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Ann Thorac Surg 2010;89:421-427. doi:10.1016/j.athoracsur.2009.10.041
© 2010 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Coagulation-Fibrinolysis Changes During Off-Pump Bypass: Effect of Two Heparin Doses

Domenico Paparella, MDa,*, Fabrizio Semeraro, MDb, Giuseppe Scrascia, MDa, Antonella Galeone, MDa, Concetta T. Ammollo, DScb, Giorgios Kounakis, MDa, Luigi de Luca Tupputi Schinosa, MDa, Nicola Semeraro, MD, PhDb, Mario Colucci, DScb

a Department of Emergency and Organ Transplant, Division of Cardiac Surgery, University of Bari, Bari, Italy
b Department of Biomedical Sciences, Section of General and Experimental Pathology, University of Bari, Bari, Italy

Accepted for publication October 15, 2009.

Abbreviations and Acronyms ACT = activated clotting time; CABG = coronary artery bypass graft surgery; CPB = cardiopulmonary bypass; F1+2 = prothrombin fragment 1+2; OPCABG = off-pump coronary artery bypass graft surgery; PAP = plasmin-antiplasmin complex; PFA = platelet function analyzer; TAFI = thrombin activatable fibrinolysis inhibitor; TAFIa = activated thrombin activatable fibrinolysis inhibitor; TF = tissue factor; TFPI = tissue factor pathway inhibitor

* Address correspondence to Dr Paparella, University of Bari, Division of Cardiac Surgery, Dipartimento di Emergenza e Trapianti di Organo (DETO), Piazza Giulio Cesare 11, Bari, 70124, Italy (Email: dpaparella{at}cardiochir.uniba.it).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: To date, no study has tested the effect of different heparin dosages on the hemostatic changes during off-pump coronary artery bypass graft (OPCABG) surgery, and a wide variety of empirical anticoagulation protocols are being applied. We tested the effect of two different heparin dosages on the activation of the hemostatic system in patients undergoing OPCABG procedures.

Methods: Forty-two patients eligible for OPCABG procedures were assigned in a randomized fashion to low-dose heparin (150 IU/kg) or high-dose heparin (300 IU/kg). Prothrombin fragment 1+2, plasmin/alpha2-plasmin inhibitor complex, D-dimer, soluble tissue factor, tissue factor pathway inhibitor, total thrombin activatable fibrinolysis inhibitor (TAFI), and activated TAFIa were assayed by specific enzyme-linked immunosorbent assays at six different timepoints, before, during, and after surgery. Platelet function was evaluated by means of an in vitro bleeding time test, platelet function analyzer-100.

Results: The OPCABG surgery was accompanied by significant changes of all plasma biomarkers, indicative of systemic activation of coagulation and fibrinolysis. A significant increase in circulating TAFIa was detected perioperatively and postoperatively, and multiple regression analysis indicated that prothrombin F1+2 but not plasmin/alpha2-antiplasmin complex was independently associated with TAFIa level. Platelet function analyzer-100 values did not change significantly after OPCABG. All hemostatic changes were similar in the two heparin groups, even perioperatively, when the difference in anticoagulation was maximal.

Conclusions: Both early and late hemostatic changes, including TAFI activation, are similarly affected in the low-dose and high-dose heparin groups, suggesting that the increase in heparin dosage is not accompanied by a better control of clotting activation during OPCABG surgery.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Off-pump coronary artery bypass surgery (OPCABG) is a widely adopted alternative technique to coronary artery bypass performed with cardiopulmonary bypass (CPB). Despite treatment with high-dose heparin, patients undergoing CPB surgery experience excessive blood clotting activation leading to massive thrombin formation [1, 2], which may last long after surgery and thus cause a "prothrombotic state" that might favor the occurrence of vein graft occlusion [3, 4]. In these patients, there is also a transient hyperfibrinolytic state that is thought to contribute, together with the consumptive coagulopathy, to the excessive bleeding associated with CPB [1, 2].

During OPCABG, blood coagulation and fibrinolysis appear to be activated to a lesser extent than during on-pump surgery [3–5]. This notwithstanding, anticoagulant treatment is still required to avoid clotting within venous or arterial grafts while performing surgical anastomoses and, hopefully, to attenuate the wide spectrum of thrombin-mediated effects [6] that might contribute to the postoperative prothrombotic state documented in OPCABG patients [3, 4, 7]. Unfractionated heparin is generally used for this task. However, because of the lack of specific studies, there is nonconsensus on the heparin dosage and a very wide variety of empirical anticoagulation protocols is being used [8].

We performed a prospective, randomized controlled trial to compare the effect of two heparin doses (150 IU/kg versus 300 IU/kg) on the coagulation and fibrinolytic changes occurring in patients undergoing OPCABG operations. To this purpose, we selected a number of biomarkers known to be influenced by heparin, which included the plasma levels of prothrombin fragment 1+2 (F1+2), soluble tissue factor (TF), plasmin-antiplasmin complex (PAP), D-dimer, and tissue factor pathway inhibitor (TFPI). In addition, we investigated the changes in thrombin activatable fibrinolysis inhibitor (TAFI), an antifibrinolytic factor whose activity appears to be strongly dependent on thrombin generation [9]. Thrombin activatable fibrinolysis inhibitor is a plasma procarboxypeptidase of liver origin and is converted to the active form (TAFIa) by several enzymes, among which are thrombin and plasmin [9]; TAFIa, in turn, downregulates fibrinolysis by removing the plasminogen binding sites from partially degraded fibrin, thereby reducing plasmin formation and fibrin removal. Numerous experimental and human studies suggest that TAFI-mediated fibrinolysis modulation may contribute to either bleeding or thrombosis depending on whether TAFI levels or activation are decreased or increased [9, 10]. We believe no data are available on the changes of TAFI and TAFIa in OPCABG surgery and, more in general, very little is known about the occurrence and mechanisms of TAFI activation in vivo in man. Considering that thrombin and plasmin, in other words, the two putative physiological activators of TAFI, represent key factors in the coagulopathy associated with coronary surgery, we hypothesized that an augmented TAFI activation might occur in this condition, thus influencing the fibrinolytic process. Therefore, we sought to determine whether and to what extent TAFI is activated in vivo during OPCABG and whether this phenomenon is variably influenced by the two heparin doses.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
The Ethics Committee of the Policlinico University Hospital of Bari approved the study protocol, and all patients gave their informed consent to participate in the study. The study design was a prospective, randomized controlled trial. The primary outcome was to evaluate the changes in coagulation and fibrinolysis variables after OPCABG in patients receiving two different heparin doses. Forty-two patients requiring elective CABG surgery, eligible for OPCABG procedure, were enrolled in the study and assigned in a computer-generated randomization to either a low-dose heparin group (150 IU/kg, n = 21) or a high-dose heparin group (300 IU/kg, n = 21). Exclusion criteria were known preexisting hemolytic or hemostatic disorders, anticoagulant treatment, antiplatelet treatment taken within 5 days before surgery, hemodynamic intolerance to the heart lifting and the exposure necessary to perform OPCABG, presence of coronary arteries surgically inaccessible (intramyocardial) for a beating-heart operation, and patients in whom a complete revascularization was not achievable with OPCABG, in which case they were shifted to CPB.

Perioperative Management
After premedication with lorazepam, anesthesia was induced with a combination of fentanyl, midazolam, and sodium thiopenthal, and maintained with proprofol. Heparin was injected as a single bolus, and the degree of anticoagulation was monitored by the activated clotting time (ACT [Hemochron 8; ITC, Pleasanton, CA]), which was performed at the bedside before and 3 minutes after heparin injection, and thereafter at intervals of 10 to 15 minutes until neutralization with protamine. Additional heparin (5,000 U) was given if the ACT fell below 300 s in the low-dose heparin group and below 400 s in the high-dose heparin group. After surgery, protamine sulphate was administered to neutralize heparin (1 mg protamine/100 IU heparin). Antifibrinolytic drugs were not administered. Cell-saving devices were not used. Deep pericardial suture was passed in the posterior pericardium to lift the heart. After surgery, patients were transferred to the intensive care unit. They were extubated when hemodynamically stable, fully rewarmed, awake, without surgical bleeding, and with optimal blood gases. Chest tubes were removed when drainage was less than 10 mL/h for at least 4 hours, which generally occurred within 24 to 48 hours. Treatment with acetylsalicylic acid (300 mg daily, orally or intravenously) and low molecular weight heparin (enoxaparin, 4,000 anti-Xa IU daily, subcutaneously) was started 12 hours after the end of the operation. Low-molecular weight heparin treatment was given until postoperative day 5, and antiplatelet therapy was included in discharge prescriptions.

Blood Collection and Plasma Preparation
Blood samples were collected at the following intervals: (1) before surgery (T0); (2) 30 minutes after heparin administration (T1); (3) 15 minutes after protamine administration (T2); (4) 3 hours after the end of the operation (T3); (5) 24 hours after surgery (T4); and (6) 5 or 6 days after surgery (T5). Blood was taken from central venous catheter or peripheral vein and anticoagulated with sodium citrate (0.39%, final concentration). Plasma was prepared within 1 hour by centrifugation at room temperature for 20 minutes at 1,000g, and stored frozen (–80°C) until assay.

Assays
Platelet function was evaluated on whole blood by the platelet function analyzer (PFA-100), a device designed to simulate platelet-dependent primary hemostasis in vitro, which is considered a useful tool for platelet function evaluation [11, 12]. The PFA-100 tests were performed within 15 minutes from blood sampling. Hematocrit, hemoglobin concentration, and platelet count were carried out by standard laboratory methods.

Plasma measurements were performed on plasma samples thawed for 15 minutes at 37°C just before assay. The following biomarkers were measured by commercially available enzyme-linked immunosorbent assays: soluble TF (Imubind TF), TFPI (Imubind total TFPI), PAP (Imuclone PAP) from America Diagnostica, Stamford, CT; F1+2 (Enzygnost F1+2) from Dade Behring, Marburg, Germany; and D-dimer (Asserachrom D-Di), TAFI (Asserachrom TAFI), activated TAFI (Asserachrom TAFIa/ai) from Diagnostica Stago, Asnieres, France (courtesy of Dr Olivier Morboef). The suitability of citrated plasma for assaying F1+2, D-dimer, and TAFIa (ie, the activation markers that might be influenced by thrombin eventually generated after blood collection) has been demonstrated by others [13, 14].

Statistical Analysis
Based on previous data in OPCABG patients [3], the study was powered to demonstrate a 30% difference in F1+2 between low and high heparin groups ({alpha} = 0.05; β = 0.2). Continuous variables are presented as mean ± SEM, and categorical variables as absolute number and percentage. Differences between groups were assessed by the Mann-Whitney U test or by Fisher's exact test, as appropriate. Two-factor repeated measures analysis of variance (ANOVA) was performed to evaluate the between-groups differences in biomarkers; single-factor repeated measures ANOVA, followed by Bonferroni corrected pairwise comparisons, was used to compare the course of biomarkers' concentration over time versus baseline (T0). The latter two analyses were carried out after log-transformation of data. A stepwise multiple regression analysis was performed to evaluate the independent contribution of tested variables to the prediction of TAFIa levels. Statistical analyses were performed using the Stat-View Statistical Software Package (SAS Institute, Cary, NC).


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
The characteristics of the patients are summarized in Table 1. Age, sex, cardiovascular risk factors, associated diseases, ejection fraction, and number of patients on statin therapy were similar in low-dose and high-dose heparin groups. As regards the intraoperative variables, there were no differences in mean number of distal anastomoses, operation time, and heparinization time (time from heparin to protamine administration; Table 2). Eight patients of the low-dose heparin group and 4 patients of the high-dose heparin group received an additional heparin bolus of 5,000 IU to maintain the ACT value above the target threshold (300 s and 400 s for low-dose and high-dose heparin groups, respectively). Despite the difference in the number of patients receiving additional anticoagulant, the mean heparin dose was clearly and markedly different between the two groups (14,000 versus 23,929 IU/patient, p = 0.005). Accordingly, not only ACT immediately after heparin injection but also peak ACT, which includes measurements after the additional bolus of heparin, were significantly higher in the high-dose heparin group (Table 2).


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  		Table 1 Patient Characteristics
 

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  		Table 2 Intraoperative and Postoperative Data
 
There were no statistically significant differences in the postoperative outcome between groups (Table 2), and none of the patients had to be reoperated on for excessive bleeding. Moreover, there were no differences between groups with respect to inotropes use, and number of patients experiencing postoperative atrial fibrillation or requiring reintubation or dialysis (not shown).

During and after OPCABG, there were significant changes of all plasma biomarkers (Table 3), indicative of systemic activation of coagulation and fibrinolysis. These changes were very similar in the two heparin groups, even perioperatively, when the difference in anticoagulation was maximal. The levels of F1+2 (Fig 1) increased early after the start of the operation and reached a peak level at T3 (3 hours after operation). Afterward, they dropped significantly at 24 hours (T4) and raised again at 5 to 6 days (T5), suggesting the occurrence of two different phases of clotting activation. The PAP complexes displayed a fairly similar pattern (Fig 1). Tissue factor levels decreased slightly perioperatively (up to T3) and then increased to some extent (T5), even though the difference with the preoperative level was not statistically significant (p = 0.228, by pairwise comparison), making unlikely an involvement of soluble TF in clotting activation. The D-dimer increased progressively, reaching a maximum at 5 to 6 days. The TFPI changes were characterized by a rapid and marked increase soon after heparin injection (T1), which was followed by a drop 15 minutes after protamine (T2) that brought the plasma concentration below the preoperative level, and then by a slow recovery.


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  		Table 3 Evolution of Plasma Biomarkers and PFA-100 Closure Time in Off-Pump Coronary Artery Bypass Graft Surgery Patients
 

Figure 1
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  		Fig 1. Evolution of plasma prothrombin fragment 1+2 (F1+2), plasmin-antiplasmin complex (PAP), thrombin activatable fibrinolysis inhibitor (TAFI), and activated TAFI (TAFIa) in off-pump coronary artery bypass graft surgery (OPCABG) patients treated with 150 IU/kg (solid symbols) or 300 IU/kg heparin (empty symbols). Samples were collected before surgery (T0), 30 minutes after heparin administration (T1), 15 minutes after heparin neutralization with protamine (T2), 3 hours after the end of the operation (T3), 24 hours after surgery (T4), and 5 or 6 days after surgery (T5). Results are expressed as mean ± SEM. *p < 0.01; {dagger}p < 0.0001 versus T0 by repeated measures analysis of variance performed on all 42 patients.

 
To evaluate the potential involvement of TAFI, we measured both total TAFI and the levels of TAFIa using specific immunoassays (Fig 1). An increase in total TAFI was only observed at 5 to 6 days, whereas the levels of TAFIa were significantly increased at 3 hours (T3) and reached a peak level at 24 hours (T4), which was maintained as long as 5 to 6 days. To evaluate the relative role of thrombin and plasmin in the in vivo activation of TAFI, we performed a multiple regression analysis. In a model that included F1+2, PAP, total TAFI, TFPI, and D-dimer, the variables emerging as independent predictors of TAFIa level were F1+2 (r = 0.510, p < 0.0001), TAFI antigen (r = 0.280, p = 0.034), and D-dimer (r = 0.507, p < 0.0001). The PFA-100 closure time, an index of platelet function, was similar in the two heparin groups and did not appreciably change during and after OPCABG, not even at T5, namely, several days after the start of aspirin treatment.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In the context of OPCABG, the hemostatic system has been studied mainly to evaluate whether avoiding CPB would attenuate the perioperative coagulopathy induced by the heart-lung machine. Several studies have confirmed that coagulation-fibrinolysis activation and platelet dysfunction are of lower intensity during OPCABG [3–5], giving a rational explanation to the reduced rate of blood loss and need of fewer blood products [15, 16]. So far, no study has tested the effect of different heparin doses on the hemostatic system during OPCABG. Currently, a wide variety of empirical anticoagulation protocols is being applied [8], the intraoperative heparin doses ranging from 70 to 500 IU/kg, and thus systematic studies addressing this point are warranted. In this study, we compared two different heparin doses (150 and 300 IU/Kg) on perioperative and postoperative hemostatic changes. As expected, a greater degree of anticoagulation was found in the high-dose group, as inferred by ACT prolongation. However, despite this difference in anticoagulation, the two doses of heparin had similar effects on in vivo clotting activation, as assessed by plasma levels of F1+2, even perioperatively, namely, immediately after heparin administration. This finding is in contrast with the results in patients undergoing CPB, in whom higher heparin doses were more effective in reducing perioperative thrombin generation [17, 18]. The reason for this discrepancy is unclear. Differences in the mechanisms behind clotting activation in OPCABG and CPB, differences in the sensitivity of such mechanisms to heparin, differences in the specific biomarkers investigated, or more simply, differences in the heparin doses compared, are some of the possible explanations that can be hypothesized. Circulating TFPI is another biomarker heavily affected by heparin administration [19]. So far, the effect of heparin infusion on plasma TFPI has been only studied in CPB, with rather conflicting results as to the relationship between the dose of anticoagulant and the rise of circulating TFPI [20–22]. In OPCABG patients, we found a marked increase in plasma TFPI immediately after heparin treatment, which, however, was not influenced by the dose of the anticoagulant, probably because a maximal release of TFPI from the endothelial surface is already obtained with the low-dose heparin regimen.

Another important objective of our study was to see whether OPCABG is associated with the in vivo activation of TAFI and whether the heparin dose has any influence on this phenomenon. The levels of TAFI zymogen increased only at postoperative days 5 to 6. The concentration of TAFIa, instead, increased early after operation, reached its peak level at 24 hours (T4), and remained high thereafter, suggesting that the surgical procedure enhanced the in vivo activation of this fibrinolytic inhibitor. The candidate activators of TAFI are thrombin and plasmin [9, 10], and therefore we evaluated the correlation of both F1+2 and PAP complex with TAFIa level. By multivariate regression analysis, we found that F1+2, together with total TAFI and D-dimer, but not PAP, were independently associated with TAFIa levels. This finding would suggest that thrombin is an important activator of TAFI during OPCABG, which is compatible with the in vitro finding that thrombin bound to thrombomodulin is the most powerful inducer of TAFI activation [9]. However, the possibility that other enzymes had contributed to the in vivo TAFI activation cannot be excluded, also considering that the patterns of TAFIa and F1+2 changes during and after OPCABG were slightly different. The occurrence of TAFI activation and the subsequent inhibition of fibrinolysis may represent an additional factor contributing to the postoperative "prothrombotic state" reported in OPCABG patients [3, 4]. In agreement with other biomarkers, no difference in the extent of TAFI activation was observed between the two heparin doses.

In conclusion, our data indicate that both early and late hemostatic changes are the same in patients receiving 150 IU/kg or 300 IU/kg of heparin, suggesting that the use of a higher concentration of anticoagulant does not result in a better control of the OPCABG-associated coagulopathy. As to the effect of the two doses of heparin on clinical outcome and safety, the lack of difference in bleeding and other postoperative variables should be taken with caution because our study was not powered to detect differences in clinical outcome. Larger clinical studies are warranted to settle this point.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Edmunds LH, Colman RW. Thrombin during cardiopulmonary bypass Ann Thorac Surg 2006;82:2315-2322.[Abstract/Free Full Text]
  2. Paparella D, Brister SJ, Buchanan MR. Coagulation disorder of cardiopulmonary bypass. A review. Intensive Care Med 2004;30:1873-1881.[Medline]
  3. Paparella D, Galeone A, Venneri MT, et al. Activation of the coagulation system during coronary artery bypass grafting operation: comparison between on pump and off pump techniques J Thorac Cardiovas Surg 2006;131:290-297.[Abstract/Free Full Text]
  4. Parolari A, Mussoni L, Frigerio M, et al. Increased prothrombotic state lasting as long as one month after on-pump and off-pump coronary surgery J Thorac Cardiovasc Surg 2005;130:303-308.[Abstract/Free Full Text]
  5. Lo B, Fijnheer R, Castigliego D, et al. Activation of hemostasis after coronary artery bypass grafting with or without cardiopulmonary bypass Anesth Analg 2004;99:634-640.[Abstract/Free Full Text]
  6. Martorell L, Martínez-González J, Rodríguez C, et al. Thrombin and protease-activated receptors (PARs) in atherothrombosis Thromb Haemost 2008;99:305-315.[Medline]
  7. Kurlansky PA. Is there a hypercoagulable state after off-pump coronary artery bypass surgery?. What do we know and what can we do?. J Thorac Cardiovasc Surg 2003;126:7-10.[Free Full Text]
  8. Englberger L, Streich M, Tevaearai H, Carrel TP. Different anticoagulation strategies in off-pump coronary bypass operations: a European Survey Interact Cardiovasc Thorac Surg 2008;7:378-382.[Abstract/Free Full Text]
  9. Bouma BN, Meijers JC. Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U) J Thromb Haemost 2003;1:1566-1574.[Medline]
  10. Leurs J, Hendriks D. Carboxypeptidase U (TAFIa): a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease Thromb Haemost 2005;94:471-487.[Medline]
  11. Harrison P. The role of PFA-100 testing in the investigation and management of haemostatic defects in children and adults Br J Haematol 2005;130:3-10.[Medline]
  12. Favaloro EJ. Clinical utility of the PFA-100 Semin Thromb Hemost 2008;34:709-733.[Medline]
  13. Neill EK, Stewart RJ, Schneider MM, Nesheim ME. A functional assay for measuring activated thrombin-activatable fibrinolysis inhibitor in plasma Anal Biochem 2004;330:332-341.[Medline]
  14. Leroy-Matheron C, Gouault-Heilmann M. Influence of conditions of blood sampling on coagulation activation markers (prothrombin fragment 1 + 2, thrombin-antithrombin complexes and D-dimers) measurements Thromb Res 1994;74:399-407.[Medline]
  15. Puskas JD, Williams WH, Duke PG, et al. Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting J Thorac Cardiovasc Surg 2003;125:797-808.[Abstract/Free Full Text]
  16. Ascione R, Williams S, Lloyd CT, et al. Reduced postoperative blood loss and transfusion requirement after beating heart coronary operations: a prospective randomized study J Thorac Cardiovasc Surg 2001;121:689-696.[Abstract/Free Full Text]
  17. Despotis GJ, Joist JH, Hogue CW, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT Thromb Haemost 1996;76:902-908.[Medline]
  18. Paparella D, Al Radi OO, Meng GH, et al. The effects of high-dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass Blood Coagul Fibrinolysis 2005;16:323-328.[Medline]
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