Vibeke Videm

Association of mannose-binding-lectin deficiency with severe atherosclerosis

which CNTF could be seen in the skin. The optical density of CNTF immunoreactivity in ALS patients (mean 11·0 [SD 1·0]) was significantly higher than in controls (8·0 [0·3] p<0·001). There was no relation between the optical density and the presence of dysphagia, weight loss, muscular atrophy, loss of active movement, and bedridden state in ALS patients or controls. Loss of CNTF has been proposed as a possible mechanism for the sporadic form of ALS, 5 but few studies have looked at CNTF expression in patients with ALS. Our results suggest that the changes of skin CNTF in ALS are likely to be related to the disease process. These results imply that increased CNTF in skin may play a neurotropic role and may help to explain why decubitus formation is rare in ALS.

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts

Fiane AE, Mollnes TE, Videm V, Hovig T, Høgåsen K, Mellbye OJ, Spruce L, Moore WT, Sahu A, Lambris JD. Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused xenografts. Xenotransplantation 1999; 6: 000‐000 ©Munksgaard, Copenhagen

Complement activation with bubble and membrane oxygentors in aortocorpnary bypass grafting

Thirty-three patients admitted for coronary bypass grafting were randomized to cardiopulmonary bypass with a bubble oxygenator (Cobe or Polystan) or a membrane oxygenator (SciMed). Plasma concentrations of C3 activation products and the terminal complement complex were measured using enzyme immunoassays. Both variables increased almost linearly after onset of cardiopulmonary bypass, with maximal concentrations at closure of the sternum. From a baseline of 7.5 to 12.0 arbitrary units (AU)/mL (medians), the concentrations of C3 activation products increased by 117.5 AU/mL (Cobe), 120.5 AU/mL (Polystan), and 213.3 AU/mL (SciMed). The increase in the membrane group was significantly higher than in the two bubble oxygenator groups (p less than 0.01). From a baseline of 0.9 to 1.3 AU/mL, the concentrations of terminal complement complex increased by 5.4 AU/mL (Cobe), 6.6 AU/mL (Polystan), and 7.7 AU/mL (SciMed) (differences not significant). The higher C3 activation caused by the membrane oxygenator may be explained by differences in flow profile and surface area in contact with blood. The study cannot confirm the general assumption that membrane oxygenators lead to lower complement activation than do bubble oxygenators.

Complement activation and bioincompatibility. The terminal complement complex for evaluation and surface modification with heparin for improvement of biomaterials.

The degree of biocompatibility of biomaterials can be evaluated using various assay systems detecting activation of the blood cascade systems, leukocytes or platelets. Activation of complement is one mechanism associated with adverse effects observed when bioincompatible materials are used. We present data showing that the terminal complement compiex, an indicator of terminal pathway activation, is suitable for evaluation of biocompatibility of biomaterials such as cardiopulmonary bypass devices. Furthermore, our results suggest that bioincompatibility is improved when artificial surfaces are modified with end point attached functionally active heparin.

Prolongation of Ex Vivo-Perfused Pig Xenograft Survival by the Complement Inhibitor Compstatin

HE COMPLEMENT system has been shown to play a central pathophysiologic role in hyperacute rejection (HAR) 1 and to contribute to the inflammation and organ injury associated with transplantation. 2 Recently, a novel phage-displayed C3-binding peptide (Compstatin) has been identified that suppresses complement activation and therefore may be of therapeutic value in clinical situations such as xenotransplantation that involve complement-mediated tissue damage. This peptide binds reversibly to the C3c portion of native C3 and inhibits both the classical and alternative pathways of complement activation. 3 Our results

Leucocyte filtration during cardiopulmonary bypass hardly changed leucocyte counts and did not influence myeloperoxidase, complement, cytokines or platelets

In some patients, coronary artery bypass surgery induces postoperative organ dysfunction despite an apparently adequate revascularization and good haemodynamic performance. This complication may be caused by activation of the body’s inflammatory systems on blood contact with large foreign surfaces in the extracorporeal circuit. Activated leucocytes may play an important role in organ damage, and it is conceivable that leucocyte removal by filtration may decrease the potential side-effects of cardiopulmonary bypass (CPB). The aim of the present study was to investigate possible effects of leucocyte filtration during the whole CPB period in elective coronary artery bypass surgery on biochemical and clinical parameters. Forty patients were randomized to extracorporeal circulation using a leucocyte-depleting filter (group L, n = 20) or to extracorporeal circulation with no leucocyte filter (group C, n = 20). In the leucocyte-depleted group, the mean total white blood cell counts increased from 6.3 (95% confidence interval, 5.5 - 7.0) × 109/l to 7.0 (5.7 - 8.3) × 109/l during extracorporeal circulation and in the control group from 6.3 (5.2 - 7.3) × 109/l to 8.5 (7.2 - 9.8) × 109/l. The intergroup difference was not statistically significant (p = 0.84). A substantial increase in concentrations of interleukin-6, myeloperoxidase and complement activation products were observed in both groups without statistically significant intergroup differences. It is concluded that the leucocyte-depletion filter did not cause a significant reduction of circulating white blood cells during CPB, and there were no significant differences between the groups with respect to the inflammatory markers studied.

Comparison of three oxygenator-coated and one total-circuit-coated extracorporeal devices

The present study was designed to compare the biocompatibility of three cardiopulmonary bypass setups with different surface coatings, and to determine if coating of the whole circuit with one of the coatings was more beneficial than coating of the oxygenator only. Extracorporeal devices entirely coated with synthetic polymers (Avecor, n = 6) were compared to oxygenators coated with synthetic polymers (Avecor, n = 6), end-point, covalently attached heparin (CBAS, n = 6) or absorbed heparin (Duraflo 2, n = 6) in an in vitro model of a heart-lung machine. The circuits were primed with fresh human whole blood and Ringer’s acetate and recirculated at 4 l/min at 30°C for 2 h. Test samples were obtained at regular intervals and analysed for myeloperoxidase (MPO), platelet counts, β-thromboglobulin, heparin, prothrombin fragment 1+2, plasmin-anti-plasmin complexes, and complement activation products. The mean MPO concentrations increased in the Avecor-coated oxygenator group (AV) from 247 at the start to 671 μg/l at the termination of the experiments, in the Avecor-coated total circuit group (AV-T) from 116 to 288 μg/l, in the Duraflo 2 coated oxygenator group (DU) from 160 to 332 μg/l, and in the CBAS-coated oxygenator (CA) group from 172 to 311 μg/l. The MPO concentrations increased significantly in all groups (p < 0.03). The increase in group A was significantly higher than in the other three groups (p = 0.007). The mean platelet counts decreased in the Avecor-coated total circuit group from 117 at start to 99 × 109/l at termination of the experiments, in the Avecor-coated oxygenator group from 119 to 103 × 109/l, in the Duraflo 2 group from 96 to 86 × 109/l, and in the CBAS group from 132 to 123 × 109/l. The platelet counts decreased significantly in all groups (p < 0.01), but the intergroup differences were not significant (p = 0.15). The mean β-thromboglobulin concentrations increased in the Avecor-coated total circuit group from 193 at the start to 754 ng/ml at the termination of the experiments, in the Avecor-coated oxygenator group from 474 to 1654 ng/l, in the Duraflo 2 group from 496 to 1280 ng/l, and in the CBAS group from 418 to 747 ng/l. The β-thromboglobulin increase was significant in each group (p < 0.01), but not between the groups (p = 0.49). The mean heparin concentrations in the Duraflo 2 group increased from 2460 at the start to 2897 IU/l at termination of the experiments, in the CBAS group from 2468 to 2518 IU/l. In the Avecor-coated oxygenator group heparin concentrations decreased from 2010 to 1968 IU/l, and in the Avecor-coated total circuit group from 2002 to 1927 IU/l. The differences in heparin concentrations were significant between the Duraflo 2 group and the other groups (p < 0.05). The mean prothrombin fragment 1+2 concentrations increased in the CBAS group from 0.4 at the start to 2.1 nmol/l at the end of the experiments, in the Avecor-coated oxygenator group from 0.4 to 0.6 nmol/l, in the Avecor-coated total circuit group from 0.3 to 0.4 nmol/l, and in the Duraflo 2 group from 1.2 to 1.3 nmol/l. The prothrombin fragment 1+2 increase was significant in all groups (p < 0.05), but there were no significant intergroup differences (p = 0.54). There were no significant differences at the termination of the experiments among the four groups regarding complement activation as measured by C3 activation products and the terminal complement complex. In the present in vitro model of a heart-lung machine, none of the three specific setups with different coatings was superior with regard to all test parameters. The CBAS group generated the highest levels of prothrombin fragment 1+2 formation, but least complement activation. The increasing plasma heparin concentrations in the Duraflo 2 group indicated more unstable heparin bonding. The Avecor-coated total circuit group were superior to the Avecor-coated oxygenator group regarding plasma concentrations of MPO, but not compared to the CBAS and Duraflo 2-coated oxygenator groups.

Complement activation by extracorporeal circulation: effects of precoating a membrane oxygenator circuit with human whole blood

In an in vitro study of extracorporeal circulation (ECC), uncoated oxygenators (UC), oxygenators precoated with whole human blood (CN) and oxygenators precoated with blood and then rinsed with Ringers acetate (CR) all significantly (p less than 0.001) activated the initial and terminal parts of the complement cascade. After 60 min C3 activation had increased by 692% (UC), 750% (CN) and 393% (CR), and terminal complement complex (TCC) concentrations by 194% (UC), 215% (CN) and 273% (CR). C3 activation was significantly (p less than 0.05) less in the CR than in the other groups. There was no statistical intergroup difference in increase of TCC concentration. Complement activation was accompanied by a significant drop in neutrophil counts, which was uninfluenced by coating or rinsing. The observed dissociation of the complement cascade shows that assessment of activation products from both parts is necessary for evaluation of total complement activation. The study suggests that protein precoating may improve biocompatibility of ECC.

Comparable biocompatibility of Phisio- and Bioline-coated cardiopulmonary bypass circuits indicated by the inflammatory response

Background: The biocompatibility of cardiopulmonary bypass surfaces has been improved by heparin and polymer surface modifications. The present study compared the effect of two such coatings on the inflammatory reactions after open heart surgery. Methods:Thirty patients undergoing elective heart surgery were randomly assigned to receive one of two types of coated circuits: Bioline (n=15) or phosphorylcholine (Phisio, n=15). The platelet and leukocyte counts, neutrophil activation (myeloperoxidase), complement activation (C3a and TCC), concentrations of lactate dehydrogenase, 27 cytokines (including interleukins, chemokines and growth factors), thrombin-antithrombin complexes, and the endothelial cell marker syndecan-1 were analyzed at five predetermined time points until 24 hrs post operatively. Results: Most measurements were comparable in both groups. However, myeloperoxidase was significantly higher in the Bioline group (p < 0.001). Postoperative lactate dehydrogenase concentrations were significantly higher in the Phisio group (p<0.01) and the maximal concentration of thrombin-antithrombin complexes 2 hours postoperatively tended to be higher in the Phisio group (p=0.08), consistent with a longer aortic cross-clamp and cardiopulmonary bypass time. Conclusions: The two circuits exhibited a comparable degree of in vivo biocompatibility.

Effects on Complement, Granulocytes and Platelets of a Leukocyte-Depletion Filter During in vitro Extracorporeal Circulation

In an in vitro study, extracorporeal circuits equipped with either a leukocyte-depleting filter (n = 5) or a standard arterial-line filter (n = 5) were perfused for 120 minutes with fresh human whole blood. Leukocyte activation, leukocyte and platelet counts and complement activation were studied. Significant reduction of leukocyte and platelet counts and significant activation of leukocytes and of platelets were found in both groups, but without significant intergroup difference for any parameter after 120 minutes of perfusion. The leukocyte-depleting filters, however, were somewhat more effective in removing leukocytes during the initial 30 minutes of circulation.