J Thorac Cardiovasc Surg 2005;130:791-796
© 2005 The American Association for Thoracic Surgery
Surgery for Acquired Cardiovascular Disease |
Prediction of the excessive perioperative bleeding in patients undergoing coronary artery bypass grafting: Role of aspirin and platelet glycoprotein IIIa polymorphism
W. Morawski, MD, PhD
a
,
*
,
M. Sanak, MD, PhD
b
,
M. Cisowski, MD, PhD
a
,
M. Szczeklik, MD
a
,
W. Szczeklik, MD, PhD
b
,
J. Dropinski, MD, PhD
b
,
T. Waclawczyk, MD
a
,
R. Ulczok, MD
a
,
A. Bochenek, MD, PhD
a
a First Cardiac Surgery Department, Medical University of Silesia, Katowice, Poland
b Department of Medicine, Jagellonian University School of Medicine, Krakow, Poland.
Received for publication November 30, 2004; revisions received February 12, 2005; accepted for publication February 24, 2005.
* Address for reprints: Wlodzimierz Morawski, MD, PhD, 45/47 Ziolowa St, 40-635, Katowice, Poland (Email: wmorski{at}wp.pl).
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Abstract
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OBJECTIVE: The presence of the glycoprotein IIIa allele PlA2 is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin, which could favor coronary thrombosis. We wondered whether PlA1/A2 genetic polymorphism could affect the postoperative bleeding in patients undergoing coronary artery bypass grafting. We also aimed to assess the effects of aspirin pretreatment and to ascertain the value of platelet function studies as predictors of postoperative bleeding.
METHODS: In a randomized, double-blind study, patients undergoing coronary artery bypass grafting were pretreated with a 150-mg dose of aspirin orally 12 and 3 hours before surgery (n = 51, 41 elective) or with placebo (n = 51, 43 elective). The hemostasis was monitored by Simplate (bioMérieux, Inc, Durham, NC) bleeding time and capillary closure time (platelet function analyzer PFA 100; Sysmex UK Ltd, Milton Keynes, United Kingdom). Postoperative bleeding and blood products transfusions were recorded. The glycoprotein IIIa polymorphism was analyzed.
RESULTS: Bleeding was significantly greater in PlA1 homozygotes from control group. Blood loss was significantly greater (by 25%) in aspirin group. The volume of blood products transfusions in aspirin patients was significantly larger (by 137%). When subjects were stratified accordingly to blood platelet glycoprotein IIb/IIIa genotype, in the aspirin group PlA2 carriers had greater blood loss than PlA1 homozygotes (1858 ± 932 mL vs 1216 ± 525 mL, P < .05).
CONCLUSION: PlA1 homozygotes normally had a greater risk of perioperative bleeding. Capillary closure time had no advantage relative to Simplate bleeding time in predicting postoperative blood loss. Aspirin pretreatment revealed no beneficial effects and resulted in increased postoperative bleeding and requirement for blood product transfusions after coronary artery bypass grafting in patients with stable angina. It was most unfavorable for PlA2 carriers.
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Introduction
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Morawski
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Aspirin is a widely established drug in the treatment of coronary artery disease. It has been proved to decrease the risk of cardiovascular events, especially in coronary artery disease. According to the American College of Cardiology and the American Heart Association, it should be used by every patient at risk for coronary artery disease unless there are specific contraindications.
The benefits of an early introduction of aspirin after coronary artery bypass grafting (CABG) have been well documented. The recent American College of Cardiology and American Heart Association Practice Guidelines for CABG
1
strongly recommend aspirin as a drug of choice against early vein graft closure in the first postoperative year
2,3
and advice its introduction in the first 6 hours after the surgery because it reduces risk of myocardial infarction, stroke, renal failure, and bowel infarction.
4
Early postoperative introduction of aspirin is associated with improved early graft patency.
5
Postoperative aspirin therefore is now a criterion standard and should be administered routinely shortly after surgery.
In contrast, aspirin administered before surgery increases the postoperative blood loss because of its antiplatelet action.
6
It is also associated with increased risk of transfusion, reexploration for bleeding, and prolonged wound healing time.
1
However, there are some data suggesting that this is not true for all patients.
7-9
Thus some patients could probably benefit from preoperative use of aspirin also.
10,11
If possible, aspirin should be stopped 7 to 10 days before the surgery, and this is often a problem. Many patients with acute coronary syndromes receive aspirin because its benefits outweigh the risk of postoperative bleeding. If an urgent operation is required, it is not possible to withdraw the aspirin.
The emerging data point to an important role of platelets early after CABG, separate and distinct from their contributing role in long-term patency of grafts. The formation of occlusive platelet aggregates involves the cross-linking of activated glycoprotein IIb/IIIa receptors on adjacent platelets by fibrinogen and other macromolecular ligands. A single nucleotide transition at position 1565 in exon 2 of the gene encoding glycoprotein IIIa leads to its diallelic polymorphism (PlA1/A2). PlA2 is present in 20% to 30% of the white population and is associated with enhanced thrombin formation and an impaired antithrombotic action of aspirin, which might favor coronary thrombosis in PlA2 carriers.
This study was based on two hypotheses, that PlA1/A2 polymorphism influences bleeding after CABG and that platelet function studies have predictive value for perioperative blood loss in patients who were taking aspirin when they were operated on.
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Patients and Methods
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The randomized, double-blind study included two groups with a total of 102 patients with coronary artery disease referred for CABG. The vast majority of cases were elective (80.4% vs 84.3%, aspirin vs control group, respectively). Ten patients in the aspirin group and 8 in the control group underwent operation on an urgent basis, and they were treated with preoperative intravenous nitroglycerin and heparin. Patients were assigned to the treatment groups (aspirin vs control) with a computer pseudorandom number generator. Odd and even numbers were used to assign aspirin and placebo, respectively, and the study team was not aware of the number assigned. After completion of the study, the numbers were decoded and the patients were analyzed according to treatment (aspirin or placebo). The study medication was prepared in the pharmacology department of our center. None of the patients was treated with any antiplatelet agents for 10 days before the operation. In the first group, patients (n = 51) received 150 mg aspirin 12 hours and 3 hours before surgery; patients from the second group (n = 51) received placebo. The study was approved by the university ethics committee, and all patients gave informed consent to participate.
All patients were anesthetized under the same protocol. Median sternotomy, cardiopulmonary bypass (CPB), moderate hypothermia (28°C), and blood cardioplegia were used. Intravenous heparin was administered (300 U/kg) before ascending aorta cannulation. Additional doses of heparin (100 U/kg) were given after 60 minutes of CPB. Activated clotting time (ACT) was kept at greater than 480 seconds. Once the patient was weaned from CPB, protamine sulfate (3 mg/kg) was given to reverse the anticoagulant action of heparin. If a patient required mechanical support (intra-aortic balloon pump), additional doses of intravenous heparin were given to maintain ACT at the level of 180 to 200 seconds. In such instances, no reversal treatment (protamine sulfate) was administered unless the patient had excessive bleeding.
Patient demographic data (sex, age, weight, height), medical history (history of stroke, hypertension, diabetes, chronic obstructive pulmonary disease, renal failure, or peripheral artery disease and Canadian Cardiovascular Society and New York Heart Association functional classes) were obtained before the operation.
During and after the operation, CPB time, crossclamp time, number of grafts, use of left internal thoracic artery, need for inotropes (dopamine, epinephrine), and mechanical (intra-aortic balloon pump) support were recorded. Serum levels of creatinine kinase and its heart fraction (CK-MB) and troponin I were monitored and recorded before the operation and on days 0, 1, and 3. When the previously mentioned markers were elevated, they were assessed during another 2 consecutive days. Electrocardiography (ECG) was recorded during admission, on the day of the operation, and on postoperative days 0, 1, 3, and 7. Perioperative myocardial infarction was diagnosed when one of the following was observed: new Q wave in ECG, CK-MB greater than 50 U with ECG changes, or 4-fold increase in CK-MB level independent of ECG changes. The need for reexploration for bleeding (differentiation between surgical bleeding and oozing), postoperative renal failure (postoperative serum creatinine level >2.0 mg/dL or elevation of >50% over baseline), infections (deep sternal site infection), need for prolonged mechanical ventilation (more than 3 days according to the analysis performed by Branca and colleagues
12
), length of stay in the intensive care unit (ICU), length of hospitalization, and deaths were recorded.
Before and after the operation (days 0, 1, 3, and 7), whole blood cell count was recorded. After operation, immediately after transfer of the patient to the ICU, and 24 hours later, Simplate R (bioMérieux, Inc, Durham, NC) bleeding time was measured. Before the operation, 10 and 30 minutes after establishment of CPB, after transfer of the patient to the ICU and 24 hours after surgery, closure time was measured with the PFA-100 analyzer (Sysmex UK Ltd, Milton Keynes, United Kingdom). This is an ex vivo study in which whole blood is sucked into capillary tube. The high shear-stress rate causes platelet activation and aggregation. Two types of membranes are used, coated with epinephrine and collagen and with adenosine and collagen, both potent platelet activating agents. The analyzer measures the time in which blood clots inside the capillary tube (closure time).
13
The glycoprotein IIIa polymorphism was analyzed after the operation. Genomic DNA samples were obtained by standard methods from peripheral blood leukocytes of the subjects studied. DNA concentration was quantified with spectrophotometry. A 282–base pair fragment from exon 2 and intron 2 of the glycoprotein IIIa gene coding region were amplified with specific primers by using polymerase chain reaction. Reaction products were digested with MspI restriction endonuclease, and 125– and 157–base pair fragments were seen only if PlA2 allele was present because of the MspI restriction enzyme cutting site at the thymine to cytosine replacement. Genotypes were scored on 1.5% agarose gel (SFR Agarose; Amresco, Solon, Ohio) and stained with 0.5µg/mL ethidium bromide under a UV transilluminator.
Intraoperative blood loss was measured by quantifying the amount of blood in the external suction reservoir and by weighing the swabs. Postoperative blood loss was recorded as the volume of chest tube drainage connected to at four-chamber Sherwood collection bag that was kept under suction of –15 mm H2O for the first 12 hours after the operation.
A hemoglobin level below 8.0 g/dL was the threshold for blood transfusion. The numbers of units transfused of packed red blood cells, fresh-frozen plasma, and platelets was recorded. No antifibrinolytic agents (
-aminocaproic acid, tranexamic acid) or serine protease inhibitors (aprotinin) were used in the study.
Platelet count, prothrombin time, and ACT were measured directly after transfer of the patient to the ICU. If ACT was elevated, an additional dose of protamine sulfate was administered. In case of elevated prothrombin time, patient was treated with fresh-frozen plasma (10-15 mL/kg). If excessive bleeding persisted or platelet count was less than 80,000 cells/µL after correction of these clotting abnormalities, platelet transfusion was done. The dose of platelet concentrate was individually calculated for every patient by the blood bank. The calculations were based on body weight, height, and platelet count. From the first postoperative day on, 150 mg of aspirin was administered orally.
Statistical Analysis
Statistical evaluation was performed with a personal computer and Statistica 5.5 software (StatSoft Inc, Tulsa, Okla). Summary statistics were expressed as means and SDs or 95% confidence intervals. The general linear model, including analysis of variance (the Kolomogorov-Smirnov variant) and multivariate analysis of variance, was used. The 
2 approach for testing Hardy-Weinberg equilibrium was used for genotype frequency analysis and for comparison of polymorphism frequency between the groups studied.
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Results
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We studied 102 subjects, 51 study patients who received aspirin preoperatively and 51 control patients who did not received the drug before CABG. Preoperative patient characteristics are presented in Table 1, and data related to CABG procedure are presented in Table 2. Three patients died in the early postoperative period, 2 in the study group and 1 in the control group. One patient in the aspirin group died of sepsis and multiorgan failure and the other of pneumonia, renal insufficiency, and congestive heart failure. One patient in the control group died of perioperative myocardial infarction resistant to pharmacologic and mechanical (intra-aortic balloon pump) support. Two patients in the control group and 4 in the aspirin group required reexploration for bleeding (P = .674). In all cases, the bleeding site was identified and surgically controlled. Eighteen patients in the aspirin group and 4 in the control group received platelet concentrate postoperatively (P = .0129)
PlA1/A2 polymorphism was ascertained in 51 patients in the aspirin group and in 51 control patients; in 3 cases, no DNA was available for genotyping. In the aspirin group, frequency of the PlA2 allele was 10.8%: 7 subjects were heterozygotic (PlA1/A2) and 2 were homozygotic (PlA2/A2). In the control group, the frequency of the PlA2 allele was 17.7%: there were 15 heterozygotes (PlA1/A2) and 1 homozygote (PlA2/A2). The difference in PlA2 allelic frequency between the groups was not significant.
Blood loss related to CABG was significantly greater (by 25%) in the aspirin group than in the control group (Figure 1). This was reflected by a significantly larger (137%) volume of blood product transfusions required during postoperative treatment of patients in the aspirin group (1.49 ± 1.41 units vs 0.76 ± 1.77, aspirin vs control, P = .021). When subjects were stratified accordingly to blood platelet glycoprotein IIb/IIIa genotype, in the aspirin group PlA2 carriers had greater blood loss than PlA1 homozygotes (1858 ± 932 mL vs 1216 ± 525 mL, P < .05). Interestingly, in the control group, this relation was reversed (760 ± 231 vs 1138 ± 656 mL, P < .05). Thus in PlA1 homozygotes postoperative blood loss was not affected by aspirin administration, whereas in PlA2 carriers bleeding increased by 152% after aspirin treatment preceding CABG (Figure 1) After exclusion of the patients who underwent reexploration for bleeding, blood loss and transfusion requirements remained different between groups (Table 3).
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Figure 1. Blood loss (in milliliters) in preoperative aspirin (ASA) and control groups. Asterisks indicate mean. P = .015 between PlA1 homozygotes and PlA2 carriers in aspirin group.
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TABLE 3. Data concerning blood loss and blood products transfused after exclusion of patients undergoing reexploration for bleeding
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Preoperative evaluation bleeding time (Simplate R) or capillary occlusion time (PFA-100) failed to correlate with postoperative bleeding. However, both Simplate and PFA-100 measurements repeated immediately after CABG were predictive of blood loss. Correlation between Simplate time and blood loss was highly significant (
= 0.201; P < .005), while PFA-100 closure time correlation with blood loss was weaker ( = 0.152; P < .05 for epinephrine, = 0.146; P < .04 for adenosine diphosphate [ADP]). The platelet levels dropped after CPB, but there were no differences between groups at any time. Thereafter, platelet counts increased to 260,000 and 289,000 cells/mm3 at day 3 and 399,000 and 411,000 cells/mm3 at day 7 (aspirin and control groups, respectively; Figure 2). No postoperative differences in CK-MB and troponin I levels were observed between the groups.
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Figure 2. Platelet count (in cells per cubic milliliter) in preoperative aspirin (ASA) and control groups.
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Discussion
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Recent American College of Cardiology and American Heart Association Practice Guidelines updates for CABG
1
acknowledged that increased postoperative bleeding and risk for reexploration associated with aspirin are outweighed by the benefits of preoperative aspirin use. The aim of study was to investigate whether a common PlA1/A2 polymorphism, functionally associated with anticlotting response to aspirin, could affect postoperative risk for patients undergoing elective CABG. The study was designed to evaluate preoperative and postoperative hemostatic measures along with risk outcomes in a series of aspirin-treated and control patients undergoing CABG intervention. Genotyping of PlA1/A2 polymorphism was completed after patient recruitment and after hospital discharge. Ex vivo studies on thrombin generation
14
had documented that PlA2 carriers were more likely to be refractory to benefits of aspirin therapy.
The platelet arachidonic acid cyclooxygenase pathway, which is irreversibly inhibited by aspirin, is one of several mechanisms amplifying prothrombotic response of these blood particles. During extracorporeal circulation, shear stress is the overwhelming stimulus for platelet activation.
15
It has been demonstrated that PlA2-positive platelets in healthy subjects present a hyperresponsive status, manifested by increased glycoprotein IIb/IIIa fibrinogen binding and lower ADP activation threshold, resulting in increased adhesion, spreading, aggregation, and clot retraction. Aspirin can impair thrombin generation, which takes place on the surface of activated platelets. Thus in the presence of aspirin, any relevant variability caused by PlA1/A2 polymorphism should be exposed during a surgical procedure characterized by massive platelet activation. Results of this study confirm relatively low risk imposed by preoperative aspirin in patients undergoing CABG. In PlA1 homozygotes, no excess bleeding or need for transfusions was observed. Patients carrying the PlA2 allele, however, in addition to a blunted response to aspirin in general, in the particular case of CABG demonstrated a wide spectrum of consequences related to a single amino acid substitution in IIIa integrin. Without aspirin, PlA2 carriers had diminished blood loss, in agreement with the genetically determined hyperresponsive status of their platelets. Unexpectedly, preoperative aspirin increased blood loss in the PlA2 group by 152%, indicating that cyclooxygenase pathway plays important role in fine-tuning blood clotting. It is possible that hyperreactive PlA2 platelets are particularly sensitive to shear stress but without thromboxane generation cannot provide sufficient hemostasis. An antiplatelet regimen achieved by concurrent use of clopidogrel and aspirin resulted in additional protection against acute vascular events in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.
16
Perhaps this effective antiplatelet therapy of cyclooxygenase inhibition and purine receptor blockade can prevent platelets wear off during CABG, when continuous shear stress washes ADP out of platelets. In the patients studied, the numbers of platelets before and after CABG did not differ significantly. Thus the possibility of bleeding related to thrombocytopenia could be excluded. Further studies on platelet activation markers and ADP platelet content during CABG should provide more insight into this unfavorable pharmacogenetic interaction between platelet PlA1/A2 polymorphism and risk imposed by preoperative aspirin in patients undergoing CABG. For PlA2 carriers receiving aspirin, one should consider the use of special precautions to minimize bleeding tendency after CABG. One of the possibilities is antithrombolytic therapy (aprotinin, -aminocaproic acid) in this group, which might be expected to effectively diminish postoperative blood loss.
17,18
Alternatively, hemostasis could be secured through scheduled transfusion of fresh-frozen plasma and platelet concentrate.
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Limitations of the Study
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The limited number of subjects studied did not allow us to evaluate major adverse clinical events and major cardiac and cerebral events. In fact, we observed only 3 deaths and 8 perioperative myocardial infarctions. Those events did not correlate with discontinuation of aspirin in patients operated on urgently; however this observation lacks statistical power. The examined blood loss and transfusion requirements could in fact be further divided as simple end points. Because of the limited number of PlA2 carriers in the study, we were not able to analyze simple clinical end points.
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Conclusions
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PlA1 homozygotes normally had greater risk of perioperative bleeding than PlA2 carriers. Capillary closure time determined with the PFA-100 analyzer showed no advantage relative to traditional bleeding time in predicting postoperative blood loss. Aspirin pretreatment 12 and 3 hours before surgery revealed no beneficial effects and in fact resulted in increased postoperative bleeding and need for blood products transfusions. For patients positive for platelet PlA2 polymorphism receiving aspirin at operation, special security measures should be considered, such as antifibrinolytic drugs or fresh-frozen plasma or platelet concentrate transfusions.
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Footnotes
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Supported by KBN (State Committee for Scientific Research).
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Abstract
Introduction
