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J Thorac Cardiovasc Surg 2006;131:290-297
© 2006 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
a Division of Cardiac Surgery, Dipartimento d'Emergenza e Trapianti di Organo (D.E.T.O.), University of Bari, Italy
b Department of Experimental Oncology, Laboratory Unit, Oncology Hospital, IRCCS, Bari, Italy
c Department of Surgery, Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, Ontario, Canada
Received for publication July 19, 2005; revisions received October 6, 2005; accepted for publication October 10, 2005. * Address for reprints: Domenico Paparella, MD, Division of Cardiac Surgery, Dipartimento di Emergenza e Trapianti di Organo (D.E.T.O.), University of Bari, Piazza Giulio Cesare 11, 70100 Bari, Italy (Email: paparella{at}tin.it).
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Abstract |
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METHODS: Thirty-two patients were randomly assigned to on-pump or off-pump coronary artery bypass grafting. Heparin was given at the same dose. Activation of the coagulation and fibrinolytic systems was evaluated by measurement of several markers. Platelet function was evaluated by in vitro bleeding time test. Blood samples were collected at 7 different times, up to postoperative day 6.
RESULTS: Overall tissue factor production was similar in the two groups. Thrombin formation was more elevated in the on-pump group (P < .001), particularly during the operation; prothrombin fragment 1.2 discharge values were higher than the preoperative ones (P = .002). Levels of tissue-plasminogen activator showed no difference between the groups (P = .1). D-dimers release was higher in the on-pump group (P = .0002). In vitro bleeding time was longer in the on-pump group (P < .0001), particularly in the first 24 hours; it was not prolonged in the off-pump group. In both groups, regardless of aspirin treatment, discharge in vitro bleeding times were lower than the preoperative ones (P < .01).
CONCLUSION: Although the extrinsic coagulation pathway is similarly activated, thrombin formation is more pronounced in patients having on-pump bypass grafting. Patients subjected to off-pump bypass grafting have normally functioning platelets and a weak activation of the fibrinolytic system. At discharge, both groups have preserved platelet function and increased thrombin formation. Further studies with angiographic evaluation are needed to establish a correlation between coagulation parameters, platelet function, and graft patency.
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Introduction |
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have shown that a significant reduction of postoperative bleeding and blood product transfusion is observed after OPCAB compared with on-pump operations. Moreover, subgroup analysis of patients with a higher rate of comorbidities (older age, renal failure, diabetes, previous stroke, calcific aorta) showed that the OPCAB technique might reduce operative mortality and morbidity.
3,4
Coagulation disorders and consequent perioperative bleeding represent one of the most frequent complications of on-pump surgery. Excessive bleeding, blood product transfusion, and chest reopening for bleeding are widely known risk factors for adverse events after on-pump surgery.
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Consequently, several strategies (technical, pharmacologic) aimed to reduce the risk of excessive bleeding have been adopted during on-pump surgery. Such strategies have also been suggested for patients undergoing OPCAB,
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although this technique, due to the absence of CPB, may result in a different coagulative state.
So far few studies have analyzed the coagulation and fibrinolytic systems during and after OPCAB in comparison with on-pump operations.
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A recent editorial
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hypothesized that OPCAB patients may have a higher risk of early graft failure because of the reduced activation of the fibrinolytic system associated with an enhanced activation of the inflammatory and coagulation systems.
The aim of the present study is to evaluate the difference in the activation of coagulation and fibrinolytic systems and platelet function in patients undergoing OPCAB operations or standard on-pump CABG.
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Methods |
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The following exclusion criteria have been applied:
Perioperative Management
After premedication with lorazepam, anaesthesia was induced with a combination of fentanyl, midazolam, and sodium thiopenthal and maintained with proprofol. Antifibrinolytic drugs were not administered. Heparin was given at the same dose (300 U/kg) in both groups. Intraoperative heparin monitoring was performed by standard activated clotting time (Hemochron 8; ITC, a subsidiary of Thoratec Corporation, Pleasanton, Calif). Additional heparin bolus (5000 U) was given if the activated clotting time was below 400 seconds in the on-pump group and below 300 seconds in the OPCAB group. In both groups protamine was administered to reverse heparin (1 mg of protamine/100 IU of heparin). In the on-pump group CPB was established with a 2-stage venous cannula and aortic return. Moderate hypothermia (34°C) was maintained during the operation. Cardiac arrest was induced and maintained with antegrade cold blood cardioplegia. Cardiotomy suction was used in all patients of the on-pump group. Cell saving devices were not used. A heart stabilizer (Octopus; Medtronic Inc, Minneapolis, Minn) has been used in all OPCAB operations and intracoronary shunts have been used in 87% of these cases to allow bloodless anastomoses.
All patients were admitted postoperatively in the intensive care unit and extubated when hemodynamically stable, fully rewarmed, awake, without surgical bleeding, and with optimal blood gases. Postoperatively, patients received aspirin (100 mg orally or intravenously) and low molecular weight heparin (nadroparin 2850 U Anti-Xa, subcutaneously) starting 12 hours after the end of the operation in the absence of significant mediastinal bleeding. Low molecular weight heparin administration was discontinued on postoperative day 5.
Assays
Specific assays were performed to assess the activation of coagulation and fibrinolytic systems between the two groups. Blood samples were centrifuged for 15 minutes at 3500 rpm and frozen at –80°C until assayed. Plasma was assayed by monoclonal antibodies sandwich enzyme-linked immunosorbent assay (ELISA) technique.
Activation of the coagulation system was evaluated by use of the prothrombin fragment 1.2 (PF-1.2) (Enzygnost F1+2 Micro; Dade Behring Marburg GmbH, Marburg, Germany), tissue factor (TF) (IMUBIND Tissue Factor ELISA; American Diagnostica GmbH, Pfungstadt, Germany), and fibrinogen (Biopool Fibrinogen Assay Kit, Biopool International, Ventura, Calif) measurements. Activation of the fibrinolytic system was evaluated by measuring tissue plasminogen activator (IMUBIND tPA ELISA; American Diagnostica GmbH, Pfungstadt, Germany), plasminogen activator inhibitor-1 (PAI-1) (IMUBIND Plasma PAI-1 ELISA; American Diagnostica GmbH, Pfungstadt, Germany), and D-dimers (ACL 9000, IL Instrumentation Laboratory, Arcore (MI), Italy).
Platelet function was evaluated by the platelet function analyzer (PFA-100; Sysmex UK Ltd, Milton Keynes, United Kingdom), a device designed to simulate platelet-dependent hemostasis in whole blood in vitro.
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The system consists of a cartridge in which a membrane and an aperture are coated with collagen/adenosine-5'-diphosphate. Anticoagulated whole blood is aspirated through a capillary under steady high shear rates. The presence of the platelet agonist and the high shear rates result in a platelet plug that gradually occludes the aperture. The time required for full occlusion of the aperture is defined closure time (range: 71-118 seconds). PFA-100 measuring was done 15 minutes after blood sampling.
Hematocrit (HKT), hemoglobin, and platelet count were measured at all sample times.
All ELISA assays were doubled tested, and the mean value was used for analysis. Results were corrected for hemodilution according to the formula: (corrected assay)Tx = (assay)Tx x (HKT)T0/(HKT)Tx.
Sample Times
Blood samples were collected at 7 different times, before, during and after the operation: T0: during induction before the beginning of the operation; T1: 45 minutes after heparin administration; T2: 15 minutes after protamine administration; T3: 3 hours after the end of the operation; T4: first postoperative day (POD); T5: fourth POD; T6: sixth POD. Samples for firbrinogen were not performed at T1 and T2.
Statistical Analysis
On the basis of preliminary data obtained with PFA-100, the trial was designed to enroll 30 patients to demonstrate a 50% reduction of in vitro bleeding time and coagulation markers after the operation in the OPCAB group compared with the on-pump group (alpha = .05, power = 0.8). Results of the measured coagulation parameters showed a nonnormal distribution. Logarithmic conversion of data was carried out to apply repeated-measures analysis of variance (ANOVA) for overall comparison between the groups and the Student t test to compare measured outcomes at each sample time. The Wilcoxon test was applied to compare preoperative values (T0) with postoperative values (T6) within each group. Categorical variables are presented as absolute numbers and percentages were compared using the Fisher exact test. Statistical analyses were performed using the Stat-View Statistical Software Package (SAS Institute Inc, Cary, NC) and Number Cruncher Statistical System (NCSS, Kaysville, Utah).
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Results |
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Preoperative patient characteristics were similar in the two study groups: age, gender, ejection fraction, cardiovascular risk factors, and body mass index were equally represented in the groups. The operation length and the number of grafts performed (3.25 vs 2.7) were slightly greater in the on-pump group without a statistically significant difference. However, duration of heparinization was significantly longer in the on-pump group (Table 1). No differences in clinical outcomes were observed between on-pump and OPCAB patients (Table 1). Postoperative blood loss and blood product transfusion were also comparable, but hemoglobin values measured on POD 6 were higher in the OPCAB group.
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Discussion |
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demonstrated that the inflammatory response is reduced but not abolished in patients undergoing OPCAB operations. The same group prospectively studied 22 patients with single-vessel disease who underwent OPCAB either through a median sternotomy or with minimally invasive thoracotomy: markers of activated coagulation system were detected 24 hours after the operation.
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Other studies have consequently compared the activation of the coagulation system in patients undergoing CABG with or without CPB. Englberger and colleagues
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analyzed 27 patients assigned in a randomized fashion to undergo myocardial revascularization either with the off-pump technique (9 patients) or with CPB (16 patients). Plasma levels of fibrin monomer, thrombin-antithrombin complex, and D-dimer were significantly higher in the on-pump group immediately after surgery, whereas they were similar 18 hours postoperatively. Their study is limited by the short period of observation: 18 hours after the end of the operation. Lo and colleagues
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evaluated 40 patients undergoing coronary surgery with or without CPB. Blood samples were drawn up to 96 hours after the end of the operation. PF-1.2 and D-dimer levels were significantly higher in the on-pump group at the end of the operation and 2 hours later; in OPCAB patients, PF-1.2 levels significantly increased 2 hours after the operation and peaked on POD day 4. In both groups, plasma concentrations of von Willebrand factor increased from the first POD compared with baseline and peaked at POD 4.
Our study adds some new insights to the results of the previously published reports.
The role of the extrinsic coagulation pathway and TF in the post-CPB coagulation state has been well documented.
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We compared, for the first time, TF production with and without CPB. We found no significant difference in TF production between on-pump and OPCAB patients, meaning that surgical trauma, even in the absence of CPB and cardiotomy suction, leads to the activation of the extrinsic pathway. In both groups, TF levels rise in the postoperative phase, probably as a result of a systemic inflammatory state rather than as a response to a topical prothrombotic stimulus. This is confirmed by the similar perioperative trend of fibrinogen, a widely known inflammatory marker. Fibrinogen is the substrate for the fibrin production, participates in platelet aggregation, and acts as acute phase protein, increasing during the inflammatory responses.
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The inflammatory and coagulation systems share a common activation pathway. The link is represented by nuclear factor 
B. Nuclear factor B, during CPB, regulates TF activation and consequent thrombin release. Nuclear factor B regulates also the inflammatory response secondary to CPB surgery.
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Our study confirms that during CPB, despite heparin administration, thrombin formation is not prevented.
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Considering the relevant perioperative difference of thrombin formation associated with similar TF values between the groups, our study suggests that the extrinsic pathway and TF should not be considered the only trigger for thrombin formation during CPB and that the intrinsic pathway also plays a role. In contrast, in OPCAB patients, administration of a heparin dose similar to the one used during CPB (300 U/Kg) eliminates the production of thrombin during the time of surgery. Future trials will clarify the optimal heparin management in patients undergoing OPCAB. We also demonstrated that in OPCAB patients there is an increase of PF-1.2 production (corresponding to TF increase) starting on POD 2 and continuing to at least POD 7. Levels are comparable with those observed in patients undergoing on-pump CABG. Patients of both groups received low molecular weight heparin postoperatively; measured procoagulant markers levels may have been affected by such treatment as it has been demonstrated in other clinical settings.
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Nevertheless, we believe that administration of low molecular weight heparin could not alter the comparison between the groups.
The correlation between plasma activation of procoagulation markers and clinical outcome (namely graft patency) is still a matter of debate. Moor and colleagues
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found that the percentage increase in PAI-1 activity on the first postoperative day was significantly higher in patients who subsequently were found to have vein graft occlusion at angiographic evaluation 3 months after CABG. In our study, PAI-1 levels were more elevated in the on-pump patients, although a steady increase was observed also in the OPCAB group. In both groups, peak release was observed 3 hours after the end of the operation. At the same time, tPA release was very modestly stimulated, particularly in the OPCAB patients. We also observed that fibrinolysis (D-dimer) is activated to a lesser extent in OPCAB patients. On the basis of our observation, the proposed use of antifibrinolytic agents in OPCAB patients
6
seems unjustified unless future randomized trials with angiographic control studies will prove the safety of antifibrinolytic administration with regard to graft patency.
Platelet function, as analyzed by an in vitro bleeding test, is better preserved during OPCAB surgery than during CPB. The lack of CPB and cardiotomy suction, together with the reduced formation of thrombin, may explain why platelet function is preserved in OPCAB patients. The preserved platelet function did not affect blood loss or transfusion rates in our study. These findings are in contrast to other studies that have shown a reduction of both blood loss and transfusion in off-pump patients, although our sample size is not sufficiently large to produce reliable clinical outcome data. The administration of aspirin 100 mg daily from POD 1 does not affect platelet function postoperatively. In both groups, bleeding times measured at discharge were lower than those measured preoperatively. PFA-100 has already been used to assess platelet dysfunction in patients undergoing CPB surgery
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; it is a validated method to assess platelet function in patients with cardiovascular disease
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and to measure aspirin resistance in patients with coronary artery disease, showing that 35% of patients who had had acute myocardial infarction seemed to be nonresponders to long-term aspirin therapy in doses of 75 and 160 mg/day.
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Other studies have evaluated platelet function in OPCAB patients
22,23
; nevertheless, our study provides the longest observation suggesting that dosages of aspirin 100 mg daily may be insufficient to prevent vein graft failure. We hypothesize that the activated inflammatory and coagulative state observed after cardiac operations, by increasing von Willebrand factor release
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and platelet leukocytes aggregates, may influence platelet response to aspirin treatment; future studies should clarify whether treatment aimed to attenuate these systems may also decrease aspirin resistance.
Vein graft failure remains a major problem after CABG. Occlusion in the first weeks is secondary to thrombosis, whereas intimal hyperplasia and eventually atherosclerotic changes with superimposed thrombus formation underlie subsequent closure. Two recent randomized controlled trials
24,25
revealed that patency rate was significantly worse in patients undergone off-pump procedures compared with patients undergoing CPB. Moreover, data from a large registry demonstrate that off-pump patients have a higher rate of perioperative myocardial infarction and have a significantly worse 3-year risk-adjusted survival.
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There are several possible explanations for the poorer graft performance in patients operated on by the off-pump technique: the poorer coronary vessel exposure, heart movement, poor coronary visualization provoked by bleeding, all render the distal anastomosis more difficult to perform and sometimes less accurate than those made with the heart arrested. The tools used during the anastomoses (intracoronary shunts, coronary occluding stitch, carbon dioxide blower) to improve visualization may all potentially damage the coronary and graft endothelium.
27
Our study shows that the coagulation state of OPCAB patients differs from that of the on-pump group only during the first 24 hours. Of particular interest is the lack of platelet dysfunction observed during this period in the OPCAB patients associated with the lack of fibrinolysis. It remains to be demonstrated whether this association should be considered a procoagulative state. After the first 24 hours, both groups continue to produce thrombin probably as a consequence of their inflammatory state rather than the intraoperative procoagulative stimulus. This is associated with an increased platelet function, as measured by a platelet function analyzer (PFA-100). The actual antiplatelet treatment is not adequate to protect the graft from early thrombosis. Our data would support the addition of more aggressive antiplatelet and antithrombotic drug regimens in both on- and off-pump patients to decrease vein graft failure. We believe this might be particularly helpful in OPCAB patients in whom less accurate distal anastomosis and coronary artery endothelial damage may occur. Further studies with angiographic evaluation are needed to establish a correlation between coagulation parameters, antiplatelet treatment, and graft patency.
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D. Paparella, A. Galeone, and G. Scrascia Reply to the editor. J. Thorac. Cardiovasc. Surg., September 1, 2006; 132(3): 734 - 734. [Full Text] [PDF]
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