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Eur J Cardiothorac Surg 2000;18:602-606
© 2000 Elsevier Science NL

Phosphorylcholine coating of extracorporeal circuits provides natural protection against blood activation by the material surface

^a Department of Cardiac Surgery, Division of Perfusion, University Hospital Gent, Centre for Cardiac Surgery 5IE–K12, De Pintelaan 185, B-9000 Gent, Belgium
^b Department of Cardiac Surgery, University Hospital Gent, Centre for Cardiac Surgery 5IE–K12, De Pintelaan 185, B-9000 Gent, Belgium
^c Department of Biomedical Engineering, University Groningen, Hanzeplein 1, PO Box 30.001, 97000 RB Groningen, The Netherlands,
^d Department of Intensive Care, University Hospital Gent, Centre for Cardiac Surgery 5IE–K12, De Pintelaan 185, B-9000 Gent, Belgium
^e Department of Paediatric Cardiology, University Hospital Gent, Centre for Cardiac Surgery 5IE–K12, De Pintelaan 185, B-9000 Gent, Belgium
^f Department of Cardiothoracic Surgery, University Hospital Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands

Received 2 March 2000; received in revised form 26 May 2000; accepted 31 May 2000.

Corresponding author. Tel.: +32-9-2404700; fax: +32-9-2403882
e-mail: filip.desomer{at}rug.ac.be

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
Objective: The aim of this study is to evaluate the use of a new coating, mimicking the outer cell membrane, in paediatric cardiac surgery. Methods: Two groups of ten patients with a body weight below 8 kg, undergoing elective cardiac operations for different congenital anomalies, were prospectively enrolled in this study. In one group the whole extracorporeal circuit, including the cannulas, was coated with phosphorylcholine (PC). In the second group the same circuit was used without coating. Platelet activation (thromboxane B2 (TXB2), ß-thromboglobulin (ßTG)), activation of the coagulation system (F1+2), leukocyte activation (CD11b/CD18) and terminal complement activation (TCC) were analyzed pre-cardiopulmonary bypass (CPB), at 15, 60 min of CPB, at the end of CPB, 20 min post CPB and at postoperative day 1 and 6. Results: No statistical differences were found for F1+2 and CD11b/CD18. After onset of CPB mean levels of TCC remained stable in the PC group whereas an increase was observed in the control group. During CPB ßTG values in both groups increased to a maximum at the end of CPB. Within groups the increase in ßTG levels during CPB was statistically significant (P<0.05) from baseline in the control group starting from 60 min of CPB whereas no statistical difference was observed in the PC group. After the start of CPB TXB2 mean levels increased to 405±249 pg/ml in the PC group vs. 535±224 pg/ml in the control group. After this initial increase there was a small decline in the PC group with further increase. This was in contrast to the control group were TXB2 levels further increased up to a mean of 718±333 pg/ml at the end of CPB (P=0.016). Conclusions: Phosphorylcholine coating had a favourable effect on blood platelets, which is most obvious after studying the changes during cardiopulmonary bypass. A steady increase of TXB2 and ßTG was observed in the control group, whereas plateau formation was observed in the phosphorylcholine group. Clinically, this effect may contribute to reduced blood loss and less thromboembolic complications. Complement activation is lower in the coated group.

Key Words: Phosphorylcholine coating • Paediatric surgery • Cardiopulmonary bypass • Platelets • Complement

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
Approximately 56 000 paediatric cardiopulmonary bypass operations were performed in Europe and the United States in 1996. The anticipated continued growth of paediatric cardiac surgical practice due to improvement of technology has shown a 10% increase in last years. Although small babies are much more vulnerable to inflammatory response due to the larger volume and foreign surface area of the extracorporeal circuit, the smaller neonatal oxygenators became available only a few years ago. A further improvement of the extracorporeal circuit is expected to be related to the surface characteristics. Depending on the treatment of polymer materials, its surface may be modified to reduce thrombogenic or inflammatory reactions. Heparin coating, which is known to reduce the inflammatory reactions, was just recently introduced for use in paediatric bypass [1]. An antithrombogenic coating is not commonly used as yet, but may be achieved by application of phosphorylcholine (PC). This coating will produce interfacial characteristics, which largely mimic the main lipid headgroup component of the outer cell membrane [2]. In contrast to the negatively charged phospholipids of the inner membrane, these neutral phospholipids do not activate the clotting system and are therefore non-thrombogenic, as would be expected for a major component of the outer surface of an erythrocyte [2,3]. Till today only limited experience with phosphorylcholine coatings is available [4,5].

Since coagulation in infants is more delicate than in adults, if not only by the reduced availability of inhibitors, an antithrombogenic coating was anticipated to be most profitable for paediatric cardiopulmonary bypass.

The use of PC coated circuits as compared with uncoated extracorporeal circuits in elective paediatric cardiac surgery was evaluated in this study, by means of clinical and biochemical evaluation.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
Two groups of ten patients with a body weight below 8 kg, undergoing elective cardiac operations for different congenital anomalies (Table 1). Patient selection was consecutive from 9/6/1998 to 20/1/1999 including all patients. In the PC group the whole extracorporeal circuit, including the cannulas, was coated with phosphorylcholine (Dideco, Mirandola, Italy). In the control group the same circuit was used without coating. Informed parental consent was obtained for all patients, according to the regulations of the hospital medical ethics committee.

Arterial and venous blood gases were taken at 15, 30 and subsequently every 30 min of CPB. Blood samples for determination of complement activation (terminal complement complex), platelet activation (thromboxane B2 (TXB2), ß-thromboglobulin (ßTG)), activation of the coagulation (fragment 1+2) and white blood cell activation (CD11b/CD18) were taken after induction, at 15 and 60 min of CPB, at the end of CPB, post CPB and at postoperative day 1 and 6.

	3. Analysis methods

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
Terminal complement activation (TCC) (C5b-9) was determined by means of an enzyme linked immunosorbent assay (ELISA) (Quidel, San Diego, CA). Thromboxane represents activation of the arachidonic pathway in platelets, and was determined by means of ELISA (Biotrak, Amersham, UK). ßTG was obtained by an ELISA technique (Diagnostica Stago, Boehringer–Mannheim, BRD) and represents the release of -granules from platelets.

Fragment 1+2 is released after cleavage of prothrombin to thrombin. Fragment 1+2 has no biological activity and remains in blood indicating activation of the clotting system. Fragment 1+2 was determined by ELISA (Dade Behring, Marburg, BRD).

Fifty microliters of whole blood was incubated with 10 µl CD18 antibody (clone 130, Becton Dickinson, USA) conjugated with FITC and 10 µl CD11b antibody (clone D12, Becton Dickinson, USA) conjugated with phycoerythrin. The cells were incubated during 20 min at room temperature in the dark, then red blood cells were lysed and white blood cells fixed with Uti-Lyse (Dako) and two color flow cytometric analyses were performed on a FACSort (Becton Dickinson, USA) equipped with a single argon ion laser. A minimum of 10 000 cells was analyzed per sample. Analyses were performed on a lymhogate with CellQuest software.

	4. Statistics

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
All data are presented as mean±SD. Statistical analysis was done using a Friedman test for the within variation, a Wilcoxon test for the paired comparison and a Kruskal–Wallis test for the between comparison. The individual P-values were corrected using following formula: _ind=1-(1-_joint)^1/m. Results were considered to be significant when P<0.05.

	5. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
5.1. Terminal complement complex
Baseline levels of TCC were different for both groups (145±94 ng/ml (PC) vs. 64±32 ng/ml (control); P=0.04) (Fig. 1) . After onset of CPB mean levels stayed stable in the PC group (130±146 ng/ml) whereas an increase to 138±110 ng/ml was observed in the control group (not significant). With progress of CPB an increase in TCC was noticed in both groups. Within groups the increase in TCC was statistical significant from baseline at end of bypass (P=0.012) and after protamine administration (P=0.005) in the PC group, while in the control group statistical difference was reached at 60 min (P=0.018), end of CPB (P=0.005) and after protamine administration (P=0.005). On postoperative day 1 levels in both groups were at baseline again.

View larger version (21K): [in this window] [in a new window]   Fig. 1. Platelet activation.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Platlet activation.

5.4. Fragment 1+2
Fragment 1+2 mean values were low in both groups and did not exceed 4 nmol/l. No statistical differences were observed between and within both groups.

5.5. CD11b/CD18
CD11b/CD18 expression rose progressively in both groups and peaked at a value of four to five times the baseline level at 60 min of CPB, being in most cases, the first measurement after release of the aortic cross-clamp. Subsequently the expression declined towards normal values on postoperative day 1.

5.6. Mass transfer
The mean oxygen transfer was 4.0±1.3 ml O₂/100 ml blood in the PC group vs. 4.4±1.3 ml O₂/100 ml blood (P=NS) in the control group. Mean CO₂ removal was 3.2±1.5 ml CO₂/100 ml blood in the PC group and 3.1±1.4 ml CO₂/100 ml blood in the control group (P=NS).

	6. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
We studied the thrombogenic and inflammatory response after the use of phosphorylcholine coating, by evaluating progression of ßTG release and thromboxane production, both related to platelet activation, and complement activation. Also the interaction of the phosphorylcholine coating on the gas transfer properties of the hollow fibre membranes was evaluated.

Although the literature shows an improved biocompatibility in adult surgery when using coatings [6], the thrombogenic and inflammatory response is usually mild in routine adult surgery, which makes it difficult to demonstrate differences in postoperative clinical response. Small babies are much more vulnerable to the adverse effects of cardiopulmonary bypass due to the relatively high priming volume and relative large blood foreign material surface in contact with blood. Additionally several organ systems are still immature.

The characteristic feature of biological membranes is their functional and compositional lipid asymmetry, which has been described in several cell types and is thought to stem from the requirement of biological membranes to have asymmetric protein distributions across the bilayer. In all of the cells for which lipid compositional asymmetry has been described, negatively charged phospholipids are found predominantly on the inner cytoplasmatic side of the membrane, while the neutral zwitterionic PC-containing antithrombotic lipids predominate in the outer membrane leaflet. Negatively charged phospholipids are thrombogenic and it has been proposed that this membrane asymmetry may serve the biological purpose in the maintenance of the delicate balance between haemostasis and thrombosis. In vitro experiments, in which various phospholipid coatings were applied to surfaces, showed a very high procoagulant activity of negatively charged phospholipids was shown. This is in contrast to the PC-containing surfaces that were not active in coagulation tests [2,3]. We did not observe an inhibition of activation of the clotting system, which may indicate a merely passive effect of the PC coating towards the clotting system. Additionally, F1+2, a cleavage product of prothrombin during thrombin generation, was very low in our study, indicating proper anticoagulation during CPB and proper sample collection throughout. Since F1+2 concentrations of 4 nmol/l are even not noteworthy in a clinical sense, a comparison between the systems cannot be made under the present conditions. However, both markers of platelet activation showed that the PC coated circuits were activating mildly and for a short period of time, whereas the uncoated circuits continued to activate platelets. A difficulty is that the platelet release product ßTG is sensitive to release during blood sampling and processing, especially in non-coagulated blood. Typical for this parameter is a large individual difference. This may have caused an increase of the ‘baseline’ ßTG concentrations, which was determined in samples collected after thoracotomy.

Concentrations of TXB2 in uncoated systems followed the pattern of previous observations with a gradual increase towards end of CPB. In contrast, TXB2 concentrations increased in the phosphorylcholine coated group for only a short period of time and were already reduced at 60 min in five out of seven determinations. It indicates a short exposure of platelets to an activating surface that rapidly became passive. TXB2 formation appeared most of all restricted to the operating period, since postoperatively a return to baseline was observed.

Cell adhesion to biomaterials is a surface dependent event, which is additionally influenced by the dynamic interaction between proteins and the material surface [7–9]. The low platelet activation may be due to the affinity of the phosphorylcholine coating for phospholipids, which may immediately adsorb to the polymer surface because they are smaller and more concentrated than most proteins [10]. The adsorbed phospholipids may then assemble by themselves and form an organized layer on the surface just like real biomembranes [10], which then interacts minimally with proteins and cells.

Few series have evaluated heparin coating in paediatric CPB [1,9–10]. Reduced complement activation has been observed as in adult CPB [1,11,12]. To our surprise, also the PC coating appeared to generate less complement activation than the uncoated systems. Although baseline concentrations were slightly different between both groups the increase of TCC was far more pronounced in the uncoated group (six times baseline) compared with the coated group (two times baseline). For the first 60 min of CPB the differences can be mainly attributed to material dependent activation by the extracorporeal circuit. Thereafter, in both groups further TCC generation was observed. In the coated group a few patients showed very high TCC generation probably due to longer reperfusion time. It is known that rewarming and return of suctioned blood markedly contribute to complement activation during the later period of CPB, which may have caused the large individual differences. After CPB no further increase of TCC was observed, although protamine can cause some additional complement activation. The return to baseline at day 1 shows rapid recovery from the CPB insult.

In vitro experiments showed decreasing complement activation with increasing surface phoshorylcholine mole fractions [10], suggesting that the phosporylcholine is responsible for the reduction. The working mechanism is probably related to lesser activation of the complement protein C5 [13] and the inhibition of monocyte and macrophage adhesion [14].

Two of the biochemical tests showed a different baseline, namely ßTG and TCC. For both of these tests it is known that particularly in infants large individual differences exist. Comparison of these variables with historical data obtained in a similar group of patients showed that ßTG baseline values ranged between 150 and 450 IU/ml [15]. Historical baseline TCC values in infants ranged between 40 and 460 ng/ml [1]. Obviously, values from most samples in our study fell within those ranges and must be considered normal baselines.

	7. General conclusion

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 
Phosphorylcholine coating appears to have a favourable effect on blood platelets, which is most obvious after studying the changes during cardiopulmonary bypass. A steady increase of TXB2 and ß TG was observed in the control group, whereas plateau formation was observed in the phosphorylcholine group. Clinically, this effect may contribute to reduced blood loss and less thromboembolic complications. Also complement activation is lower in the coated group. The limited number of patients in this study, however, only allows speculations as to the clinical relevance.

7.1. Limitations of the study
Due to the fact that our study concerns a biological system with relatively large standard deviations in a limited number of patients, our data should be interpreted with caution. Moreover, the relative extensive use of blood suckers during many cases in this study, will cause an important activation of the coagulation and complement cascades. For these reasons large randomized studies are necessary to investigate in depth the efficacy of coated CPB circuits during paediatric open heart operations.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Analysis methods 4. Statistics 5. Results 6. Discussion 7. General conclusion References

 

1. Scheurs H.H., Wijers M.J., Gu J., van Oeveren W., van Domburg T., de Boer J.H., Bogers A.J.J.C. Heparin-coated bypass circuits: effects on inflammatory response in pediatric cardiac operations. Ann Thorac Surg 1998;66:166-171.[Abstract/Free Full Text]
2. Zwaal R.F.A., Hemker H.C. Blood cell membranes and haemostasis. Haemostasis 1982;11:12-39.[Medline]
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11. Kagaisaki K., Masai T., Kadoba K., Sawa Y., Nomura F., Fukushima N., Ichikawa H., Ohata T., Suzuki K., Taketani S., Matsuda H. Biocompatibility of heparin-coated circuits in pediatric cardiopulmonary bypass. Artif Organs 1997;21:836-840.[Medline]
12. Ashraf S., Tian Y., Cowan D., Entress A., Martin P.G., Watterson K.G. Release of proinflammatory cytokines during paediatric cardiopulmonary bypass: heparin-bonded versus nonbonded oxygenators. Ann Thorac Surg 1997;64:1790-1794.[Abstract/Free Full Text]
13. Yu J., Lamba N.M.K., Courtney J.M., Whateley T.L., Gaylor J.D.S., Lowe G.D.O., Ishihara K., Nakabayashi N. Polymeric biomaterials: influence of phosphorylcholine polar groups on protein adsorption and complement activation. Int J Artif Organs 1994;7:499-504.
14. DeFife K.M., Yun J.K., Azeez A., Stack S., Ishihara K., Nakabayashi N., Colton E., Anderson J.M. Adhesion and cytokine production by monocytes on poly(2-methacryloyloxymethyl phosphorylcholine-co-alkyl methacrylate)-coated polymers. J. Biomed. Mater. Res. 1995;29:431-439.[Medline]
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