than 75 mg/day for no less than 7 days before operation. Patients were excluded if they had a known allergy to aprotinin, had a past history of pancreatitis, or were undergoing a reoperation. Patients with unstable angina requiring intravenous administration of heparin or other cardiac drugs were also excluded.

Patients were allocated to receive either the placebo or active treatment in accordance with a previously determined randomization schedule in a double blind fashion. Active drug and placebo were contained in identical bottles, identifiable only by the random number. The active drug was aprotinin (Trasylol, Bayer plc, Newbury Berks, UK) 70 mg in 50 mL. Aprotinin or placebo was administered according to our previously described regimen: a loading dose after anesthesia of 280 mg over 20 minutes and an infusion of 70 mg/h until the end of the procedure. Another 280 mg was added to the prime of the CPB circuit [13].

All patients gave written, informed consent to enter this study. The protocol was reviewed and approved by the Ethical Committee of our institution.

The primary criterion for efficacy was total hemoglobin loss into the chest drains after chest closure. Intraoperative blood loss in the swabs and suction was carefully recorded, as was chest drainage, which was recorded at six hourly intervals until removal (usually 18 to 24 hours postoperatively), at which time the total hemoglobin content was measured. All infusions of blood and blood products throughout the hospital stay were recorded.

Before operation, after physical examination, electrocardiogram, chest roentgenogram, baseline hematologic and biochemical variables were measured. These were repeated 24 hours and 7 days after operation.

Intraoperatively, blood samples were taken after induction of anesthesia, after aprotinin loading dose, 10 minutes on CPB, 45 minutes on CPB, at the end of CPB, 10 minutes after protamine administration, and 60 minutes after protamine administration. Blood samples taken at these time points were placed into appropriate anticoagulants and over ice if needed. Citrated plasma (1/10) was separated by centrifugation at 2000g for 20 minutes at 4°C, and transferred to microcentrifuge tubes, frozen and stored at -80°C for later analyses. Samples for immediate hematologic analysis were taken into potassium ethylenediaminetetraacetic acid.

Blood samples previously stored were analyzed using commercially available kits for antithrombin III (Instrumentation Laboratory, Milan, Italy), kallikrein inhibition capacity (Channel Diagnostics, Kent, UK), Thrombin–antithrombin III complex (Behring, Marburg, Germany), prothrombin fragment 1 + 2 (Behring), tissue plasminogen activator antigen (Porton, Cambridge, UK), and urokinase plasminogen activator antigen (Biopool, Porton). Fibrin degradation products (D-dimer) were measured by enzyme-linked immunosorbent assay. Normal ranges were established by sampling from healthy volunteers who had refrained from platelet-active drugs before sampling. Analyses were performed at the Hematology Research Center, Harefield Hospital.

Patients underwent first time ACBG in a manner similar to that previously described [13]. Harvey-H5000 membrane oxygenators were used in all cases (Bard Pty Ltd, Kent, England). Myocardial preservation was achieved with intermittent, antegrade cold blood cardioplegia. All patients were cooled to a core temperature of 29°C and warmed to 37°C before discontinuation of CPB. When deemed appropriate by the surgical team, 1 U (approximately 440 mL) of autologous blood was withdrawn into an anticoagulant-containing bag after induction of anesthesia but before CPB, stored at room temperature and reinfused after the cessation of CPB. Chest drains were placed in the mediastinum and pericardial cavities, and in the pleural cavity where it had been opened to facilitate removal of the internal mammary artery. Chest drainage measurements represent the aggregate of all drains in place. Mediastinal reinfusion was not used in this study.

The remainder of the procedure was standardized in keeping with appropriate patient management.

Logistic problems led to detailed biochemical hematology analyses being carried out consecutively on the last 48 of the 60 patients admitted to this study.

Statistical analysis
Patient data were analyzed on an intention-to-treat basis. All data were analyzed for safety. Statistical analyses of continuous variables were performed by the use of appropriate t tests, and those of discrete variables by the use of ² tests. Blood loss data were transformed on the assumption that the population was log normally distributed, and this was based on inspection of the data. Repeated measures analysis of variance was carried out on data collected at multiple time points during the study where appropriate.

For all tests on the hypothesis, a significance level of 0.05 was used. The size of the study population had been selected based on previous pilot data that assumed that the hemoglobin loss in untreated patients would be approximately 44 g in 24 hours, and that a 50% reduction was significant [14].

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Both groups were similar in respect to age, sex, and body weight (Table 1). All patients filled the criteria for evaluation of primary efficacy and safety variables.

Blood loss intraoperatively as measured by swab weighing and suction measurement was reduced by 33% (p = 0.002). Postoperative chest drainage at each of the 6-hour postoperative intervals was significantly less. In particular the difference after the first 6-hour period was 61%, p < 0.001. Total chest drainage was reduced from 837 to 368 mL, p < 0.001 (Fig 1). Donor blood transfusion was significantly less in the treated patients with 17 (56.7%) of the aprotinin group and 7 (23.3%) of the placebo group receiving no donor blood. This difference was statistically significant (p = 0.008). The mean volume of transfused donor blood was 389.5 ± 563 mL in the aprotinin group and 656 ± 656 mL in the placebo group. Although there was a trend toward reduced donor blood requirements in the aprotinin group, this did not reach statistical significance (p = 0.096). The reinfusion of autologous blood had no effect on either blood loss or use of other blood products.

View larger version (12K): [in this window] [in a new window]   Fig 1. Chest drainage after 6 hours and total. Reduction in drainage was statistically significant between aprotinin and placebo at both time points (p < 0.001; mean ± standard deviation [SD]).

Platelet counts were identical preoperatively, decreased during the course of CPB, and then were returned within the normal range by 24 hours postoperatively. There were no significant differences between the two groups. White cell counts followed a similar course in both groups, with a leukocytosis present 60 minutes and 24 hours postoperatively, but returning to within the normal range by 7 days.

Renal and hepatic function measurements showed no differences between the two groups preoperatively, 24 hours postoperatively, and at 7 days. In particular, urea and creatinine levels were similar. Two patients in the aprotinin group had increases in serum creatinine levels to more than 44 mmol/L, which is equivalent to 0.5 mg/dL, above baseline at either 24 hours or 7 days postoperatively. Both of these patients had elevated baseline creatinine levels, indicating compensated renal insufficiency.

Antithrombin III levels were measured at the previously indicated time points. This showed a decrease associated with the onset of CPB and in keeping with the amount of hemodilution that occurred. The levels remained relatively constant throughout the course of CPB. Levels were not statistically significantly between each group. Kallikrein inhibition was similar after anesthesia induction and increased significantly in the aprotinin-treated patients after the administration of the loading dose (p < 0.001, by analysis of variance). This difference was maintained throughout the course of bypass and postoperatively.

The levels of tissue plasminogen activator antigen were similar between the two groups. There was a slight decrease associated with hemodilution after the onset of CPB. There was a gradual increase during the course of bypass, although this was only slightly higher than the normal range at the end of CPB. Levels increased immediately after the administration of protamine, but at 60 minutes after administration they were identical and similar to that seen at the baseline measurement (Fig 2). Urokinase plasminogen activator antigen levels remained constant after onset of CPB despite hemodilution and did not decrease subsequently. There was no significant difference between the two groups.

View larger version (18K): [in this window] [in a new window]   Fig 2. Tissue plasminogen activator (tPA) antigen levels. There were significant changes within each group during the course of cardiopulmonary bypass (CPB) but not between groups. p (by analysis of variance) = 0.0001. (Prot = protamine.)

View larger version (20K): [in this window] [in a new window]   Fig 3. Thrombin–antithrombin III (TAT III) complex levels. There was a significant increase in levels within each group. Levels differed significantly at the end of cardiopulmonary bypass (CPB) and after protamine (prot). *p = 0.001.

View larger version (19K): [in this window] [in a new window]   Fig 4. Prothrombin fragment 1 + 2 levels. The levels increase significantly within each group with time. They differ significantly at the end of cardiopulmonary bypass (CPB) and after protamine (Prot). *p = 0.0001.

View larger version (14K): [in this window] [in a new window]   Fig 5. D-dimer levels. The levels increase significantly after the onset of cardiopulmonary bypass (CPB) in each group. They differed significantly between groups after the onset of cardiopulmonary bypass; *p < 0.0001. (Prot = protamine.)

	Comment

Top Abstract Introduction Patients and methods Results Comment References

The ability to reduce the bleeding tendency associated with aspirin during cardiac operation has important clinical implications. More patients are presenting with unstable angina or poorly controlled angina despite maximal medical therapy, a major component of which is aspirin. Clinical circumstances often override deferment. Comorbidity is also increased as excessive bleeding results in prolonged operations, prolonged intensive care unit stay, and an increased incidence of reoperation [9]. This study did not set out to determine the effect of aspirin before operation on each patient. This is one possible cause for some of the variability seen in other studies such as the one by Taggart and colleagues [15] on blood loss after coronary artery bypass grafting.

Previous studies using high-dose aprotinin from this center excluded patients who had been exposed to aspirin and similar platelet inhibitor agents. The blood loss in the placebo group in the current study was some 30% higher than these earlier studies [13, 16]. This is in keeping with the presence of aspirin leading to an increase in blood loss. There had been little change in the procedures likely to affect bleeding apart from the introduction of a less traumatic membrane oxygenator. When the losses in patients (not on aspirin) treated with high-dose aprotinin in the two recent studies are compared (309 mL [13], 390 mL [16]) with patients on aspirin in the current study (368 mL), there is no significant difference. The addition of aspirin does not increase the risk of postoperative bleeding if high-dose aprotinin is used.

Adverse events were equally distributed between the two groups of patients. In particular, the incidence of perioperative myocardial infarction was equally distributed with 2 patients per group. This is at variance with the findings of Cosgrove and colleagues [17], and may represent a protective effect of aspirin against perioperative myocardial infarction, or may represent a different approach to anticoagulation and systemic heparin management during the course of the bypass procedure. The mean bypass time in this particular study was 67 minutes, which is considerably less than that reported by Cosgrove and associates on patients undergoing repeat coronary operations. The patient population is different, but under the circumstances of bypass grafting, one would expect to see a higher incidence of perioperative myocardial infarction in the aspirin-treated patients in this study if aprotinin was prothrombotic as suggested by that group. Other reports have shown that the incidence of myocardial infarction is not increased by aprotinin [18, 19] Another indicator of thrombotic events, neurologic injury, was equally distributed. Murkin and colleagues [20] reported that there was a lower incidence of neurologic injury in the aprotinin-treated group, suggesting that aprotinin provided protection against neurologic damage. There were minimal changes in the serum creatinine levels in this study, with increases seen only in patients who had preoperatively impaired renal function as indicated by an increased serum creatinine.

The markers of hemostatic activation, thrombin–antithrombin III and prothrombin fragment 1+2 (released when the complex acts on prothrombinase) showed there was less thrombin generation in the aprotinin-treated patients at the end of bypass and after the reversal of heparin. This is in keeping with the findings of Dietrich and colleagues [21] and has been described as an anticoagulant effect. It has been presumed that this is related to the antikallikrein effect of aprotinin, thus reducing the activation of the intrinsic coagulation pathway, for kallikrein increases the release of factor XIIa. This is probably relevant to hemostatic activation during CPB despite the hypothesis of Boisclair and associates [22] that the major source of this activation is not through the intrinsic pathway but related to tissue factor generation during CPB. The source of tissue factor is likely the endothelium, in response to complement and cytokine generation [23].

Despite the mild anticoagulant effect, aprotinin is not a substitute for heparin. Such recommendations have been based mainly on the findings of prolonged activated clotting times with aprotinin. This is mainly due to an artifactual elevation of the clotting time relating to the use of celite as the activating agent, although the decrease in thrombin–antithrombin III levels suggest there is a mild anticoagulant effect toward the end of CPB, when the patient is being rewarmed to 37°C. There is less prolongation of the activated clotting time when kaolin is used as the activating agent (BP Bidstrup, unpublished data) [24].

There were marked differences in the levels of D-dimers, which were elevated immediately after the onset of anesthesia. After aprotinin administration, there was a marked decrease in fibrinolytic activity, which persisted early into the postoperative phase. Urokinase plasminogen activator antigen levels did not decrease with hemodilution and remained constant during and after bypass. This suggests that there was initial release with the commencement of CPB that was not sustained. In contrast, tissue plasminogen activator levels decreased after onset of CPB but then increased to greater than baseline. This suggests that the early phase of increased fibrinolytic activity is mediated through the intrinsic or direct pathway, whereas the latter phase is through the tissue plasminogen activator (extrinsic) pathway [25, 26]. This supports the concept that aprotinin is acting mainly as an antiplasmin agent.

Whether aprotinin has a direct effect on platelets as suggested by Van Oeveren and colleagues [27] in the past, it can be reevaluated in the light of other recent publications. Kestin and associates [28] have suggested that the platelet defect after CPB may well be secondary to the lack of a suitable agonist (thrombin) in the presence of high doses of heparin. They showed minimal reductions of the adhesive glycoprotein receptor GP1B. George and Rinder and their colleagues [29, 30], who have also examined this using slightly different methods, have shown that there has been a slight reduction of GP1B, but the levels have been maintained within the normal range. Orchard and associates [31] compared the effect of aprotinin and placebo on GP1B and glycocalicin release (from lysis of GP1B). They found no difference in GP1B levels or glycocalicin release. The early hypothesis that plasmin causes proteolysis of platelet GP1B during CPB can now be discounted. There may, however, be other effects of plasmin activation as suggested earlier.

This study demonstrates that aprotinin reduces bleeding in aspirin pretreated patients undergoing ACBG without increased perioperative morbidity. The hemostatic data supports other studies that demonstrate the main mechanism of action of aprotinin is as an antiplasmin agent with no direct effect on platelets.

	Footnotes

 
This study was sponsored in part by Bayer UK Ltd. Doctors Bidstrup and Hunt at times have received honoraria from Bayer UK Ltd for participation in scientific panels and advisory boards.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Second International Study of Infarct Survival (ISIS 2) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction. Lancet 1988;2:349-360.[Medline]
2. Gavaghan T.P., Gebski V., Baron D.W. Immediate postoperative aspirin improves vein graft patency early and late after coronary bypass surgery. Circulation 1991;83:1526-1533.[Abstract/Free Full Text]
3. Goldman S., Copeland J., Moritz T., et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy. Circulation 1988;77:1324-1332.[Abstract/Free Full Text]
4. Theroux P., Ouimet H., McCans J. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105-1111.[Abstract]
5. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-1294.[Free Full Text]
6. Johnson W.D., Kayser K.L., Hartz A.J., Saedi S.F. Aspirin use and survival after coronary bypass surgery. Am Heart J 1992;123:603-608.[Medline]
7. Beving H., Eksborg S., Nordlander R., Olsson P., Olsson U. Effects on cyclo-oxygenase of low and high dose aspirin. Thrombosis Research 1990;59:227-235.[Medline]
8. Ferraris V.A., Ferraris S.P., Lough F.C., Berry W.R. Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 1988;45:71-74.[Abstract]
9. Sethi G.K., Copeland J.G., Goldman S., Moritz T., Zadina K., Henderson W.G. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy. J Am Coll Cardiol 1990;15:15-20.[Abstract]
10. Bashein G., Nessly M.L., Rice A.L., Counts R.B., Misbach G.A. Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 1991;151:89-93.[Abstract/Free Full Text]
11. Lemmer J., Jr, Stanford W., Bonney S.L., et al. Aprotinin for coronary bypass operations. J Thorac Cardiovasc Surg 1994;107:543-551.[Abstract/Free Full Text]
12. Havel M., Grabenwoger F., Schneider J., et al. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994;107:807-810.[Abstract/Free Full Text]
13. Bidstrup B.P., Royston D., Sapsford R.N., Taylor K.M. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364-372.[Abstract]
14. Bidstrup B.P., Royston D., McGuiness C., Sapsford R.N. Aprotinin in aspirin-pretreated patients. Perfusion 1990;5(Suppl):77-81.
15. Taggart D.P., Siddiqui A., Wheatley D.J. Low-dose preoperative aspirin therapy, postoperative blood loss, and transfusion requirements. Ann Thorac Surg 1990;50:425-428.
16. Bidstrup B.P., Underwood S.R., Sapsford R.N., Streets E.M. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993;105:147-153.[Abstract]
17. Cosgrove D.M., III, Heric B., Lytle B.W., et al. Aprotinin therapy for reoperative myocardial revascularization. Ann Thorac Surg 1992;54:1031-1038.[Abstract]
18. Lemmer J.J., Dilling E., Morton J., et al. Aprotinin for primary coronary artery bypass grafting. Ann Thorac Surg 1996;62:1659-1667.[Abstract/Free Full Text]
19. Pifarre R. Use of aprotinin in the control of bleeding during cardiopulmonary bypass surgery—current status. Clini Appl Thromb Hemost 1998;4:2-6.
20. Murkin J.M., Lux J., Shannon N.A., et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994;107:554-561.[Abstract/Free Full Text]
21. Dietrich W., Spannagl M., Jochum M., et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-1126.[Medline]
22. Boisclair M.D., Lane D.A., Philippou H., et al. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-3357.[Abstract/Free Full Text]
23. Boyle E.M., Jr, Verrier E.D., Spiess B.D. Endothelial cell injury in cardiovascular surgery. Ann Thorac Surg 1996;62:1549-1557.[Abstract/Free Full Text]
24. Wang J.S., Lin C.Y., Hung W.T., Karp R.B. Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin. Anesthesiology 1992;77:1080-1084.[Medline]
25. Stibbe J., Kluft C., Brommer E.J., Gomes M., de Jong D.S., Nauta J. Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 1984;14:375-382.[Medline]
26. Kluft C., Dooijewaard G., Emeis J. Role of the contact system in fibrinolysis. Semin Thromb Hemost 1987;13:50-68.[Medline]
27. Van Oeveren W., Eijsman L., Roozendaal K.J., Wildevuur C.R. Platelet preservation by aprotinin during cardiopulmonary bypass. Lancet 1988;1:644.[Medline]
28. Kestin A., Valeri C., Khuri S., et al. The platelet function defect of cardiopulmonary bypass. Blood 1993;82:107-117.[Abstract/Free Full Text]
29. George J., Pickett E., Saucerman S., et al. Platelet surface glycoproteins. J Clin Invest 1986;78:340-348.
30. Rinder C.S., Mathew J.P., Rinder H.M., Bonan J., Ault K.A., Smith B.R. Modulation of platelet surface adhesion receptors during cardiopulmonary bypass. Anesthesiology 1991;75:563-570.[Medline]
31. Orchard M.A., Goodchild C.S., Prentice C.R.M., et al. Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol 1993;85:533-541.[Medline]

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