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J Thorac Cardiovasc Surg 1999;117:803-809
© 1999 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

HEPARIN-COATED CARDIOPULMONARY BYPASS EQUIPMENT. II. MECHANISMS FOR REDUCED COMPLEMENT ACTIVATION IN VIVO

From the Department of Surgery A, Institute for Surgical Research, Department of Anaesthesiology, and Department of Clinical Chemistry, The National Hospital, Oslo University, Oslo; Department of Immunology and Blood Bank and Department of Microbiology, The Regional Hospital, Norwegian University of Science and Technology, Trondheim; and Department of Immunology and Transfusion Medicine, Nordland Central Hospital, Bodø, University of Tromsø, Tromsø, Norway.

The study was supported by The Norwegian Research Council, Medical Innovation at The National Hospital, and the Norwegian Council on Cardiovascular Research.

Received for publication March 10, 1998. Revisions requested July 9, 1998. Revisions received Oct 26, 1998. Accepted for publication Nov 6, 1998. Address for reprints: Vibeke Videm, MD, PhD, Department of Immunology and Blood Bank, The Regional Hospital, N-7006 Trondheim, Norway.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective: Our objective was to study mechanisms for reduced complement activation by heparin coating of cardiopulmonary bypass equipment in clinical heart surgery.
Methods: Adults undergoing elective coronary artery bypass grafting were randomized to cardiopulmonary bypass with Duraflo II heparin-coated (n = 15) or uncoated (n = 14) sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill). Blood samples were analyzed with the use of enzyme immunoassays for C1rs-C1 inhibitor complexes and the activation products Bb, C4bc, C3bc, C5a-desArg, and the terminal complement complex. Data were compared by repeated-measures analysis of variance.
Results: C1 was activated during bypass, and increases in C1rs-C1 inhibitor complexes were larger with heparin coating (P = .03). C4bc increased after administration of protamine, without intergroup differences (P = .69). Bb (P = .22) and C5a-desArg (P = .13) tended to increase less with heparin coating. Formation of C3bc (P = .03) and the terminal complement complex (P < .01) was significantly reduced with heparin coating. C5a-desArg increased 2-fold during bypass, whereas the terminal complement complex increased 10- to 20-fold. Maximal terminal complement complex concentrations were significantly correlated to maximal Bb and C3bc (R = 0.6, P < .001), but not to C1rs-C1 inhibitor complexes or C4bc (R < 0.05, P > .8).
Conclusions: C1 activation during bypass was increased by heparin coating, but further classical pathway activation was held in check until administration of protamine. Heparin coating significantly inhibited C3bc and terminal complement complex formation. Terminal complement complex concentrations were related to alternative pathway activation and may be useful for evaluation of differences in bypass circuitry. Increases and intergroup differences in terminal complement complex concentrations were much larger than those in C5a-desArg.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Heparin-coating of foreign surfaces for use in extracorporeal circulation was introduced more than 30 years ago to reduce the need for systemic anticoagulants. Such reduction is now feasible, but there is still controversy concerning the safety of reduced systemic heparinization in cardiac surgery. The modern heparin-coated cardiopulmonary bypass (CPB) equipment has gained much interest, not only because of its anticoagulatory properties, but also because it inhibits activation of many inflammatory systems, for example, complement, granulocytes, and platelets. ^1-3 The mechanisms for these anti-inflammatory effects of heparin coating are largely unknown.

Initiation of complement activation may take place via three pathways (Fig. 1). In the classical pathway, binding of factor C1q to antigen-antibody complexes, aggregated immunoglobulins, or certain other substances activates a series of reactions leading to formation of the classical pathway C3 convertase. C1 inhibitor is the main regulatory protein of the initial reaction in this pathway. In the lectin pathway, binding of circulating lectin-binding proteins to carbohydrates on surfaces of pathogens leads to formation of a similar C3 convertase. Finally, a host of non-self surfaces on pathogens or foreign substances such as plastics in heart-lung machines activate factor B of the alternative pathway, leading to formation of the alternative pathway C3 convertase. Classical activation may also initiate the alternative pathway, amplifying C3 convertase formation.

View larger version (25K): [in this window] [in a new window]   Fig 1. Simplified overview of the complement cascade. C4bC2a and C3bBb are the classical and alternative C3 convertases, respectively. C4aC2aC3b and C3bBbC3b are the corresponding classical and alternative C5 convertases. See text for further details.

The present study was performed to gain further insight into possible mechanisms for complement inhibition by heparin coating in clinical heart surgery, by studying markers of activation at various levels of the cascade.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Twenty-nine adult patients admitted for elective coronary bypass surgery at the National Hospital were included in the study after giving informed consent. Half of the patients were randomly chosen from each of the two groups of participants in a larger study of complications after CPB, which is presented elsewhere. ⁴ Exclusion criteria for the present study were left ventricular ejection fraction less than 0.40, ongoing infections, liver failure, other major noncardiac illness, or use of steroids or nonsteroid anti-inflammatory agents except acetylsalicylic acid.As part of the larger study, the patients had been randomly assigned to CPB with one of the following setups:

• Heparin-coated group (n = 15): Univox oxygenator and tubing/connectors, cardiotomy suction and a 25-mm arterial line screen filter (Bentley/Baxter, Uden, The Netherlands) with the entire blood-contact surface heparin-coated by the Duraflo II method (ionically bound heparin) (Baxter International, Inc, Deerfield, Ill)
  
• Uncoated group (n = 14): Uncoated, otherwise similar oxygenator, tubing, and filter set
  

The number of grafts and duration of the operation, CPB, and aortic occlusion were noted.

Blood samples and analyses
Samples anticoagulated with ethylenediaminetetraacetic acid were obtained just before systemic heparinization, after 30 minutes of CPB, at termination of CPB, during closure of the skin over the sternum, and 3 hours after the operation. The exact sampling times were recorded. So that in vitro activation could be avoided, the tubes were kept on ice until centrifugation within 8 hours, and plasma was stored at –70°C. ⁵

Hemoglobin, hematocrit, and blood cell counts were determined in an automated analyzer (Technicon H-l, Miles, Tarrytown, NY).

Complexes between C1 inhibitor and C1r and C1s (C1rs-C1inh) were measured in an enzyme immunoassay (EIA) specific for a neoepitope exposed in C1 inhibitor when complexed to its proteases, using a mixture of anti-C1r and anti-C1s antibodies in the second step. ⁶ C1rs-C1inh is formed during the first activation steps in the classical complement pathway.

C4 activation products (C4bc) were quantitated in an EIA ⁷ specific for a neoepitope expressed on C4b, iC4b, and C4c, but not on native C4. C4bc is formed at a later stage during classical pathway activation than C1rs-C1inh. The monoclonal C4 and C1 inhibitor antibodies were a kind gift from Professor C. E. Hack, Amsterdam, The Netherlands.

Factor B activation was measured by a Bb kit (Quidel, San Diego, Calif) according to the manufacturer's instructions. Bb is formed during activation of the alternative complement pathway.

C3 activation products (C3bc) were measured in an EIA ⁷ specific for a neoepitope expressed on C3b, iC3b, and C3c, but not on native C3. C3bc is formed on activation of either the classical or the alternative pathway.

C5a-desArg was analyzed in a neoepitope-specific sandwich EIA as earlier described. ⁸

The TCC was determined in an EIA ⁷ specific for a C9 neoepitope.

Zymosan-activated serum, defined as containing 1000 arbitrary units per milliliter (AU/mL), was used as standard in the C3bc and TCC assays, because use of SI units requires that the neoepitope be confined to one particular molecule with a defined molecular weight. ⁷ Likewise for the C4bc and the C1rs-C1inh assays, normal human serum activated through the classical pathway using heat aggregated immunoglobulins and defined to contain 1000 AU/mL was used as standard. ⁷

The results were corrected for hemodilution with the use of the hematocrit value. ⁹

Statistics
Data are presented as medians with 95% nonparametric confidence intervals based on Walsh numbers. All variables were first analyzed by 2-way analysis of variance (ANOVA) for repeated measures, using the SPSS program package (SPSS, Inc, Chicago, Ill). Because of non-normal variables and unequal variances, the conditions for such testing were only partly met. Therefore changes by time within each group were subsequently studied by the Friedman test and intergroup differences by the Mann-Whitney U test. The P values from ANOVA were used as criteria for the smallest significant P values in the subsequent Friedman and Mann-Whitney tests. The conclusions from the ANOVA were unaltered if performed on rank transformed data. Maximal concentrations for each patient irrespective of time of occurrence were compared between the two groups by the Mann-Whitney U test, and Pearson's correlation coefficients between maximal concentrations of the various complement activation parameters were calculated.

The study was approved by the regional ethical committee on February 25, 1993.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Patient characteristics and variables pertaining to the operation are given in Table I. There were no significant intergroup differences with respect to these variables or with respect to sampling time points.

View larger version (31K): [in this window] [in a new window]   Fig. 2 Classical complement activation (median and 95% confidence intervals) by median sampling times in patients undergoing aorta-coronary bypass operations with (n = 15) and without (n = 14) Duraflo II heparin-coated CPB circuits. A, Plasma concentrations of C1rs-C1 inhibitor complexes. Groups were significantly different (P = .03, ANOVA). B, Plasma concentrations of C4 activation products (C4bc). Groups were not significantly different (P = .69, ANOVA).

View larger version (19K): [in this window] [in a new window]   Fig 3. Plasma concentrations of activated factor B (Bb) (median and 95% confidence intervals) by median sampling times in patients undergoing aorta-coronary bypass operations with (n = 15) and without (n = 14) Duraflo II heparin-coated CPB circuits. Groups were not significantly different (P = .22, ANOVA).

View larger version (19K): [in this window] [in a new window]   Fig 4. Plasma concentrations of C3 activation products (C3bc) (median and 95% confidence intervals) by median sampling times in patients undergoing aorta-coronary bypass operations with (n = 15) and without (n = 14) Duraflo II heparin-coated CPB circuits. Groups were significantly different (P = .03, ANOVA).

View larger version (30K): [in this window] [in a new window]   Fig 5. Terminal complement activation (median and 95% confidence intervals) by median sampling times in patients undergoing aorta-coronary bypass operations with (n = 15) and without (n = 14) Duraflo II heparin-coated CPB circuits. A, Plasma concentrations of C5a-desArg. Groups were not significantly different (P = .13, ANOVA). B, Plasma concentrations of the TCC. Groups were significantly different (P =.004, ANOVA).

The correlation coefficients between the maximal concentrations of the complement activation parameters are given in Table II. The markers of classical activation (C1rs-C1inh and C4bc) were significantly correlated. TCC was significantly correlated with Bb, C3bc, and C5a-desArg.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

C4 activation was substantial after termination of CPB, probably as a consequence of the formation of circulating heparin-protamine complexes. ¹⁵ Thus maximal concentrations of C1rs-C1inh were significantly correlated to maximal concentrations of C4bc, even if the time course for formation was different.

Taken together, these findings indicate efficient inhibition after C1 activation during CPB, but not after administration of protamine. The importance of such C1 inhibitor–mediated classical pathway inhibition during CPB is underscored by the substantial increase in classical activation found in a patient with C1 inhibitor insufficiency. ¹⁶

As expected, there was significant activation of the alternative pathway during CPB, as reflected in the Bb concentrations (Fig. 3). Even if the Bb concentration tended to be lower in the heparin-coated group, activation of the alternative pathway was not significantly influenced by heparin coating, but the study was small.

Heparin-protamine complexes are activators of the classical complement pathway. ¹⁵ The C4 activation related to protamine administration was followed by increased formation of C3bc in 22 of the 29 patients. However, in only 7 patients did we detect an increase in TCC after administration of protamine, indicating that the C3 convertase formed might not be very efficient or that some form of inhibition occurs during the subsequent assembly of TCC. This is in keeping with previous observations of a relative inefficiency of terminal complement activation compared with C3 cleavage in vitro. ¹⁷ We may speculate that the C5 convertase formed by alternative pathway activation is more efficient than that formed by classical pathway activation.

There was significant correlation between TCC and the alternative pathway markers Bb and C3bc, but not between TCC and the classical pathway markers C1rs-C1inh and C4bc. This finding supports the hypothesis that TCC formation in cardiac surgery is more closely related to alternative pathway activation than classical pathway activation. Thus TCC may be more an indicator of factors connected to the oxygenator and other parts of the CPB circuit and less sensitive to differences in heparin-protamine regimens, which would be an advantage in studies of biocompatibility.

Inhibition of C3 activation and TCC formation by heparin coating
As previously shown by us and others, ^1,13 heparin coating substantially reduced the formation of C3 activation products and TCC. In the mentioned study on complement activation by microtiter plates, ¹¹ bound C3b was more rapidly converted to iC3b after heparin coating, indicating more sufficient factor I–mediated and/or factor H–mediated inhibition of C3 activation. A potentiating effect of heparin on factor H has been demonstrated. ¹⁸ Heparin may also inhibit formation of the C3 convertase C3bBb by binding to C3b at the site for factor B. ¹⁹ These mechanisms may explain the reduced formation of C3 activation products in the present study.

The reduced formation of TCC after heparin coating is a natural consequence of reduced C3 activation. However, the reduction of maximal TCC concentrations by heparin coating was relatively larger than that of maximal C3bc concentrations, indicating that the surface-bound heparin might directly influence the formation of TCC during CPB. In vitro, heparin inhibited formation of the C5b67 complex, which is one of the steps in TCC formation, ²⁰ and we may hypothesize that such an effect takes place in vivo as well. Furthermore, heparin may bind fluid-phase TCC via S-protein (vitronectin) in such complexes. ²¹ Because we did not measure surface-bound complement factors, we do not know whether binding of TCC to the heparin coating contributed to the reduced amounts in plasma. This seems unlikely, however, because virtually no binding of TCC to another heparin-coated surface was found in vitro. ²²

Measurement of terminal complement activation
This study included measurement of both plasma C5a-desArg and TCC as indicators of terminal (C5-C9) activation. Both were significantly correlated with C3bc (Table II). Even if C5a-desArg concentrations were slightly lower in the heparin-coated group, the differences were not significant despite the significant reductions in both C3bc and TCC. Rapid binding of C5a-desArg to leukocytes may explain this apparent contradiction. Furthermore, the study was small. In a previous investigation, C5a-desArg formation was completely abolished with heparin coating in model CPB with recirculation of human blood, but no differences were found between 10 patients operated on with uncoated CPB equipment and 10 patients operated on with heparin-coated CPB sets. ²³

TCC has been a good discriminator of complement activation differences in vitro. ²⁴ The usefulness of TCC may be due to the very low baseline concentrations combined with large increases during complement activation: approximately 10-fold to 20-fold in the present study. C5a-desArg increases, on the other hand, were about 2-fold, and C3bc increases were approximately 3-fold to 4-fold. These figures may explain why C5a-desArg differences between the groups were not significant, C3bc differences were moderately significant, and TCC differences were highly significant. Simultaneous measurement of cell-bound and circulating C5a-desArg may increase the sensitivity for discrimination of complement activation differences, ²⁵ but this approach is more time consuming. Quantitation of plasma TCC, which has a half-life of approximately 50 minutes, ²⁶ is probably the best marker of TCC activation available at present.

	Acknowledgments

 
We are grateful to Grethe Bergseth, Bente Falang, Hilde Fure, and Kirsti Løseth for excellent assistance with the complement assays.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

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