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Ann Thorac Surg 1997;63:57-63
© 1997 The Society of Thoracic Surgeons
Departments of Haematology and Cardiac Surgery, The Prince Charles Hospital, Brisbane, Queensland, Australia
Accepted for publication July 13, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. In a double-blind, randomized study, patients received high-dose aprotinin (n = 54) or placebo (n = 52). Whole blood aggregation was measured preoperatively. Platelet function and activation in both groups were assessed intraoperatively and postoperatively at five times.
Results. Aprotinin significantly reduced perioperative bleeding and postoperative blood transfusion. Placebo-treated patients with reduced preoperative platelet aggregation bled more postoperatively, but aprotinin reduced the bleeding in patients with normal or reduced platelet function to similar levels. Any cardiopulmonary bypass–induced changes in platelet aggregation, platelet activation as measured by P-selectin expression, and von Willebrand factor antigen and function were similar in aprotinin-treated and placebo-treated groups.
Conclusions. The mechanism by which aprotinin reduced bleeding was independent of any effect on platelet function. However, aprotinin produced a greater reduction in bleeding among patients whose condition was hemostatically compromised by preoperative platelet dysfunction.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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As well as causing thrombocytopenia either by hemodilution or sequestration, CPB has been reported to induce platelet dysfunction through hypothermia [6] or contact of the patient's blood with the CPB pump surfaces [7]. Either factor or both factors can lead to increased blood loss.
In recent years, the use of the serine protease inhibitor aprotinin during CPB has led to significant reductions in intraoperative and postoperative blood loss with a subsequent decrease in blood product transfusion requirements [8, 9]. The mechanism whereby aprotinin confers this advantage is uncertain, but reports have indicated that aprotinin may improve platelet function. Levels of thromboxane A2 during CPB have been shown to be lower in aprotinin-treated patients [10], a finding suggesting inhibition of platelet activation during CPB. Platelets from aprotinin-treated patients are more readily activated in vitro by cultured corneal endothelial cells than platelets from a matched placebo group [11], which may indicate a protective effect of aprotinin on platelet function. Alternatively, aprotinin may improve platelet function by its effect on components extrinsic to the platelet, such as VWF [12].
This study was designed to quantify the reduction in intraoperative and postoperative bleeding produced by aprotinin therapy in patients with normal or reduced preoperative platelet function and undergoing valve replacement with CPB. Various aspects of platelet function were studied during and after CPB.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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).
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Bypass technique and anticoagulation and blood replacement policies were as follows: Cobe CML membrane oxygenator (Cobe Cardiovascular, Arvada, CO) median temperature of 30.5°C with an interquartile range of 28° to 32°C; flow of 2.4 L/m2; heparin sodium regimen, 300 IU/kg initially plus 10,000 IU in the oxygenator before bypass (activated clotting time adjusted to >480 seconds); postoperative anticoagulation, started on the first postoperative morning and comprising aspirin and subcutaneous heparin; and blood transfusion trigger, hemoglobin level less than 80 g/L and bleeding of more than 150 mL/h for 2 successive hours.
Sample Collection
Blood was obtained from an indwelling catheter. Of the amount taken, 4.5 mL was added to 0.5 mL of 0.11 mol/L trisodium citrate (Labco, Exeter, UK) and 5.0 mL to the dipotassium salt of EDTA (ethylenediaminetetraacetic acid) for a final concentration of 3.7 mol/L (Exetainer; Labco), and stored at room temperature in unopened vials to minimize pH increase with storage [13]. Platelet function testing was performed within 30 minutes of collection (with the exception of the platelet mixing studies).
Blood samples were collected at five times: 5 minutes after induction of anesthesia (A); 5 minutes into cross-clamping (B); 30 minutes into cross-clamping (C); 60 minutes after the end of bypass (D); and about 24 hours after operation (E).
Preoperative Testing
Recent aspirin ingestion was recorded. Patients receiving aprotinin who had ingested aspirin stopped treatment 1, 3, 5, 6, 7 (n = 2), and 8 days before operation; placebo-treated patients stopped aspirin treatment 2, 5, 8, and 9 (n = 2) days before operation. A coagulation profile consisting of thrombin clotting time, prothrombin time, activated partial thromboplastin time, fibrinogen, and template bleeding time (Simplate II; Organon Teknika, Durham, NC) was done 1 day preoperatively. Whole blood aggregation was performed on a Whole-Blood Aggro-meter (model 560 VS; Chronolog Corporation, Haverton, PA) using collagen (Hormon-Chemie, Munich, Germany) at a final concentration of 1 µg/mL [13]. Platelet aggregation was considered reduced when the change in impedance after 2 minutes was less than 1.2 
[13].
Aprotinin or Placebo Administration
Patients assigned to the aprotinin group were given a test dose of aprotinin (preservative-free Trasylol; Bayer AG, Leverkusen, Germany) of 10,000 kallikrein inactivator units (KIU) (1.4 mg) to see whether there was a potential allergic reaction. Then aprotinin was administered as a dose of 2 x 106 KIU (280 mg) over 20 minutes after induction of anesthesia followed by 0.5 x 106 KIU/h (70 mg/h) until the patient was returned to the postoperative ward. In addition, 2 x 106 KIU (280 mg) was added to the oxygenator prime. Patients allocated to the placebo group received the equivalent volume of normal saline solution.
Blood Loss Measurements
The cumulative volume of postoperative mediastinal chest tube drainage was recorded hourly to the nearest 50 mL. Cumulative chest tube drainage was calculated 4, 8, 12, 16, 20, and 24 hours after the patient first reached the postoperative ward.
The hemoglobin level of the drainage fluid was measured once the drainage tubes were removed. With the 4-hourly drainage volume, median cumulative hemoglobin lost was calculated, normalized to body surface area (g/m2) for each 4-hour period in the first 24 hours postoperatively.
The frequencies of both intraoperative and postoperative transfusion of blood, platelets, and fresh frozen plasma were also recorded.
Perioperative Platelet Measurements
Platelet count and mean platelet volume were performed on EDTA specimens using an H•2 Technicon Haematology Analyser (Bayer AG).
Perioperative Platelet Aggregometry
A citrated sample was centrifuged at 150 g for 7 minutes to provide platelet-rich plasma (PRP). Another citrated blood sample was centrifuged at 3,000 g for 10 minutes to provide platelet-poor plasma. This was used to dilute PRP to provide a platelet count of 80 x 109/L, the estimated highest count that would accommodate all degrees of thrombocytopenia likely to be encountered during CPB. An optical aggregometer (Chronolog Lumi Aggro-meter model 400; Chronolog Corporation) was used for testing platelets with two agonists: collagen (final concentration in PRP, 4 µg/mL) and a thrombin receptor agonist (Auspep P/L, Melbourne, Australia) [14] (final concentration of 0.04 mol/L). This thrombin receptor agonist is an activating peptide directed to thrombin receptors of platelets that has been found to stimulate platelet activation and secretion. The amplitudes of the tracings were recorded 2 minutes 30 seconds after the addition of the agonist.
Platelet mixing aggregation studies were performed to investigate any effect of plasma factors present during or after CPB that might affect preoperative platelet function. These studies were carried out on citrated blood samples from times A, B, C, and D. Using blood collected at A as the source of preoperative platelets, PRP at a platelet count of 160 x 109/L was prepared, and 250-µL aliquots were added to four cuvettes. To each aliquot was added 250 µL of platelet-poor plasma from time A, B, C, or D; the diluted PRP had a platelet count of 80 x 109/L. Platelet function of these mixtures was measured by platelet aggregation with collagen and the thrombin receptor agonist.
Flow Cytometry
To assess the ability of platelets to be activated in vitro, phorbol 1 2-myristate 13-acetate (PMA) and (final concentration of 2 x 10-6 mol/L) was added to 500 µL of the EDTA sample, mixed, and allowed to stand for 60 seconds at room temperature. One hundred microliters of the activated sample was fixed by adding it to 1 mL of chilled 3.3 x 10-1 mol/L paraformaldeyde. For testing of in vivo platelet activation, 100 µL of EDTA blood was added to 1 mL of chilled 3.3 x 10-1 mol/L paraformaldehyde.
Fixed samples were washed with Dulbecco's phosphate-buffered saline solution without calcium and magnesium. To separate platelets from other cells during analysis, blood was stained with CD61 fluorescein isothiocyanate (Becton-Dickinson, San Jose, CA), an antibody directed against glycoprotein IIIa, a determinant present on all nonactivated and activated platelets. To detect platelet activation, blood was stained with CD62 phycoerythrin (Becton-Dickinson) directed against P-selectin, an antigen present on the alpha granule and internal in a resting platelet but externalized after platelet activation.
Flow cytometry analysis was performed on a FACScan analyzer (Becton-Dickinson). Results were expressed as the percentage of platelets staining positively for P-selectin, this value for platelets activated in vitro being expressed as PSACT.
Von Willebrand Factor
At each of the five times, antigenic levels of the adhesive protein VWF were measured by enzyme-linked immunosorbent assay [15], and the function of VWF was assessed by the ristocetin cofactor and collagen-binding assays [16]. The latter measures the more active large multimers of VWF.
Statistical Analysis
Nonparametric analyses were performed using SPSS version 6.1 statistical program, and values were expressed as medians and interquartile ranges. The Mann-Whitney U test was used for comparison of blood loss and platelet test results from the aprotinin-treated and placebo-treated groups; the Wilcoxon matched-pairs signed-rank test, for changes between perioperative and preoperative results; the Kruskal-Wallis one-way analysis of variance, for differences in bleeding between the three surgical procedures; Spearman correlation coefficients, for significant correlation between platelet count and blood loss; and 
2 analysis to evaluate differences in frequency of transfusion in the two treatment groups.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Surgeons' Assessment of Bleeding
The surgeons, unaware of which patients received the drug, graded the patients who received aprotinin as experiencing significantly less intraoperative bleeding than the placebo-treated group (p = 0.01). A majority of aprotinin-treated patients (64%) were assessed as having minimal to mild bleeding, whereas a majority of placebo-treated patients (53%) were assessed as having moderate or severe bleeding.
Blood Loss Measurements
During each of the six 4-hour postoperative periods, patients receiving aprotinin had greatly reduced median cumulative chest tube drainage compared with the placebo-treated group (p < 0.001) (Fig 1). The greatest reduction was in the first 4 hours postoperatively when the aprotinin-treated group had a median drainage rate of 25 mL/h compared with 50 mL/h in the group given the placebo. Between 4 and 8 hours postoperatively, median drainage rates in the aprotinin and placebo groups were 12.5 mL/h and 25 mL/h, respectively. For the 24-hour postoperative period, median total drainage in the aprotinin and placebo groups was 350 mL (interquartile range, 200 to 450 mL) and 525 mL (interquartile range, 350 to 700 mL), respectively (p < 0.001).
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). During the first and second 4-hour periods postoperatively, the loss was 1.2 and 2.2 g/m2, respectively, in the aprotinin group and 4.7 and 6.8 g/m2 in the placebo group (p < 0.0001). Over the first 24 hours postoperatively, there was a median hemoglobin loss of 5.0 g/m2 and 11.0 g/m2 in the aprotinin and placebo groups, respectively (p < 0.0001).
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). Postoperatively, only 7 (13%) of the 53 aprotinin-treated patients required blood transfusion compared with 19 (37%) of the 52 placebo-treated patients (p < 0.01). In the aprotinin group, no patient required platelet transfusion and only 1 (2%) was given fresh frozen plasma, whereas in the placebo group, 3 patients (6%) received platelets and 6, fresh frozen plasma (12%). The platelet and fresh frozen plasma transfusion rates were not significantly different between groups.
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).
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Platelet counts at each time after A were adjusted in proportion to the change in hematocrit from A to that time. In contrast to the actual platelet counts, these mathematically corrected counts were little different from A at B, C, D, or E (see Fig 4
). As this adjustment was artificial, no statistical analyses were performed on these counts. The corrected values demonstrated that platelet counts tended to drop at the same rate as red blood cell counts.
Once patient blood was circulating through the bypass pump (time B), there was a significant drop in mean platelet volume (p < 0.05). From time A to time B, median values for mean platelet volume in the aprotinin-treated group and the placebo-treated group dropped from 9.2 to 8.5 fL and 9.4 to 9.0 fL, respectively. These reduced values persisted at times C and D but had returned to preoperative values next day at time E. The changes in mean platelet volume were similar in the two groups.
Preoperative Platelet Function: Whole Blood Aggregometry
Preoperative WBAGG showed that 12 patients receiving aprotinin and 13 patients receiving the placebo had reduced platelet function. The results in ohms were as follows (median and interquartile range): normal WBAGG-aprotinin-treated patients, 2.3 (1.8 to 2.9), and placebo-treated patients, 1.8 (1.6 to 2.5); reduced WBAGG-aprotinin-treated patients, 0.7 (0.1 to 0.9), and placebo-treated patients, 0.6 (0.2 to 0.9). This could be related to recent aspirin ingestion in only 6 patients.
In the following assessment, median cumulative hemoglobin loss at each of the six 4-hour time intervals was used as the measure of postoperative bleeding. Initially, bleeding in the two subgroups of patients receiving aprotinin (ie, those with normal WBAGG and those with reduced WBAGG) was compared at each time interval. The difference between the two subgroups was not significant (Fig 5). As it was not possible to demonstrate a difference, the data were pooled in later comparisons.
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). This finding confirms the conclusion of our previous study [13].
Comparisons between the pooled aprotinin subgroups and each of the two placebo subgroups revealed a significant reduction in hemoglobin loss in the aprotinin group at each time interval (p < 0.001) (see Fig 5).
Platelet Aggregometry at Each Time
Platelet function, as reflected by platelet aggregometry using collagen and a thrombin receptor agonist as agonists, was not significantly different between the aprotinin and placebo groups at any of the five times. As the PRP platelet count was kept constant throughout, testing measured individual platelet function independently of concentration. Interestingly, there was no change in this platelet function measurement from A to any of the later times with either agonist in each group.
The platelet-poor plasma of each patient from times A, B, C, and D was mixed with his or her own PRP from A. The baseline was taken as the aggregation result when the PRP was mixed with the platelet-poor plasma from A. Platelet-poor plasma from later measurement times produced a marginal, but significant, enhancement of collagen- and thrombin receptor agonist–induced aggregation in both groups. However, again there was no difference in this effect between the aprotinin and placebo groups.
Flow Cytometry
IN VIVO PLATELET ACTIVATION DURING AND AFTER BYPASS.
The percentage of platelets expressing P-selectin was measured at each time from A to E. P-selectin expression results at all times were similar in the aprotinin and placebo groups. Increased platelet activation was not detected; the median percentages of P-selectin expression for the two groups at all five times were within the normal reference range established with healthy volunteers (0.4% to 4.6%).
ABILITY OF PLATELETS TO BE ACTIVATED IN VITRO WITH PMA.
Aprotinin produced no alteration in the ability of platelets to be activated in vitro, as PSACT with PMA was the same in the aprotinin and placebo groups (Fig 6). However, significant changes relative to A occurred at subsequent times in both groups. At B and C, the platelets were more readily activated as shown by the increase in the percentage of platelets expressing P-selectin after in vitro activation (p < 0.01). Values returned to preoperative levels by E.
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). This is consistent with the hemodilution resulting from the nonblood priming of the extracorporeal circuit occurring at this stage. Subsequently the levels of VWF increased significantly for 24 hours (p < 0.05). Measurements of VWF as antigen and as ristocetin cofactor showed comparable changes. Levels of VWF were similar in the aprotinin and placebo groups, except at times B and C when VWF levels measured as antigen and ristocetin cofactor were lower in the aprotinin group (p < 0.05).
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The main reductions in drainage and hemoglobin loss occurred during the first 4 hours in the postoperative ward. This is important, as it is during this period that patients most frequently are returned to the operating room because of excessive bleeding. Thus, as well as reducing the risk to the CPB patient, use of aprotinin provides cost savings through diminished transfusion requirements and the potentially lower incidence of further immediate operation for excessive bleeding. Against these pluses must be considered the considerable cost of the drug and the possibility of allergic reactions [17]. In this cost/benefit equation, it would be advantageous if patients needing aprotinin could be determined preoperatively. The surgeons were not able to predict which patients would have more bleeding. Previous work [13] at this institution has demonstrated that preoperative WBAGG testing provides an indicator of which patients will bleed excessively after CPB. The study described here demonstrated an increased benefit from aprotinin in patients with reduced preoperative platelet function. Preoperative WBAGG testing may help determine which patients will benefit most from aprotinin therapy.
The study has shown that aprotinin does not diminish bleeding through any protective effect during CPB on intrinsic platelet function. By diluting the PRP used in platelet aggregation testing to a constant platelet count, the effect of decreasing platelet concentration causing lower measurements was removed. Results showed that there was no diminution of the intrinsic ability of platelets to aggregate throughout bypass and the following 24 hours. The prolonged bleeding time observed by others [6, 18] during and after CPB may be a consequence of the lower tissue temperature associated with the procedure rather than CPB–induced platelet dysfunction. This hypothesis is supported by a study that showed a lack of clinical improvement in CPB patients receiving prophylactic platelet transfusion [19]. As expected, with no loss of platelet function for aprotinin therapy to prevent, there was no difference in platelet aggregation results between the aprotinin-treated and placebo-treated groups.
Although flow cytometry failed to demonstrate any significant platelet activation during CPB, it was shown that during the circulation of blood through the bypass circuit (times B and C), platelets had an increased susceptibility to activation in vitro. Like other sensitive indicators, eg, plasma ß-thromboglobulin levels [4], this measurement may show a degree of activation during bypass as platelets contact pump surfaces. Importantly, there was still no significant difference between the aprotinin and placebo groups.
Studies of factors extrinsic to the platelet failed to reveal any benefit from aprotinin on platelet function. Mixing intraoperative plasma with preoperative platelets failed to reveal in vitro any factor in intraoperative plasma that may have been impairing platelet function in vivo in either group. Thus, there was no imbalance for aprotinin to improve, and indeed there was no difference in the results of these mixing studies between the two treatment groups.
Von Willebrand factor was studied in detail as an extrinsic factor vital to platelet adhesion. It was not found to be part of the mechanism whereby aprotinin reduces blood loss. Levels rose significantly from B through C, D, and E. Confirming findings by Hamilton and associates [5], we found that VWF release from endothelial cells or alpha granules of platelets is the important event rather than its proteolytic degradation. Antigenic levels of VWF measure all VWF forms present, and it was shown that these levels were slightly lower in aprotinin-treated patients at B and C. Similar reductions in levels of VWF as assessed by collagen-binding assay at these times suggest decreased release of the more active multimeric forms of VWF with higher molecular weight. This indicates that aprotinin reduces VWF release, possibly through inhibition of the acute-phase inflammatory response. The clinical significance of these minor differences is doubtful, especially as they were not present at D and E.
The only other change detected in platelets during CPB was that brought about by thrombocytopenia. This thrombocytopenia is consistent with the degree of hemodilution, although consumption of platelets may have been compensated for by platelet release from the spleen [20]. As the platelet counts in the aprotinin and placebo groups were similar at each stage, aprotinin is not producing any effect on this, the only significant induced platelet dysfunction demonstrated.
In conclusion, high-dose aprotinin is effective in reducing bleeding during and after CPB. Aprotinin was more efficient in reducing bleeding in patients whose normal hemostatic mechanism was compromised by preoperative platelet dysfunction. However, it seems that CPB does not induce any change in platelets other than the temporary thrombocytopenia produced by hemodilution during the procedure. The mechanism of aprotinin-reduced blood loss is not conferred through any intrinsic or extrinsic effect on platelets.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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We thank all the cardiac surgeons, anesthetists, perfusionists, and nursing staff whose cooperation made the study possible; Dr Katherine McGrath, The Hunter Area Pathology Service, for advice on the manuscript; and Ian Smith for his invaluable help with the statistics and graphics. We appreciate the generous assistance of Laurie Kear, Lorraine McLoughlin, Jacci Green, and the phlebotomy staff. We also thank Dr Michael Berndt, Baker Medical Research Institute, Victoria, for his advice.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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