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Ann Thorac Surg 1998;65:712-718
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Activation of Coagulation and Fibrinolysis During Cardiothoracic Operations

Department of Cardiothoracic Surgery, Imperial College School of Medicine at The National Heart and Lung Institute, Harefield Hospital, Middlesex, United Kingdom

Accepted for publication September 15, 1997.

Dr Hunt, Research Haematology, Heart Science Centre, Harefield Hospital, Harefield, Middlesex UB9 6JH UK.

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. During open cardiac operations using cardiopulmonary bypass, there is activation of coagulation and fibrinolysis. We assessed the separate contributions of the surgical procedure itself and cardiopulmonary bypass to this, by studying sequential samples from patients undergoing routine open cardiac operations or thoracic operations without cardiopulmonary bypass.

Methods. Activation of coagulation and the extent of fibrinolysis were measured from sequential samples obtained before the operation to 48 hours after the operation for 7 thoracic patients and 8 cardiac patients.

Results. In the thoracic group operation length was shorter (p = 0.002), and there was no significant increase in thrombin–antithrombin III complexes or D-dimers until 24 hours postoperatively. In contrast, there was a highly significant increase in thrombin–antithrombin III complexes (p = 0.0043) and D-dimer levels (p = 0.009) during cardiopulmonary bypass. The increase in fibrinolytic activity was caused by an increase in tissue plasminogen activator (p = 0.013). At 48 hours postoperatively, the cardiac patients had a more hypercoagulable state than thoracic patients with significantly higher levels of thrombin–antithrombin III complexes (p = 0.041) and plasminogen activator inhibitor-1 activity (p = 0.0033).

Conclusions. This study suggests the major activation of coagulation and fibrinolysis seen during cardiac operations is caused by the use of cardiopulmonary bypass.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Activation of hemostasis is well recognized in patients undergoing cardiac operations with cardiopulmonary bypass (CPB) [1][2]. Cardiopulmonary bypass involves extensive contact between blood and the artificial surfaces of the bypass circuit, and thus produces activation of coagulation necessitating the use of systemic heparinization to prevent clotting in the extracorporeal circuit. The use of CPB is also characterized by a reduction in platelet number and function, activation of fibrinolysis, and hemodilution [2].

The dosage of heparin used during CPB was reached empirically, in that it is the minimum dosage at which clotting did not occur in the CPB equipment [3]. Subsequent studies have shown that despite standard heparinization there is an increase in the levels of molecular markers of activation of coagulation, such as thrombin–antithrombin III complex (TAT) levels and prothrombin fragment F1+2 [4][5], perioperatively in patients undergoing open cardiac surgical procedures. The mechanisms of activation of coagulation by CPB is under review. Previously it was thought that activation of coagulation during CPB occurred through the contact pathway [6][7]. Current evidence suggests that the activation of the extrinsic pathway may be the main mechanism of thrombin generation during operations [5][8]. There are no studies to indicate whether this increased thrombin generation is related to local clot formation at the site of surgical cutting, activation of coagulation by the bypass equipment despite heparinization, or both.

Another aspect of cardiac operations is the activation of fibrinolysis [9]. Hyperfibrinolysis has been found to be related to postoperative blood loss and D-dimer levels after CPB correlate positively with postoperative blood loss [10][11]. This finding has been supported by the efficacy of the antifibrinolytic agents, such as tranexamic acid and aprotinin, in reducing blood loss during surgical procedures using CPB, although aprotinin may also have an effect on platelet preservation [12][13]. The increase in fibrinolytic activity has been attributed to increased plasma levels of tissue plasminogen activator (tPA) [14] and the contact activation of fibrinolysis [6]. Increased perioperative fibrinolytic activity has been recognized to occur in surgical operations without CPB since Macfarlane noted in 1937 [15] that blood removed from a patient immediately after cholecystectomy clotted normally but was " quite fluid" when inspected the following day. However the extent of fibrinolytic activity in patients undergoing routine operations without CPB has been poorly studied. The use of prophylactic antifibrinolytic agents to reduce perioperative blood loss could be logically extended to thoracic operations if increased fibrinolytic activity occurred.

We hypothesized that not all of the activation of coagulation and fibrinolysis seen in open cardiac operations was caused by the direct effect of CPB. We investigated this by measuring markers of coagulation and fibrinolysis in sequential samples taken from patients undergoing routine cardiac surgical procedures and compared this with samples taken at similar time points in patients undergoing thoracic operations without CPB.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patient Details
All patients gave informed consent to participate in this study that was approved by the Ethical Committee of Hillingdon Health Authority. Patient details are shown in Table 1. Cardiac operating times were significantly longer than thoracic operations (p = 0.002). Four of the eight patients undergoing cardiac operations had received aspirin during the 7-day period before the operation, but none had taken warfarin. None of the thoracic patients were receiving aspirin or warfarin preoperatively.

Thoracic
Samples were also obtained from 7 patients undergoing thoracotomy. Three patients required thoracotomies for pulmonary resection, 4 had esophagastrectomy for cancer. No heparin was administered to the thoracic patients. The same surgical and anesthetic teams were used throughout all the cardiac operations and another team for thoracic operations.

Sample Collection
Sequential samples were taken from patients undergoing cardiac operation at the following time points: (1) preoperatively, (2) before CPB (after heparin), (3) 5 minutes into CPB, (4) at the end of CPB, (5) 20 minutes postoperatively, (6) 24 hours postoperatively, and (7) 48 hours postoperatively.

For the thoracic patients blood samples were taken at time points similar to the cardiac patients, ie, (1) preoperatively, (2–4) at half-hourly intervals throughout the operation, and (5–7) the same time points as cardiac patients.

Sample Processing
Ten milliliters of venous blood was collected from a central venous line into 0.105 mol/L trisodium citrate in a 9:1 ratio of blood to anticoagulant. Five milliliters was immediately placed on ice and then centrifuged at 2,000 g for 30 minutes at 4°C; these samples were later used for fibrinolytic assays. The remaining 5 mL was centrifuged at 2,000 g at room temperature for coagulation assays. The platelet-poor plasma was removed, aliquoted, snap-frozen, and stored at -70°C until assayed.

Assay Methods
Each assay had a normal range established as the mean ± 2 standard deviations using 43 normal healthy nonsmoking adults (25 men and 18 women), median age 40 years (range 21 to 62 years). The intrareproducibility and interreproducibility (coefficient of variation, CV) of each assay was determined. The assays described were not affected by heparin.

Coagulation Pathway Assays
Thrombin generation was measured by thrombin–antithrombin III complexes (Behring, UK). This was performed by enzyme immunoassay with an intraassay and interassay CV of 1% and 2%, respectively.

Antithrombin III activity (Instrumentation Laboratories Ltd, Warrington, UK), was measured by chromogenic assay using an Automated Coagulation Laboratory (ACL 300R, IL, UK), which has intraassay and interassay CV of 5%.

Fibrinolytic Assays
The euglobulin clot lysis time was performed as described previously [16] by precipitation of the euglobulin fraction at pH 6.0 (intraassay and interassay CV = 6.6% and 10%, respectively). Tissue plasminogen activator antigen levels were determined by enzyme-linked immunosorbent assay (Biopool TintElize tPA, Umea, Sweden) (CV = 6.6% and 10.5%). Urokinase plasminogen activator (uPA) antigen was measured by enzyme-linked immunosorbent assay (Tint Elisa uPA, Umea, Sweden) (CV = 4% and 14%). This assay measures single-chain plasminogen activator (scu-PA), high-molecular-weight uPA (two-chain plasminogen activator and scu-PA), and low-molecular-weight forms (high-molecular-weight split products), but not uPA-inhibitor complexes. Plasminogen activity (CV = 3% and 3%) and -2-antiplasmin activity (CV = 5% and 6%) were measured by automated chromogenic substrate assays on the ACL 300R. Plasminogen activator inhibitor activity was measured using a chromogenic microtiter plate method (Quadratech Ltd, UK) (CV = 3% and 9.6%). Cross-linked fibrinogen degradation levels, measured as D-dimer levels were quantitated by immunoassay (Behring Ltd, UK) (CV = 4% and 7%).

Statistical Analysis
Samples 3 and 4 taken during CPB from the cardiac patients were adjusted for hemodilution by multiplying the results by the ratio of the hematocrit at baseline to the hematocrit at that timepoint.

The data were tested at each time point for normality using the Shapiro-Wilk test. If the data were normally distributed values were expressed as means and standard deviations. Analysis of variance was used for changes within each patient group from the baseline (before operation). The separate variance t test for normally distributed data was used to compare the cardiac and thoracic groups at each time point. Nonparametric data were summarized using median and ranges, and data were compared using the Mann-Whitney U test. Significance was taken at p less than 0.05.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Coagulation Pathway Assays
Thrombin–Antithrombin III Complex Levels
Median TAT levels are summarized in Fig 1; preoperative levels were within the normal range. During thoracic operation there was no significant increase in TAT values from baseline. The highest values were attained 24 hours after operation, median 15.7 µg/L (range, 3.6 to 36.7 µg/L, p = 0.065 compared with baseline levels). There was no significant difference in TAT values at time points 1 and 2 (preoperative and before CPB) between the cardiac and thoracic patients.

View larger version (20K): [in this window] [in a new window]   Median levels of thrombin–antithrombin III (TAT) complexes during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the Mann-Whitney U test.)

Antithrombin III Activity
Mean (standard deviation) antithrombin III levels are summarized in Fig 2; baseline levels were within the normal range. Levels of antithrombin III during thoracic operation tended to decrease from baseline; this reached significance at sample 5 (p = 0.0435), but levels remained within the normal range throughout the operation.

View larger version (20K): [in this window] [in a new window]   Mean and standard deviation levels of antithrombin III (ATIII) during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

Levels were significantly lower in the cardiac patients compared with thoracic patients at time point 3 (5 minutes on CPB, p = 0.022), at time point 5 (20 minutes postoperatively, p = 0.0001), and at time point 6 (24 hours postoperatively, p = 0.0147).

Fibrinolytic Assays
Fibrin Degradation Products (D-Dimer Levels)
Median D-dimer levels are shown in Fig 3; preoperative levels were within the normal range. Preoperative and sample 2 levels for both patient groups were similar and within the normal range. D-dimer levels were significantly higher in the cardiac group compared with the thoracic group at the end of CPB (p = 0.009) and 20 minutes after CPB (p = 0.007). There was a trend for levels to increase during thoracic operation, becoming significantly elevated from baseline at 24 hours (time point 6, p = 0.009) and 48 hours (time point 7, p = 0.02).

View larger version (19K): [in this window] [in a new window]   Median levels of D-dimers during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the Mann-Whitney U test.)

Euglobulin Clot Lysis Time
Median (range) euglobulin clot lysis times are summarized in Fig 4; preoperative levels were within the normal range. There was a significant fall in euglobulin clot lysis time compared with baseline levels in both patient groups after the start of the operation (time point 2 for cardiac and thoracic patients, p = 0.01). However, in the thoracic group euglobulin clot lysis time returned to near normal values at the end of the operation, whereas the cardiac patients had significantly shorter values at the end of CPB (time point 4), compared with baseline (p = 0.02).

View larger version (19K): [in this window] [in a new window]   Median levels of euglobulin (ECLT) clot lysis time during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the Mann-Whitney U test.)

Plasminogen and -2-Antiplasmin Levels

View larger version (22K): [in this window] [in a new window]   Mean ± standard deviation levels of plasminogen during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

View larger version (22K): [in this window] [in a new window]   Mean ± standard deviation levels of alpha-2-antiplasmin during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

View larger version (21K): [in this window] [in a new window]   Mean ± standard deviation levels of tissue plasminogen activator (tPA) during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

Urokinase Plasminogen Activator Antigen
Mean (standard deviation) uPA antigen levels are shown in Fig 8. Baseline levels were within the normal range. These were within the normal range in both groups and did not change from baseline values throughout the operation.

View larger version (22K): [in this window] [in a new window]   Mean ± standard deviation levels of urokinase plasminogen activator (uPA) during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

View larger version (24K): [in this window] [in a new window]   Mean ± SD activity levels of plasminogen activator inhibitor (PAI-1) during coronary artery bypass graft (CABG) and thoracic operations. Sample points 1 through 7 are described in Material and Methods. Broken lines denote limits of normal ranges. (*p < 0.05, significant difference between the two patient groups using the separate variance t test.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

There was increased thrombin generation during CPB as demonstrated by the increased levels of TATs, suggesting that despite heparin, the bypass foreign surfaces exert a powerful prothrombotic stimulus. These results show that surgical dissection is not responsible for this major activation of coagulation, for during thoracic surgery, and during the dissection of donor grafts from leg veins or internal mammary artery (between the start of the operation and before CPB) in the cardiac patients, there was no significant increase in TAT levels.

The ideal control group to compare with open cardiac operation is cardiac operation performed without CPB, using the same surgical team, but this type of operation is infrequently performed nowadays. Thus major thoracic operation requiring thoracotomy was the best control group available. Unfortunately, this resulted in significantly longer operating times in the cardiac patients and each group had a different operating team and type of operation. It is recognized that the anesthetic technique used can slightly alter hemostatic response, for levels of von Willebrand factor and factor VIIIC after CPB are related to the plasma levels of arginine vasopressin, which can be increased with a " stress" anesthetic agent such as enflurane [17]. However, it seems unlikely that the large and clear-cut change in activation of coagulation and fibrinolysis we describe could be caused by these factors. Moreover the temporal changes of TAT and D-dimer levels suggest they were related to the use of CPB for they increased significantly after the initiation of CPB, and fell rapidly after cessation of CPB. The thrombogenicity of the bypass circuit can vary according to the biocompatibility of its surface, but in this study the same type of circuit was used in all the cardiac patients. The cause of the increased TAT levels may not all be related to the direct thrombogenic effect of the CPB circuit, but may be caused by other factors, notably the retransfusion of suctioned blood. Chung and associates [18] showed that in suctioned blood the extrinsic pathway was activated after contact with the pericardial cavity.

The use of cardiopulmonary bypass resulted in increased fibrinolytic activity as shown by a sixfold increase in D-dimer levels. It was associated with an increase in median t-PA activity, increasing to a peak that was twofold greater than in the thoracic patients. The wide range in values, confirmed by Chandler and colleagues [19], has shown there is large individual variation in the fibrinolytic response during CPB. Valen and associates [20] have shown that some of the increase in t-Pa is from the coronary circulation after cardioplegic arrest has been performed. The increase and peak of D-dimer levels during CPB occurred at the same time as the increase and peak of TAT levels. Other studies have found that the peak of TATs during CPB preceded the evolution of high D-dimer levels at the end of surgery and postoperatively [1][5][10][11][19], suggesting that a major component of t-PA release is secondary to thrombin generation. D-Dimer levels have been correlated with blood loss and postoperative bleeding time [11], and hyperfibrinolysis will affect other aspects of hemostasis. Plasmin may reduce platelet adhesion and aggregation by degradation of platelet receptors glycoprotein Ib and IIb/IIIa [21].

Urokinase levels have been poorly studied perioperatively in thoracic operations. The source of plasma urokinase is not clear; its main source may be the kidney [22] with a contribution from monocytes. It occurs in human plasma as an inactive single-chain zymogen form (scu-PA). Single-chain u-PA is converted to active, two-chain uPA by plasmin and kallikrein. The latter involves scu-PA in the intrinsic pathways of fibrinolysis and is not regarded as playing an important role in plasma fibrinolysis. There was no significant change in urokinase levels in either patient group perioperatively, as shown by other investigators [20][23]. Spannagl and coworkers [23] used a different enzyme-linked immunosorbent assay to measure scu-PA, two-chain u-PA antigen, and uPA antigen complexed with inhibitors in patients undergoing CPB. They found higher concentration of scu-PA in shed mediastinal blood suggesting that there is cellular release of scu-PA at the bleeding site, but that the use of high-dose aprotinin during CPB protected both circulating and released scu-PA from activation and thus attenuated local bleeding. Unless this local effect of aprotinin is important in reducing perioperative bleeding, the lack of perioperative activation of plasma fibrinolysis during thoracic surgery suggests that prophylactic antifibrinolytic agents would have at best only a minor effect in reducing bleeding in thoracic operations.

Plasminogen activator inhibitor-1 activity increased postoperatively; this was significant in patients who had cardiac operations, suggesting that the postoperative fibrinolytic " shut-off" may be more marked after cardiac than thoracic operations, although the difference in length of operation is a confounding factor. The postoperative responses between cardiac and thoracic operations have not been previously compared. Mannucci and associates [24] noted that alterations in TAT complexes and D-dimer levels were increased for a month after cardiac surgery.

In conclusion, this study shows that the increase in the major activator of coagulation during cardiac operations is caused by the effect of the extracorporeal circuit, and that surgical cutting produces little change. Increased intraoperative fibrinolytic activity only occurred during CPB, and may be at least partly secondary to thrombin generation. In this study cardiac patients had a more hypercoagulable state postoperatively with higher TAT levels and plasminogen activator inhibitor-1 activity than after thoracic operation. This study emphasizes the need for further research into improving the biocompatibility of extracorporeal circuits, and exploring different surgical techniques to perform cardiac operation without the need for CPB.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Edward R. Townsend, FRCS, for allowing us to study his patients. We also thank the Theatre Staff of Harefield Hospital.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Teufelsbauer H, Proidl S, Havel M, Vukovich T Early activation of haemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost 1992;68:250-252.[Medline]
2. Demeyer R Coagulation in cardiac surgery. Curr Opin Anaesthesiol 1990;3:77-85.
3. Bull MH, Huse WM, Bull BS Evaluation of tests used to monitor heparin therapy during extracorporeal circulation. Anesthesiology 1975;43:346-353.[Medline]
4. Boisclair MD, Philippou H, Lane DA Thrombogenic mechanisms in the human: fresh insights obtained by immunodiagnostic studies of coagulation markers. Blood Coagul Fibrinolysis 1993;4:1007-1021.[Medline]
5. Boisclair MD, Lane DA, Philippou H, et al. Mechanism of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-3357.[Abstract/Free Full Text]
6. Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE Studies on components of the plasma kallikrein-kinin system in patients undergoing cardiopulmonary bypass. Adv Exp Med Biol 1986;198b:185-191.
7. Wachtfogel YT, Harpel PC, Edmunds LH, Colman RW Formation of C1-C1-inhibitor, kallikrien-C1-inhibitor and plasmin-alpha 2-antiplasmin-inhibitor complexes during cardiopulmonary bypass. Blood 1989;73:468-471.[Abstract/Free Full Text]
8. Burman JF, Chung HI, Lane DA, Philippou H, Adami A, Lincoln JCR Role of factor XII in thrombin generation and fibrinolysis during cardiopulmonary bypass. Lancet 1994;344:1192-1193.[Medline]
9. Stibbe J, Kluft C, Brommer E, Gomes M, de Jong D, Nauta J Enhanced fibrinolytic activity during cardiopulmonary bypass in open heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 1984;14:375-382.[Medline]
10. Gram J, Janetzko T, Jespersen J, Bruhn HD Enhanced effective fibrinolysis following the neutralisation of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 1990;63:241-245.[Medline]
11. Havel M, Teufelsbauer H, Knobl Dalmatiner R, et al. The effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass surgery. J Thorac Cardiovasc Surg 1991;101:968-972.[Abstract]
12. Blauhut B, Harringer W, Bettelheim P, Doran JE, Spath P, Lundsgaard-Hansen P Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;108:1083-1091.[Abstract/Free Full Text]
13. Davis R, Whittington R Aprotinin. A review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery. Drugs 1995;49:954-983.
14. 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.[Medline]
15. Macfarlane RG Fibrinolysis following operation. Lancet 1937;I:10-12.
16. Mackie I, Machin S Fibrinolysis. In: Chanarin I, ed. Laboratory haematology. London: Churchill Livingstone, 1989:362-363.
17. Kuitunen A, Hynynen M, Salmenpera M, et al. Anaesthesia affects plasma concentrations of vasopressin, von Willebrand factor and coagulation factor VIII in cardiac surgical patients. Br J Anaesth 1993;70:173-180.[Abstract/Free Full Text]
18. Chung JH, Gikakis N, Rao AK, Drake TA, Colman RW, Edmunds H Pericardial blood activates the extrinsic coagulation pathway during clinical cardiopulmonary bypass. Circulation 1996;93:2014-2018.[Abstract/Free Full Text]
19. Chandler WL, Fitch JCK, Wall MH, et al. Individual variations in the fibrinolytic response during and after cardiopulmonary bypass. Thromb Haemost 1995;74:1293-1297.[Medline]
20. Valen G, Eriksson E, Risberg B, Vaage J Fibrinolysis during cardiac surgery. Eur J Cardiothorac Surg 1994;8:324-330.[Abstract]
21. Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI Plasmin effect on platelet glycoprotein 1b-von Willebrand factor interactions. Blood 1985;65:32-40.[Abstract/Free Full Text]
22. Hong SY, Yang DH, Kim PN Urokinase concentration in the renal artery and vein. Nephron 1992;61:176-180.[Medline]
23. Spannagl M, Dooijewaard G, Dietrich W, Kluft C Protection of single-chain urokinase-type plasminogen activator (scu-PA) in aprotinin treated cardiac surgical patients undergoing cardiopulmonary bypass. Thromb Haemost 1995;73:825-828.[Medline]
24. Mannucci L, Gerometta PS, Mussoni L, et al. One month follow-up of haemostatic variables in patients undergoing aortocoronary bypass surgery. Thromb Haemost 1995;73:356-361.[Medline]

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				J. M. Albes, I. M. Stohr, M. Kaluza, A. Siegemund, D. Schmidt, R. Vollandt, and T. Wahlers Physiological coagulation can be maintained in extracorporeal circulation by means of shed blood separation and coating J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1504 - 1512. [Abstract] [Full Text] [PDF]

				C. Grima The effects of intermittent prebypass heparin dosing in patients undergoing coronary artery bypass grafting Perfusion, September 1, 2003; 18(5): 283 - 289. [Abstract] [PDF]

				P. Biglioli, A. Cannata, F. Alamanni, M. Naliato, M. Porqueddu, M. Zanobini, E. Tremoli, and A. Parolari Biological effects of off-pump vs. on-pump coronary artery surgery: focus on inflammation, hemostasis and oxidative stress Eur. J. Cardiothorac. Surg., August 1, 2003; 24(2): 260 - 269. [Abstract] [Full Text] [PDF]

				W. L. Chandler and T. Velan Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass Blood, June 1, 2003; 101(11): 4355 - 4362. [Abstract] [Full Text] [PDF]

				C R Daane, H D Golab, J H. Meeder, M J Wijers, and A J. Bogers Processing and transfusion of residual cardiopulmonary bypass volume: effects on haemostasis, complement activation, postoperative blood loss and transfusion volume Perfusion, March 1, 2003; 18(2): 115 - 121. [Abstract] [PDF]

				A. Parolari, S. Colli, L. Mussoni, S. Eligini, M. Naliato, X. Wang, S. Gandini, E. Tremoli, P. Biglioli, and F. Alamanni Coagulation and fibrinolytic markers in a two-month follow-up of coronary bypass surgery J. Thorac. Cardiovasc. Surg., February 1, 2003; 125(2): 336 - 343. [Abstract] [Full Text] [PDF]

				L. Y. Lee, W. J. DeBois, K. H. Krieger, and O. W. Isom Transfusion Therapy and Blood Conservation Card. Surg. Adult, January 1, 2003; 2(2003): 389 - 400. [Full Text]

				T. G. DeLoughery Thrombocytopenia in Critical Care Patients J Intensive Care Med, November 1, 2002; 17(6): 267 - 282. [Abstract] [PDF]

				M. Johnell, G. Elgue, R. Larsson, A. Larsson, S. Thelin, and A. Siegbahn Coagulation, fibrinolysis, and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting with a new heparin-coated surface J. Thorac. Cardiovasc. Surg., August 1, 2002; 124(2): 321 - 332. [Abstract] [Full Text] [PDF]

				L. Englberger, B. Kipfer, P. A. Berdat, U. E. Nydegger, and T. P. Carrel Aprotinin in coronary operation with cardiopulmonary bypass: does "low-dose" aprotinin inhibit the inflammatory response? Ann. Thorac. Surg., June 1, 2002; 73(6): 1897 - 1904. [Abstract] [Full Text] [PDF]

				M. Cugno, J. Nussberger, P. Biglioli, F. Alamanni, R. Coppola, and A. Agostoni Increase of Bradykinin in Plasma of Patients Undergoing Cardiopulmonary Bypass : The Importance of Lung Exclusion Chest, December 1, 2001; 120(6): 1776 - 1782. [Abstract] [Full Text] [PDF]

				N. J. Skubas and G. J. Despotis Optimal Management of Bleeding Complications After Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 217 - 228. [Abstract] [PDF]

				V. Casati, C. Gerli, A. Franco, G. Torri, A. D'Angelo, S. Benussi, and O. Alfieri Tranexamic acid in off-pump coronary surgery: a preliminary, randomized, double-blind, placebo-controlled study Ann. Thorac. Surg., August 1, 2001; 72(2): 470 - 475. [Abstract] [Full Text] [PDF]

				G. J. Despotis and L. T. Goodnough Management approaches to platelet-related microvascular bleeding in cardiothoracic surgery Ann. Thorac. Surg., August 1, 2000; 70(2): S20 - 32. [Abstract] [Full Text] [PDF]

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