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Ann Thorac Surg 1997;63:105-111
© 1997 The Society of Thoracic Surgeons
Department of Cardiothoracic Surgery, Ullevål Hospital, University of Oslo, Oslo, Norway
Accepted for publication July 16, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Low-risk patients accepted for coronary artery bypass grafting were randomized to operation with the cardiopulmonary bypass surface either completely heparin coated (Duraflo II) or uncoated. There were 12 patients in each group. Blood plasma sampled during cardiopulmonary bypass was analyzed for complement activation (C3bc and terminal SC5b-9 complement complex) and neutrophil activation (lactoferrin and myeloperoxidase). In addition, neutrophils, monocytes, and platelets were counted, and the expression of surface markers on the neutrophils and monocytes (complement receptor [CR] 1, CR3, CR4, and L-selectin) and on the platelets (P-selectin and CD41) was quantified with flow cytometry.
Results. Clinical and surgical results were similar in both groups. In the group with the heparin-coated surface, the formation of the terminal SC5b-9 complement complex was significantly reduced, and the counts of circulating leukocytes and platelets were significantly less reduced initially but were higher at the end of cardiopulmonary bypass compared with baseline. Also, the expression of CR1, CR3, and CR4 was significantly less upregulated and the L-selectin, significantly less downregulated on monocytes and neutrophils.
Conclusions. We conclude that heparin coating reduces complement activation and attenuates the leukocyte integrin and selectin response that occurs when uncoated circuits are used.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The evaluation of CPB biocompatibility improvements should take into account both the activation of blood cascades (such as complement and coagulation systems), the release of cytokines, and the activation and degranulation of leukocytes and platelets. The activation of neutrophils may cause endothelial cell damage [2]. Activation of complement has been associated with postperfusion organ dysfunction and has been claimed to play a pathogenic role in the development of lung injury after CPB [3]. Also, leukocyte adhesion to the vascular endothelium may be important for the postperfusion inflammatory response, as this precedes a series of events that mediate inflammatory damage to the tissues [4].
A slowing down of the neutrophils ("rolling state") mediated by the adhesion molecule L-selectin (LAM-1) is the first step in an adhesion cascade [5, 6], the second being a firmer adhesion of neutrophils to endothelial ligands. The adhesion of neutrophils to endothelial ligands has been recognized to depend on the activation of the ß2-integrins, which constitute the CD11/CD18 complex, ie, CD11a/CD18 (LFA-1), CD11b/CD18 [complement receptor 3, (CR3), Mac-1), and CD11c/CD18 (CR4). Neutrophil adhesion to the vascular endothelium has been demonstrated to occur as the result of interaction between the intercellular adhesion molecule-1 (ICAM-1) (CD54) and the integrin CR3 [5]. The ß2-integrins are expressed exclusively on leukocytes. The adhesion molecules P-selectin (CD62, GMP-140, expressed on platelets and endothelial cells) and CD41 (glycoprotein IIb/IIIa, expressed on platelets) have been recognized to mediate platelet adhesion to neutrophils [6]. Complement receptor 1 (C3b receptor, CD35) participates in the regulation of complement activation, and a recombinant soluble form of this receptor has been found to be protective in ischemia-reperfusion injury [7].
Several CPB biocompatibility studies have investigated complement and neutrophil activation. These studies have focused mainly on changes in plasma concentrations of complement activation products and on the release to plasma of neutrophil granule contents. It has been claimed that the heparin-coated CPB circuit reduces the complement and neutrophil activation compared with uncoated systems, although the results from different studies are not fully consistent, especially regarding the activation of the early part of the complement cascade and the release of neutrophil granule contents (such as elastase, calprotectin, lactoferrin, and myeloperoxidase) [8, 9]. Only a few studies have been reported on adhesion molecules during CPB [10–13], and only one animal study on the influence of heparin coating of the circuit on these adhesion molecules [14]. It has been demonstrated that L-selectin is downregulated, and CR3 is upregulated during CPB [4, 10]. Apart from this, little is known of the effect of CPB on the cell surface markers. The formation of the terminal SC5b-9 complement complex (TCC) has been suggested to be a relevant indicator of the biocompatibility of artificial surfaces [15].
The aim of the present study was to investigate the influence of heparin coating of the extracorporeal circuit during CPB on the expression of the chosen cell surface markers and on complement activation, degranulation of neutrophils, and changes in leukocyte and platelet counts.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Sampling and Biochemical Analysis
Test samples were drawn from the arterial line at the start of CPB, after 10 minutes of circulation, at the end of CPB, and 10 minutes after protamine administration. Samples for routine hematologic study and blood cell counts were drawn in EDTA (ethylenediaminetetraacetic acid) Vacutainers and kept at room temperature before analysis in a Technicon analyzer (Technicon Instruments Corporation, Tarrytown, NY). Samples for analysis of C3bc (which refers to the activation products C3b, iC3b, or C3c), TCC, lactoferrin, and myeloperoxidase were drawn in EDTA tubes, kept in melting ice, and centrifuged for 10 minutes at 1,300 g within 3 hours. The plasma samples were stored at -70°C before analysis.
C3bc was quantified in a double antibody enzyme immunoassay using the monoclonal antibody bH6 specific for a C3 neoepitope expressed on C3b, iC3b, and C3c but not on the native C3 component [16]. The TCC was quantified in a double antibody enzyme immunoassay using the monoclonal antibody aE11 specific for a C9 neoepitope expressed on TCC, but not on the native C9, as capture antibody [17]. A zymosan-activated human serum pool (n = 80) defined to contain 1,000 arbitrary units/mL of TCC was used as standard. Lactoferrin was quantified in a radioimmunoassay as previously described [18]. Myeloperoxidase was measured by a commercial radioimmunoassay according to the instructions of the manufacturer (Pharmacia Diagnostics, Uppsala, Sweden).
Samples for flow cytometry were drawn from the arterial line with a syringe and ejected into sodium-heparin tubes without vacuum. One milliliter of heparinized blood was mixed with 1 mL of 0.4% formaldehyde in phosphate-buffered saline solution for fixation for 10 minutes at room temperature in 50-mL Falcon tubes (Oxnard). The whole blood specimen was used to avoid false upregulation of the markers during cellular separation and the fixation, to avoid activation during the preparation. After fixation, lysis of the red blood cells was accomplished after 4 minutes by adding 40 mL of 156 mmol/L ammonium chloride containing 10 mmol/L NaHCO3 and 0.12 mmol/L EDTA. After centrifugation (for 5 minutes at 1,000 g), pellets were resuspended in 40 mL of phosphate-buffered saline solution containing 1 mmol/L EDTA and 1% bovine serum albumin to prevent cell clumping and again centrifuged for 5 minutes at 1,000 g. The pellets were resuspended in 1 mL of phosphate-buffered saline solution containing 1% bovine serum albumin, and 1% 
-globulin to block Fc receptors (Kabi Vitrum) and kept in melting ice before staining. Staining was performed in microtiter plates (NUNC, Roskilde, Denmark) by adding 5 µL of antibody to 45 µL of cell suspension in each well. After incubation of the plates on ice with no exposure to light for 30 minutes, the specimens were transferred to flow tubes with 1% paraformaldehyde in phosphate-buffered saline solution for fixation. The cells were analyzed in a FACScan flow cytometer (model 440; Becton-Dickinson, San Jose, CA). Monocytes, neutrophils, and platelets were identified by their distinct patterns on forward scatter and 90-degree side scatter and by appropriate surface markers. For monocyte identification, monoclonal phycoerythrin (PE)-conjugated anti-CD14 (DAKO A/S, Glostrup, Denmark) was applied. For neutrophil identification, monoclonal PE-conjugated anti-CD15 (Sigma Chemical Company, St. Louis, MO) was used, and for platelets, monoclonal PE-conjugated anti-CD41 (DAKO) was applied. Double staining was used: in all experiments a PE-conjugated antibody identified the cell, and a fluorescein isothiocyanate (FITC)-conjugated antibody served to quantify the molecule of interest. We applied the following FITC-conjugated monoclonal antibodies: CLB-CR1-F, CLB-CD11b-F (CLB-mon-gran/1), and CLB-P-Selectin-F (Central Lab Netherlands Red Cross, Amsterdam, the Netherlands); anti-CD11c (DAKO); and LAM-1-FITC (L-selectin) (Pharmingen, San Diego, CA). Relative fluorescence intensity of the staining of the respective monoclonal antibodies on monocytes, neutrophils, and platelets was then calculated (10,000 events per sample) from the obtained information converted by a Hewlett-Packard converter and analyzed using PCLYSYS software (Beckton-Dickinson). The monoclonal antibodies for negative controls were IgG1-PE control (Becton-Dickinson) and IgG1-FITC (DAKO).
The concentrations of C3bc, TCC, lactoferrin, and myeloperoxidase and the blood cell counts were corrected for hemodilution by adding to the sample measurements the values obtained by multiplying the actual sample measurement with a correction factor yielded by the following formula: [100/(100 - initial hemoglobin)] x [(initial hemoglobin - sample hemoglobin)/sample hemoglobin] [19].
Statistical Analysis
We used the Wilcoxon test for intergroup differences, the Friedman test for within-group comparisons, and the Spearman test for correlations. A p value (two-sided) of less than 0.05 was considered significant.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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shows that the heparin-coated and uncoated groups did not differ with respect to the clinical and surgical variables examined.
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). A delay in C3bc formation was observed in the coated group. The C3bc concentration was significantly increased 10 minutes after the start of CPB in the uncoated group (p = 0.00001) and at the end of cpb in the coated group (p = 0.00003) compared with baseline. the c3bc concentration was significantly higher in the uncoated group 10 minutes after the start of cpb. no significant difference was demonstrated between the maximum c3bc concentrations or between the sum of the concentrations in each group.
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). from 10 minutes after initiation of cpb, the tcc concentration was significantly lower in the heparin-coated group compared with the uncoated group (p = 0.006), both when the maximum concentrations and the sum of the concentrations were compared.
CORRELATION BETWEEN TERMINAL SC5B-9 COMPLEMENT COMPLEX AND OTHER VARIABLES.
The TCC concentrations were closely correlated to the expression of CR3 on the monocytes (rs = 0.89, p = 0.002) and on the neutrophils (rs = 0.91, p = 0.001). the tcc concentrations did not correlate with CR1, CR4, L-selectin, lactoferrin, or myeloperoxidase.
Blood Cell Counts
LEUKOCYTES (TOTAL), MONOCYTES, AND NEUTROPHILS.
We observed an initial (from the start of CPB to 10 minutes) leukopenia in both groups. The drop in leukocyte numbers was significant (p = 0.04) in the uncoated group but not in the heparin-coated group (Fig 2). There was an initial drop in monocyte and neutrophil counts as well, followed by an increase from 10 minutes after the start of CPB to 10 minutes after administration of protamine in both groups. The increased leukocyte and neutrophil counts from baseline to 10 minutes after protamine administration was significant in the heparin-coated group (p = 0.006 for leukocytes and p = 0.001 for neutrophils) but not in the uncoated group. The change in monocyte count from the start of CPB to 10 minutes after protamine did not differ significantly between groups. The changes in cell counts were not significantly correlated to C3bc or TCC concentrations or to the concentration changes in lactoferrin or myeloperoxidase.
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). The drop was significant in the uncoated group (p = 0.00002) but not in the coated group.
Neutrophil Release
LACTOFERRIN.
The lactoferrin concentration was significantly increased from the start of CPB to its end (p = 0.0001). A drop in lactoferrin concentration was observed 10 minutes after administration of protamine in both groups (Fig 3). The change in lactoferrin concentration did not differ significantly between groups.
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). The change in myeloperoxidase concentration did not differ significantly between groups.
Cell Surface Markers
CR1 (CD35).
The CR1 expression was upregulated on the monocytes 10 minutes after the start of CPB in both groups (p < 0.03) but was not significantly different between groups (Fig 4). On the neutrophils, the CR1 expression was also significantly increased 10 minutes after the start of CPB in the uncoated group (p < 0.04), but the changes in the heparin-coated group were not significant. There was a significantly lower expression of CR1 on the neutrophils during CPB in the coated group compared with the uncoated group (p = 0.03).
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). The CR3 expression was significantly lower in the coated compared with the uncoated group during CPB on both monocytes (p = 0.04) and neutrophils (p = 0.01).
CR4 (CD11C/CD18).
The CR4 expression was significantly upregulated during CPB on both monocytes (p = 0.01 after 10 minutes of cpb) and neutrophils (p = 0.007 at the end of cpb) in the uncoated group but was not significantly changed in the heparin-coated group (see fig 4). the expression of cr4 during cpb was significantly lower on both monocytes (p = 0.01) and neutrophils (p = 0.01) in the coated compared with the uncoated group.
L-SELECTIN (LEUKOCYTE ADHESION MOLECULE 1 OR LAM-1).
The expression of L-selectin was significantly downregulated during CPB in the uncoated group (p < 0.04) after 10 minutes of CPB on both monocytes and neutrophils (see Fig 4). In the coated group, the expression of L-selectin showed an increase after 10 minutes. There was a significant difference in baseline for L-selectin expression on monocytes between the two groups. On the neutrophils, however, there was a significant reduction in L-selectin in the uncoated group compared with the coated group (p = 0.0007).
P-SELECTIN (CD62, GMP-140).
The expression of P-selectin was upregulated on platelets during CPB, and the level was significantly higher after 10 minutes compared with that at the start of CPB in both groups (p < 0.004) (Fig 5). There were no significant differences between groups with respect to the expression of P-selectin.
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). Compared with baseline, it was significantly increased after 10 minutes in the uncoated group (p = 0.04) and at the end of cpb in the heparin-coated group (p = 0.05). there were no significant differences between groups with respect to the expression of cd41. |
Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The changes in the cell surface markers CR1, CR3, CR4, and L-selectin and the formation of TCC were significantly reduced in patients undergoing CPB with a heparin-coated surface. The initial leukopenia was reduced, and the number of circulating neutrophils and platelets were significantly higher at the end of bypass compared with baseline in the heparin-coated group. On the other hand, we could not demonstrate a significant difference between the groups regarding the two platelet surface markers (P-selectin and CD41), the C3 activation products (except for a significantly lower concentration after 10 minutes on CPB in the heparin-coated group), or the lactoferrin and myeloperoxidase release to plasma.
The flow cytometric quantification of the several surface markers in this study was obtained by analyzing together in one blood sample the markers on monocytes, neutrophils, and platelets, which demonstrates that this approach is possible. It should be pointed out that the demand of resources for these analyses is high compared with the assessment of, for instance, lactoferrin and myeloperoxidase.
The CPB bioincompatibility is, in general, reflected in an increased "blood activation," such as increased cellular and blood cascade activation [1]. An upregulation of ß2-integrins and a downregulation of L-selectin on neutrophils and monocytes have previously been demonstrated during CPB [4, 12, 13], and the increased CR3 and the decreased L-selectin expression during CPB in the present study are consistent with these studies. Platelet activation during CPB has previously been reported [1] and was also demonstrated in one study. However, the Duraflo II heparin coating did not reduce the upregulation of P-selectin and CD41.
The most important observation in the present study was that when the blood was exposed to the heparin-coated surface, there was a significantly lower integrin and L-selectin response compared with that for the uncoated surface, and this corresponded to a reduced TCC formation.
The reduced upregulation of CR1, CR3, and CR4 and the reduced downregulation of L-selectin in the heparin-coated group indicates that the heparin coating "protects" the leukocytes from activation by the foreign CPB surface; as a result, they are less prone to adhere to surfaces. We hypothesize that the heparin coating directly or indirectly inhibits leukocyte activation, possibly by reducing complement activation, and results in a more "biocompatible profile" of the leukocytes. Why this was not reflected in a reduced degranulation of the neutrophils is not easily explained.
Previously, reduced degranulation was noted in Carmeda Bioactive Surface heparin-coated compared with uncoated CPB systems [8, 9]. Whether the use of Duraflo II and Carmeda Bioactive Surface heparin-coated CPB circuits results in different degrees of degranulation has not been demonstrated. Two studies [20, 21] compared the Duraflo II and Carmeda Bioactive Surface methods. With reference to degranulation, using reduced systemic heparin in the coated groups, one study [20] found reduced lactoferrin concentration with both coatings compared with uncoated circuits but equal myeloperoxidase levels, whereas the other study [21] used the same systemic heparinization in both groups and did not demonstrate significant differences between the two methods. This may indicate an influence of the systemic heparinization on lactoferrin and myeloperoxidase release. Whether the Duraflo II heparin coating reduces degranulation less effectively than the Carmeda Bioactive Surface method remains unanswered because some of the observed differences may be attributable to differences between the oxygenators. We would expect, on the basis of the results from the comparative studies [20, 21], that the observed missing effect on degranulation by the heparin coating in the present study may in part be related to the impact of the equipment, the oxygenator in particular. The degranulation and the release to plasma of granule contents such as lactoferrin and myeloperoxidase occur as a late response to the neutrophil activation compared with the upregulation of surface markers [4, 5, 11]. Thus, the concentration changes in granule proteins in plasma during CPB may be a less sensitive measure of cellular activation than the assessment of cell surface markers.
The formation of TCC has been proposed as a highly reliable variable for the evaluation of CPB–induced complement activation and in the discrimination of effects attributable to CPB surface modifications [15]. The finding in the present study of reduced TCC formation combined with reduced change in the important ß2-integrin leukocyte cell surface activation marker CR3 (CD11b/CD18) in the heparin-coated group compared with the uncoated group is an indication of the causal relationship between terminal pathway complement activation and leukocyte activation [22]. The observation is in accord with the conclusions in a recent study [23] discussing the importance of C5a in neutrophil and platelet activation, where it is suggested that C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. This effect may be due to sublytic TCC attacks, as some TCC is deposited in the cell membranes of leukocytes (or any cell), resulting in increased membrane permeability allowing stimulatory ion fluxes [24]. There is some evidence that such sublytic attacks occur during CPB. The formation of TCC is, in principle, accompanied by equimolar formation of C5a, an extraordinarily potent anaphylatoxin that is more likely responsible for the observed cellular changes. C5a is known to upregulate leukocyte surface markers in vitro [23].
C5a has been demonstrated to induce an initial leukopenia followed by leukocytosis, especially a neutrophilic response [25]. The initial leukopenia during CPB was reduced and the subsequent leukocytosis more pronounced in the heparin-coated group. This further supports the assumption that heparin coating inhibits complement-mediated leukocyte activation.
In conclusion, we have demonstrated that heparin coating of the whole CPB circuit attenuates the changes in monocyte and neutrophil surface markers that occur when uncoated circuits are used. Part of the improved surface profile correlated with reduced complement activation, which supports a role for complement in activation of white cells during CPB.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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We acknowledge the very skillful technical help with the flow cytometry of Ms Merethe Sanna at the Institute for Immunology and Rheumatology, The National Hospital, Oslo. The C3 activation was quantified by Eric Hack, Central Lab The Netherlands Red Cross Blood Transfusion Service, Amsterdam, the Netherlands. The valuable assistance of perfusionists Conny Anderson and Geir Heggen is much appreciated.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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V. Videm, T. E. Mollnes, E. Fosse, B. Mohr, MD, K. Bergh, T.-A. Hagve, A. O. Aasen, and J. L. Svennevig HEPARIN-COATED CARDIOPULMONARY BYPASS EQUIPMENT. I. BIOCOMPATIBILITY MARKERS AND DEVELOPMENT OF COMPLICATIONS IN A HIGH-RISK POPULATION J. Thorac. Cardiovasc. Surg., April 1, 1999; 117(4): 794 - 802. [Abstract] [Full Text] [PDF]
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V. Videm, T. E. Mollnes, K. Bergh, E. Fosse, B. Mohr, T.-A. Hagve, A. O. Aasen, and J. L. Svennevig HEPARIN-COATED CARDIOPULMONARY BYPASS EQUIPMENT. II. MECHANISMS FOR REDUCED COMPLEMENT ACTIVATION IN VIVO J. Thorac. Cardiovasc. Surg., April 1, 1999; 117(4): 803 - 809. [Abstract] [Full Text] [PDF]
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G. Asimakopoulos and K. M. Taylor Effects of cardiopulmonary bypass on leukocyte and endothelial adhesion molecules Ann. Thorac. Surg., December 1, 1998; 66(6): 2135 - 2144. [Abstract] [Full Text] [PDF]
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A. Wahba, A. Philipp, R. Behr, and D. E. Birnbaum Heparin-Coated Equipment Reduces the Risk of Oxygenator Failure Ann. Thorac. Surg., May 1, 1998; 65(5): 1310 - 1312. [Abstract] [Full Text] [PDF]
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H. Aebert, A. Brawanski, A. Philipp, R. Behr, O.-W. Ullrich, C. Keyl, and D. E. Birnbaum Deep hypothermia and circulatory arrest for surgery of complex intracranial aneurysms Eur. J. Cardiothorac. Surg., March 1, 1998; 13(3): 223 - 229. [Abstract] [Full Text] [PDF]
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