Eur J Cardiothorac Surg 2006;29:933-940
© 2006 Elsevier Science NL
Heparin resistance and increased platelet activation in coronary surgery patients treated with enoxaparin preoperatively
Hilde Pleym
a
,
*
,
Vibeke Videm
b
,
f
,
Alexander Wahba
c
,
g
,
Arne Åsberg
d
,
Tore Amundsen
e
,
Lise Bjella
a
,
Ola Dale
g
,
Roar Stenseth
a
,
g
a Department of Cardiothoracic Anesthesia and Intensive Care, St. Olav University Hospital, Trondheim, Norway
b Department of Immunology and Transfusion Medicine, St. Olav University Hospital, Trondheim, Norway
c Department of Cardiothoracic Surgery, St. Olav University Hospital, Trondheim, Norway
d Department of Medical Biochemistry, St. Olav University Hospital, Trondheim, Norway
e Department of Pulmonary Medicine, St. Olav University Hospital, Trondheim, Norway
f Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway
g Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
Received 5 December 2005;
received in revised form 3 February 2006;
accepted 6 February 2006.
* Corresponding author. Address: St. Elisabeth Department of Cardiothoracic Surgery, Hans Nissens gate 3, N-7018 Trondheim, Norway. Tel.: +47 73 86 70 00; fax: +47 73 86 70 29. (Email: hilde.pleym{at}stolav.no).
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Abstract
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Objective: Patients with unstable coronary disease have changes in the hemostatic system. These patients are often treated with low molecular weight heparin. In patients who are accepted for coronary artery bypass grafting, treatment with low molecular weight heparin is frequently continued until surgery. We hypothesized that in coronary artery bypass grafting, the hypercoagulable state seen in unstable patients persists into the intra- and postoperative phase despite preoperative treatment with low molecular weight heparin. The aim of this study was to explore and describe the perioperative hemostatic process in patients with unstable coronary artery disease undergoing coronary artery bypass grafting. Methods: Thirty-two patients with unstable coronary disease treated preoperatively with enoxaparin, and 32 stable control patients not treated with enoxaparin, were included. All patients were taking low dose aspirin until the day before surgery. Before cardiopulmonary bypass, all patients were given tranexamic acid as a bolus injection. Blood samples for analysis of platelet counts, international normalized ratio, activated partial thromboplastin time, fibrinogen, protein S, protein C, prothrombin fragment 1 + 2, thrombin–antithrombin complex, antithrombin, plasmin–antiplasmin complex, D-dimer, neutrophil-activating peptide 2, platelet–monocyte complexes, and heparin concentrations were drawn preoperatively, after 30 min on cardiopulmonary bypass, and 30 min, 3 h, and 20 h postoperatively. Heparin was given during cardiopulmonary bypass to maintain an activated clotting time above 480 s. Results: Patients in the enoxaparin group needed more heparin to maintain an activated clotting time above 480 s, and had higher heparin concentrations and lower antithrombin values compared with control patients. Neutrophil-activating peptide 2 concentrations were higher in the enoxaparin group. Conclusions: Patients treated with enoxaparin before coronary artery bypass grafting showed signs of heparin resistance intraoperatively. Enoxaparin-treated patients also had increased perioperative platelet activation. Reasons for the observed difference in platelet activation remain unclear.
Key Words: Anticoagulants • Coagulation • Coronary surgery • Hemorrhage • Heparin • Platelets
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1. Introduction
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Patients with unstable angina pectoris or acute myocardial infarction have changes in the hemostatic system that indicate the presence of a hypercoagulable state [1,2], and also have a risk of recurrent coronary events [3]. Treatment with low molecular weight heparin (LMWH) in combination with aspirin reduces the incidence of new ischemic events in these patients [4–6]. In unstable patients who are accepted for coronary artery bypass grafting (CABG), treatment with LMWH in combination with aspirin is often continued until surgery. While reducing the incidence of ischemic events, this treatment does not necessarily ameliorate the procoagulative changes seen in the hemostatic system. Bjessmo et al. [7] have shown the presence of a preoperative hypercoagulable state also in unstable patients treated with LMWH until surgical intervention. Patients with a hypercoagulable state may have an increased risk of graft failure after CABG [7].
We hypothesized that the hypercoagulable state seen preoperatively in unstable CABG patients treated with LMWH persists into the intra- and early postoperative phase, and the aim of the present study was to explore and describe the perioperative hemostatic process in these patients. To this end, various factors involved in coagulation, fibrinolysis, and platelet activation were investigated preoperatively as well as intra- and postoperatively in a group of patients treated with LMWH before surgery and a group of patients not treated with LMWH undergoing CABG.
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2. Materials and methods
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The study was a prospective and observational investigation. After approval from the Regional Committee for Medical Research Ethics, Central Norway, 64 patients below 70 years of age scheduled for first-time CABG were included consecutively after giving written informed consent. The patients were included between February 2004 and May 2005. The ideal study design would have been a randomized and controlled trial where patients with unstable coronary artery disease (CAD) were randomized to receive either enoxaparin or placebo preoperatively. However, large studies have shown positive effects of LMWH in unstable angina and non-ST-elevation myocardial infarction (NSTEMI) [4–6], and subcutaneous injections with enoxaparin are given as routine treatment to these patients. It could not be justified from an ethical point of view to perform a randomized controlled trial, and we therefore settled for an observational trial. Patients were diagnosed as having unstable CAD if they had an elevated troponin T (cTnT) level [unstable angina (cTnT 0.010–0.100 µg/L) or NSTEMI (cTnT > 0.100 µg/L), 21 patients], or if they had known coronary artery disease, recurrent chest pain at rest, electrocardiogram (ECG) changes, but no rise in cTnT (unstable angina, 11 patients). No patients with an ST-elevation myocardial infarction were included.
The patients were stratified in two groups. The enoxaparin group consisted of 32 patients with unstable CAD scheduled for urgent surgery. All patients in this group had been treated with subcutaneous injections of enoxaparin 1 mg/kg body weight twice daily for at least 5 days prior to surgery, and the last enoxaparin dose was given 12–16 h before surgery. The control group consisted of 32 patients with stable CAD scheduled for elective surgery who had not been treated with LMWH. All patients in both groups were taking low dose aspirin (75 or 160 mg) until the day before surgery. The aspirin dose was similar on a milligram/kilogram body weight basis in the two groups. Patients on heparin, oral anticoagulants, non-steroidal anti-inflammatory drugs, clopidogrel or other platelet inhibitors the past 5 days before surgery, patients on systemic glucocorticoids, and patients with a serum creatinine concentration above 140 µmol/L or an international normalized ratio (INR) > 1.5 were excluded from participation in the study. All patients who were asked to participate in the study consented.
All patients went through first-time CABG with the use of the left internal thoracic artery and saphenous vein bypass grafts. Before cardiopulmonary bypass (CPB), all patients were given tranexamic acid 30 mg/kg body weight as an intravenous bolus injection according to departmental routines. No additional intra- or postoperative doses were given. Aprotinin, 
-aminocaproic acid, or desmopressin were not given. CPB was employed in all cases, and all patients were anesthetized with a standard technique based on a combination of fentanyl and isoflurane. Before CPB, heparin 300 U/kg (Leo, Copenhagen, Denmark) was given through a central venous line to achieve a kaolin activated clotting time (ACT) (Medtronic Blood Management, Parker, CO, USA) of >480 s. The ACT was measured in duplicate and the mean value was recorded. Additional heparin was given when needed to keep the ACT above 480 s. During CPB the ACT was monitored every 20 min. The perfusion circuit was primed with 1800 mL of Ringer's acetate solution to which 7500 U of heparin was added. A membrane oxygenator without heparin coating was used. Cold antegrade crystalloid or blood cardioplegia and moderate hypothermia to 34 °C were employed during CPB. Cardiotomy suction was used while the patients were fully anticoagulated, and the blood was returned to the patients without centrifugation. The patients were warmed to a rectal temperature of at least 36 °C before termination of CPB. After CPB, protamine sulphate 1 mg for every 100 U of previously administered heparin (prime heparin not included) was given to achieve an ACT within 10% of the baseline value. Additional doses of protamine were given when necessary. Blood remaining in the CPB circuit was collected and transfused to the patients.
At the end of surgery the patients were transferred to the intensive care unit (ICU). All patients were sedated with a low dose infusion of propofol (0.5–1 mg/(kg h)) until extubation. Postoperatively, blood from the mediastinal and pleural drains was collected in a sterile cardiotomy reservoir (Cardiotomy Reservoir, filtered; Sorin Biomedica UK, Ltd, Harrogate, UK) and autotransfused to the patients until bleeding was less than 20 mL/h, but for a maximum of 8 h. All patients were autotransfused shed blood. Transfusions of packed red blood cells were given when the blood hemoglobin concentration was <8.5 g/dL, while transfusions with fresh frozen plasma and/or platelets were given when patients had a persistent postoperative bleeding of >200 mL/h.
The primary study outcome was the preoperative, intra- and postoperative measurements of variables indicative of hemostatic function. Blood samples were drawn from the arterial line preoperatively before induction of anesthesia, 30 min after the start of CPB, 30 min and 3 h after the end of surgery, and in the morning of the first postoperative day, approximately 20 h after surgery. Routine coagulation variables were analyzed consecutively by standard methods and included platelet counts, INR, activated partial thromboplastin time (APTT), fibrinogen, protein S, and protein C. Prothrombin fragment 1 + 2 (F1 + 2) and thrombin–antithrombin complex (TAT) were measured as indicators for increased thrombin formation, and TAT and antithrombin were also measured as indicators of increased inhibitor consumption. Plasmin–antiplasmin (PAP) concentrations were measured as an indicator of increased plasmin formation and inhibition, and D-dimer was measured as an indicator of fibrinolysis. Neutrophil-activating peptide 2 (NAP-2) was measured as an indicator of platelet 
-granule release. Formation of complexes between platelets and monocytes was quantified in flow cytometry and served as an additional marker of platelet activation. Blood samples for analysis of F1 + 2, TAT, PAP, NAP-2, and heparin concentrations were drawn and immediately centrifuged. The plasma samples were frozen immediately after centrifugation and kept at –70 °C until they were analyzed in batch. The concentrations of F1 + 2 and TAT were measured in citrate plasma using enzyme immunoassay kits (Dade-Behring, Marburg, Germany). The concentration of PAP was measured in citrate aprotinin benzamidin plasma using an enzyme immunoassay kit (Technoclone, Vienna, Austria). NAP-2 concentrations were analyzed in citrate theophylline adenosine dipyridamol plasma using an enzyme immunoassay (NAP-2 duoset, R&D Systems, Abingdon, UK). At each sampling point 50 µL blood was immediately fixed in 200 µL Tyrode's buffer containing 0.35% human serum albumin and 250 µL 1% paraformaldehyde and kept at 4 °C until parallel staining for flow cytometry of all five samples from each patient. The samples were stained with a PE-conjugated anti-CD41 antibody (GP IIb, Dako, Glostrup, Denmark), which binds strongly to platelets. A negative control antibody (Dako) was also used. Platelet conjugates with monocytes were then identified as CD41-positive cells in the scatter regions of monocytes on a forward scatter/side scatter plot, employing a FACScan flow cytometer (Becton Dickinson). Division of the number of aggregates by the total number of monocytes within the region and multiplication with 100 yielded the stated percentages of platelet–monocyte aggregates.
In addition to the primary study outcome measures, heparin and protamine doses, ACT values, plasma heparin concentrations, postoperative blood loss volumes, amount of postoperative blood autotransfused to the patient, and other transfusion requirements were also recorded. The heparin concentrations were measured in citrate plasma by a photometric method where added factor Xa was neutralized by heparin present in the sample (Coatest Heparin, Chromogenix, Milan, Italy). The time from termination of CPB to skin closure was recorded as a measure for the time spent on surgical hemostasis during the final part of the operation.
The number of patients who were diagnosed as having a perioperative myocardial infarction was also recorded. The diagnosis of a perioperative myocardial infarction was based on the detection of new development of Q-waves in the postoperative ECG combined with a postoperative increase in serum concentrations of myocardial band isoenzymes of creatin kinase (CK-MB) and/or cTnT. A CK-MB concentration > 50 µg/L and a cTnT concentration > 1.000 µg/L were considered to indicate myocardial necrosis.
Data from an unpublished pilot investigation in which preoperative antithrombin levels were compared in a group of CABG patients pretreated with dalteparin and a control group were used to calculate the required number of individuals per group. The mean difference in antithrombin level between the groups was 14, with a standard deviation of 21.2 and 14.5, respectively. Aiming for a power of 0.8 and an alpha of 0.05, 27 patients had to be included in each group.
Data are presented as means (SD) and medians (range). Statistical analyses were carried out using the program package SPSS for Windows®, version 13.0 (SPSS Inc., Chicago, IL, USA). Baseline patient data were compared using Student's t-test or Wilcoxon–Mann–Whitney U-test for scale variables, and Fisher's exact test for categorical variables. If necessary, variables were logarithmically transformed to show an acceptable fit to the normal distribution. Repeated measurement analysis of variance (ANOVA) was used for analysis of variables measured more than once, using the ln-transformed data. When repeated measurement ANOVA showed a statistically significant interaction, indicating a different change by time in the two groups, and the interaction was considered to be of clinical interest, the difference between the preoperative and the specific postoperative values was calculated. The calculated difference was then compared using Student's t-test. P values < 0.05 were considered statistically significant.
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3. Results
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Thirty-two unstable patients treated with enoxaparin prior to surgery and 32 stable control patients were included in the study. Three patients were excluded after inclusion. One patient in the control group had a preoperative INR of 1.6 and did, therefore, not meet the inclusion criteria, while two patients in the enoxaparin group received tranexamic acid and desmopressin postoperatively, which was a protocol violation. Patient characteristics, medical data, and data on surgical procedures for the remaining 61 patients are presented in Table 1
. More patients in the enoxaparin group had a history of a previous myocardial infarction. The patients in the enoxaparin group also had significantly lower ejection fractions and preoperative blood hemoglobin concentrations compared with the control patients, and more patients in the enoxaparin group were in New York Heart Association (NYHA) class IV and American Society of Anesthesiologists (ASA) risk classification class IV preoperatively.
The median (range) postoperative serum concentrations of CK-MB were 10.0 µg/L (2.3–233.4 µg/L) versus 10.0 µg/L (2.0–78.4 µg/L) (P
= 0.64) in the enoxaparin group and control group, respectively, while the postoperative serum concentrations of cTnT were 0.209 µg/L (0.052–3.030 µg/L) versus 0.227 µg/L (0.047–0.858 µg/L) (P
= 0.73). Two patients in the enoxaparin group and one patient in the control group were diagnosed as having a perioperative myocardial infarction. One patient in the control group and one patient in the enoxaparin group developed respiratory failure and had a prolonged stay in the ICU, while one patient in the enoxaparin group suffered from a postoperative cerebral insult. All patients made a full recovery. Two patients in the enoxaparin group were reexplored. One patient developed signs of cardiac ischemia. All grafts were found intact. The other patient had increased postoperative bleeding. No surgical source of bleeding was found, and it was concluded that the bleeding was of microvascular origin. For both patients the postoperative phase thereafter was uneventful.
The total doses of heparin and protamine given, and the ACT values before and after the administration of heparin and after the administration of protamine, are presented in Table 2
. The enoxaparin group had significantly lower ACT values after the first dose of heparin, and the total doses of heparin and protamine given to this group were significantly larger compared with the control group.
Postoperative bleeding volumes, volumes of shed blood autotransfused, the time from termination of CPB to skin closure, and packed red blood cell transfusion requirements for the whole hospital stay are presented in Table 3
. Significantly more patients in the enoxaparin group received packed red blood cell transfusions. Nine patients in this group received at least one transfusion before the end of the study period, while all transfused patients in the control group received their transfusions after the last blood samples were drawn. In addition to packed red blood cell transfusions, the patient in the enoxaparin group who was reexplored because of bleeding also received 4 units of fresh frozen plasma and 3 units of platelets. No other patients received fresh frozen plasma or platelet transfusions.
Antithrombin and heparin concentration measurements are shown in Fig. 1
. The enoxaparin group had significantly lower antithrombin values and higher heparin concentrations compared with the control group (antithrombin P
= 0.001, heparin concentrations P
< 0.001). For the heparin concentrations there were also a significant interaction between the groups (P
< 0.001). The difference between the concentration measured during CPB and the preoperative concentration was larger in the enoxaparin group compared to the control group [6.10 IU/mL (1.47 IU/mL) vs 5.20 IU/mL (1.08 IU/mL), P
= 0.009].
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Fig. 1. Mean values of antithrombin (P
= 0.001) and plasma heparin concentrations (P
< 0.001). The P values represent constant intergroup differences. The error bars represent 95% confidence intervals for means. Samples for measurements were drawn preoperatively before induction of anesthesia, 30 min after the start of cardiopulmonary bypass (CPB), 30 min and 3 h after the end of surgery, and approximately 20 h after surgery.
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NAP-2 measurements and flow cytometry results are presented in Fig. 2
. The enoxaparin group had significantly higher NAP-2 concentrations compared with the control group (P
< 0.001). By flow cytometry there was no statistically significant difference in the percentage of platelet–monocyte complexes between the groups (P
= 0.092).
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Fig. 2. Mean concentrations of neutrophil-activating peptide (NAP-2) (P
< 0.001) and mean percentages of platelet–monocyte complexes (P
= 0.092). The P values represent constant intergroup differences. The error bars represent 95% confidence intervals for means. Samples for measurements were drawn preoperatively before induction of anesthesia, 30 min after the start of cardiopulmonary bypass (CPB), 30 min and 3 h after the end of surgery, and approximately 20 h after surgery.
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The results from the measurements of platelet counts, INR, APTT, fibrinogen, D-dimer, PAP, protein S, protein C, F1 + 2, and TAT are summarized in Table 4
. APTT was significantly higher in the enoxaparin group compared with the control group. For the other variables there were no significant differences between the two groups.
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Table 4. Platelet counts, INR, APTT, fibrinogen, D-dimer, PAP, protein S, protein C, F1 + 2, and TAT concentrations in the two groups
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4. Discussion
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Despite the relatively large doses of heparin given before CPB, some degree of activation of coagulation during and immediately after CPB is shown consistently in the literature [8–12]. We hypothesized that the hypercoagulable state seen preoperatively in unstable CABG patients treated with LMWH persists into the intra- and early postoperative phase, and that these patients therefore have an increased activation of coagulation perioperatively compared with control patients. Our results on the coagulation variables showed that antithrombin levels were lower in the enoxaparin group throughout the perioperative period. However, F1 + 2 and TAT, markers of thrombin formation and inhibitor consumption, did not differ between the groups. Both groups showed activation of coagulation during CPB as well as postoperatively (Table 4), but the activation was comparable in the two groups. Also, apart from APTT, other routine coagulation variables did not differ between the groups (Table 4). Our results therefore do not support the hypothesis that there is a more intense activation of coagulation intra- and postoperatively in patients treated with enoxaparin preoperatively.
The patients in the enoxaparin group had a mean ACT value below the target ACT of 480 s after the first dose of heparin, and this value was also significantly lower than the mean ACT value obtained in the control group (Table 2). It has been suggested that low antithrombin levels cause heparin resistance [13–15], and the lower antithrombin levels seen in the enoxaparin group may, therefore, explain why these patients were less responsive to the initial standardized heparin dose. During CPB both groups had ACT values above target, and there were no differences in ACT between the groups. The total dose of heparin given and the plasma heparin concentrations were, however, significantly higher in the enoxaparin group compared with the control group (Table 2 and Fig. 1), and this explains why both groups had ACT values above the target during CPB. It also shows that the patients treated with enoxaparin were in fact less responsive to heparin than the control patients. The lack of difference in ACT values indicates that when given different heparin doses, both groups were equally anticoagulated during CPB. This is also supported by the lack of difference in F1 + 2 and TAT between the groups. The larger dose of heparin given to the patients in the enoxaparin group may, therefore, explain why the activation of coagulation during and after CPB did not differ between groups.
There is no universal method for measuring platelet activation. Quantification of mediators such as NAP-2, formed during -granule release, is one possibility. Another possibility is the quantification of platelet–leukocyte complexes. During platelet activation, up-regulation of adhesion molecules results in the formation of these complexes, and it has previously been shown that platelet–monocyte aggregates are formed during cardiac surgery, demonstrating the presence of platelet activation [16,17]. The results of the present study showed that the enoxaparin-treated patients had increased platelet activation compared with the control group as measured by NAP-2 (Fig. 2). Fig. 2 also shows that there was a trend (P
= 0.092) towards a difference between the two groups in the percentage of platelet–monocyte complexes, as the enoxaparin group had a numerically higher percentage of platelet–monocyte complexes compared with the control group. The study was not powered to show differences in percentages of platelet–monocyte complexes, and the relatively small sample size may be one reason for us not being able to show a statistically significant difference. Also, the platelet activation seen during and after CPB may result in adherence of platelets to the surface of the extracorporeal circuit, while less active platelets remain in the circulation, contributing to the platelet function defect seen after CPB [18]. By flow cytometry, only circulating platelets may be evaluated, and the most activated platelets that are adherent to the extracorporeal circuit or the patient's microvasculature are inaccessible. This may explain why the NAP-2 measurements were more sensitive at detecting the inter-group differences in platelet activation compared to the flow cytometry method, since released granule products may still reach the circulation. The results of the present study, therefore, indicate that platelet activation was increased in enoxaparin-treated patients. Reasons for this finding are unclear. Previous investigations have shown platelet activation in patients with unstable CAD [18,19]. It is therefore possible that the observed difference in platelet activation between the two groups in our investigation was caused by underlying preoperative differences in platelet activation between unstable and stable CAD patients. However, also patients with stable CAD have circulating activated platelets, circulating monocyte–platelet aggregates, and increased platelet reactivity [20]. It has been shown that therapeutic doses of heparin induce platelet activation [21–23]. In our study the enoxaparin group received significantly more heparin than the control group, but both groups received doses that were within the common dose range, and it seems unlikely that a moderately larger heparin dose can explain the increased platelet activation seen in this group. One may speculate that the preoperative treatment with enoxaparin has contributed to increased platelet activation seen during and shortly after CPB. However, further investigations are warranted to clarify this issue.
There were no statistically significant differences in fibrinolysis between the two groups (Table 4). However, the results from the PAP measurements were very close to significant (P
= 0.056), with the numerically highest values found in patients treated with enoxaparin. This indicates that plasmin formation and inhibition may have been increased in the enoxaparin group. We have previously shown that a single bolus dose of tranexamic acid given before CPB reduces bleeding and suppresses fibrinolysis as measured by D-dimer in CABG patients treated with aspirin until surgery [24]. Tranexamic acid is now a routine treatment for patients on aspirin at our department. Accordingly, all patients included in the study were treated with tranexamic acid before CPB. This may explain the lack of difference in fibrinolysis between the two groups, and it explains the very moderate rise in D-dimer seen in all the study patients. The relatively small number of patients included in the study may also explain why we were not able to show a statistically significant difference in PAP concentrations between the two groups.
Postoperative bleeding was not different between the two groups (Table 3). The fact that both groups were treated with tranexamic acid may explain this, and it is also in conjunction with a previous investigation showing that postoperative bleeding is not increased in patients treated with enoxaparin preoperatively when the last dose is given 8 h or more before surgery [25]. However, more patients in the enoxaparin group received transfusions of packed red blood cells (Table 3). A reason for the observed discrepancy between postoperative bleeding and transfusion requirements may be that the preoperative blood hemoglobin concentration was significantly lower in the patients treated with enoxaparin (Table 1). The patients in this group were, therefore, more likely to have a postoperative hemoglobin level below the transfusion threshold.
The possibility that differences in transfusions may have influenced the study results must be considered. One patient in the enoxaparin group received transfusions of packed red blood cells, fresh frozen plasma, and platelets during the study period, while another patient received a transfusion of packed red blood cells during CPB. The exclusion of these two patients from the analyses did not change the main study results. The remaining seven patients in the enoxaparin group who received transfusions before the end of the study period were all transfused with packed red blood cells several hours after CPB, but before the final blood sampling 20 h after surgery. It is unlikely that these transfusions of red blood cells have had major influence on the main findings of the study.
In this study we have shown that patients treated with enoxaparin before CABG had signs of heparin resistance and were in need of more heparin intraoperatively compared to control patients to reach the target ACT. The perioperative activation of coagulation was equal in the two groups. However, patients in the enoxaparin group had increased perioperative platelet activation compared with control patients. Reasons for the observed difference in platelet activation remains unclear, and further studies should be performed to confirm these results and investigate possible mechanisms.
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Acknowledgments
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Hilde Pleym is supported by The Norwegian Health Association, Grant 6432. The study was also supported financially by The Research Foundation at St. Olav University Hospital, and by Alf and Aagot Helgesens Legacy. The authors thank Frode Vågen for technical assistance, Anne Hole for performing the F1 + 2, TAT, and PAP analyses, Mona Undeland for performing the plasma heparin concentration analyses, Toril Holien for performing the NAP-2 analyses, and Toril Anita Weisethaunet, Marit Aarhaug, and Toril Holien for performing flow cytometry.
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References
|
|---|
- Merlini PA, Bauer KA, Oltrona L, Arddissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994;90:61-68.[Abstract/Free Full Text]
- Hoffmeister HM, Jur M, Wendel HP, Heller W, Seipel L. Alterations of coagulation and fibrinloytic and kallikrein–kinin systems in acute and postacute phases in patients with unstable angina. Circulation 1995;91:2520-2527.[Abstract/Free Full Text]
- The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990;336:827-830.[CrossRef][Medline]
- Fragmin during instability in coronary artery disease (FRISC) study group. Low molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347:561-568.[CrossRef][Medline]
- The efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events study group A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447-452.[Abstract/Free Full Text]
- Antman EM, McCabe CH, Gurfinkel EP, Turpie AGG, Bernink JLM, Salein D, Bayes de Luna A, Fox K, Lablanche JM, Radley D, Premmereur J, Braunwald E, for the TIMI 11B investigators Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999;100:1593-1601.[Abstract/Free Full Text]
- Bjessmo S, Ivert T, Egberg N. Coagulation system activity before coronary artery bypass surgery for unstable angina. Scand Cardiovasc J 2001;35:280-284.[CrossRef][Medline]
- Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-3357.[Abstract/Free Full Text]
- Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B. Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment F1 + 2. Thromb Haemost 1993;70:253-258.[Medline]
- Hunt BJ, Parratt RN, Segal HC, Sheikh S, Kallis P, Yacoub M. Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 1998;65:712-718.[Abstract/Free Full Text]
- Slaughter TF, LeBleu TH, Douglas JM, Leslie JB, Parker JK, Greenberg CS. Characterization of prothrombin activation during cardiac surgery by hemostatic molecular markers. Anesthesiology 1994;80:520-526.[Medline]
- Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181-188.[CrossRef][Medline]
- Ranucci M, Isgro G, Cazzangia A, Ditta A, Boncilli A, Cotza M, Carboni G, Brozzi S. Different patterns of heparin resistance: therapeutic implications. Perfusion 2002;17:199-204.[Abstract/Free Full Text]
- Despotis GJ, Levine V, Joist JH, Joiner-Maier D, Spitznagel E. Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg 1997;85:498-506.[Abstract]
- Lemmer JH, Despotis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2002;123:213-217.[Abstract/Free Full Text]
- Wahba A, Videm V. Heart surgery with extracorporeal circulation leads to platelet activation at the time of hospital discharge. Eur J Cardiothorac Surg 2003;23:1046-1050.[Abstract/Free Full Text]
- Pleym H, Wahba A, Videm V, Åsberg A, Lydersen S, Bjella L, Dale O, Stenseth R. Increased fibrinolysis and platelet activation in elderly patients undergoing coronary bypass surgery. Anesth Analg 2006;102:660-667.[Abstract/Free Full Text]
- Becker RC, Tracy RP, Bovill EG, Mann KG, Ault K, for the TIMI-III thrombosis and anticoagulation study group The clinical use of flow cytometry for assessing platelet activation in acute coronary syndromes. Coron Artery Dis 1994;4:339-345.
- Parker III C, Vita JA, Freedman JE. Soluble adhesion molecules and unstable coronary artery disease. Atherosclerosis 2001;156:417-424.[CrossRef][Medline]
- Furman MI, Benoit SE, Barnard MR, Valeri CR, Borbone ML, Becker RC, Hechtman HB, Michelson AD. Increased platelet reactivity and circulating monocyte–platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998;31:352-358.[Abstract/Free Full Text]
- Wahba A, Black G, Koksch M, Rothe G, Preuner J, Schmitz G, Birnbaum DE. Cardiopulmonary bypass leads to a preferential loss of activated platelets. Eur J Cardiothorac Surg 1996;10:768-773.[Abstract]
- Wahba A, Rothe G, Lodes H, Barlage S, Scmitz G, Birnbaum DE. Effects of extracorporeal circulation and heparin on the phenotype of platelet surface antigens following heart surgery. Thromb Res 2000;97:379-386.[CrossRef][Medline]
- Khuri SF, Valeri CR, Loscaloz J, Weinstein MJ, Birjiniuk V, Healey NA, MacGregor H, Doursounian M, Zolkewitz MA. Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 1995;60:1008-1014.[Abstract/Free Full Text]
- Pleym H, Stenseth R, Wahba A, Bjella L, Karevold A, Dale O. Single-dose tranexamic acid reduces postoperative bleeding after coronary surgery in patients treated with aspirin until surgery. Anesth Analg 2003;96:923-928.[Abstract/Free Full Text]
- Medalion B, Frenkel G, Patachenko P, Hauptman E, Sasson L, Schachner A. Preoperative use of enoxaparin is not a risk factor for postoperative bleeding after coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003;126:1875-1879.[Abstract/Free Full Text]
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Abstract
1. Introduction
