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PubMed1996

Contribution of vascular catheter material to the pathogenesis of infection: depletion of complement by silicone elastomer in vitro.

We previously have shown that vascular catheters made of silicone elastomer carry a greater risk of subcutaneous infection with Staphylococcus aureus than do polyurethane (PU), polyvinylchloride (PVC), or Teflon catheters. We further have shown that there is greater inflammation surrounding silicone catheters than there is surrounding catheters made of the other materials, suggesting that silicone produces a greater chemotactic gradient than do the other materials. This study used a functional complement opsonization assay and radioimmunoassays to compare the relative abilities of silicone, polyurethane, and polyvinylchloride to activate complement. Serum incubated in silicone catheters for 24 h had less than 30% of the opsonizing ability of fresh serum while > or = 78% of the opsonizing ability remained with serum incubated in PU or PVC catheters. Measurement of C3a des Arg, C4a des Arg, C5a des Arg, and SC5b-9 demonstrated that the loss of opsonizing ability was due to 10-fold greater alternate pathway complement activation by silicone than by PU or PVC. This finding suggests that excessive complement activation by silicone may explain the greater inflammation seen around silicone catheters in vivo and also might play a role in silicone's creating a greater risk of infection.

Catheterization↗
PubMed2004

Prestorage pooled whole-blood-derived leukoreduced platelets stored for seven days, preserve acceptable quality and do not show evidence of a mixed lymphocyte reaction.

BACKGROUND: Prestorage pooling of whole-blood-derived PCs (WBD-PCs) would be advantageous to transfusion services in that it would make the product available in a more timely manner, reduce wastage of untransfused pools, and simplify bacterial screening by allowing testing of the pool rather than each single PLT concentrate (PC). STUDY DESIGN AND METHODS: Four to six individual leukoreduced PCs were pooled into a 1.5-L CLX-HP PLT storage bag using a sterile connecting device. Controls were individual prestorage leukoreduced PCs that were stored as single products. Products were sampled on Days 5 and 7 for measures of PLT quality; coagulation, fibrinolytic and complement activation; and for evidence of a mixed lymphocyte reaction. RESULTS: The pH level was well maintained to Day 7 with no prestorage pool having a pH below 6.7. Day 7 studies showed no evidence of coagulation or difference in complement activation. F1.2 levels did not differ between Days 5 and 7, but a 10- to 15-percent increase in C3a des-Arg was observed between these days in all product types. Day 7 activated lymphocyte surface markers (CD69, CD71, HLA-DR) were all at lower limits of detection in the prestorage pooled products, and levels of supernatant cytokines were either not different between product types on either study day or, if different, were lower in the prestorage pooled products. CONCLUSION: There is no evidence of a deterioration in quality, activation of coagulation or complement, or a mixed lymphocyte reaction attributable to the prestorage pooling process with up to 7 days of storage.

Blood Component Removal↗
PubMed2004

Influence of cold ischemia time on complement activation, neopterin, and cytokine release in liver transplantation.

OBJECTIVES: The aim of this study was to determine whether a cold ischemia time (CIT) of >12 hours influences the activation of complement as well as the plasma concentrations of neopterin, interleukin (IL)-6, or IL-8 in orthotopic liver transplantation (OLT). PATIENTS AND METHODS: Eighteen consecutive patients undergoing OLT using a veno-venous bypass technique were divided into 2 groups: duration of CIT >12 hours (group 1; n = 11), and CIT <12 hours (group 2; n = 7). Blood samples were drawn preoperatively, 1 minute before, and 120 minutes after reperfusion. RESULTS: Preoperatively, complement split products, neopterin, IL-6, and IL-8 levels did not differ between the groups. At 120 minutes after reperfusion, the concentrations of C3a, SC5b-9, neopterin, IL-6, and IL-8 were significantly increased in both groups compared with the preoperative values or the levels determined 1 minute before reperfusion (P < .05). Patients in group 1 showed significantly higher IL-8 levels at 120 minutes after reperfusion (P < .05). CONCLUSION: Complement is activated and pro-inflammatory cytokines released after reperfusion in OLT using a veno-venous bypass technique, but only IL-8 plasma levels were influenced by the duration of CIT. Therefore, alterations following prolonged CIT seem to not be complement-mediated.

Cold Temperature↗
PubMed1992

Significance of the concentrated red cell and albumin priming method with particular reference to anaphylatoxin generation.

Anaphylatoxins generated by cardiopulmonary bypass were observed in basic and clinical studies (n = 120 in the latter). In vitro immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a, but albumin identically treated did not. Therefore concentrated red cells with albumin were used to prime homologous blood for clinical application during cardiopulmonary bypass. Complement levels were compared with type of oxygenator (bubble or membrane) and the ratio of primed homologous blood to circulating autologous blood volume. With the bubble oxygenator at a low ratio of homologous to autologous blood (arbitrarily defined as less than 20%), C3a levels during cardiopulmonary bypass tended to be lower in the concentrated red cells plus albumin priming group than in the ordinary priming group (p less than 0.1, at 60 and 90 minutes of cardiopulmonary bypass). C4a and C3a levels increased less after protamine administration with concentrated red cells plus albumin priming (p less than 0.05, p less than 0.01, respectively, 90 minutes after protamine) than with ordinary priming. Such changes in the membrane oxygenator group were less remarkable. Thus C3a levels were approximately the same in both oxygenator groups primed with concentrated red cells plus albumin. The higher the homologous to autologous ratio, the steeper the C4a and C3a increase from the beginning of cardiopulmonary bypass with the bubble oxygenator. This tendency was less remarkable in the membrane oxygenator group. Early postoperative pulmonary function was improved by concentrated red cells plus albumin priming, especially in the bubble oxygenator group. In conclusion, (1) oxygenator systems primed with concentrated red cells plus albumin produced less anaphylatoxin than those with homologous blood, especially with the bubble oxygenator, and (2) our clinical results support the importance of immunoglobulin denatured by oxygen bubbling in anaphylatoxin generation (by means of the classical pathway), as shown by our in vitro study.

Anaphylatoxins↗
PubMed1988

Granulocyte activation during haemodialysis in the absence of complement activation: inhibition by calcium channel blockers.

The effect of the calcium channel blockers nifedipine (9 and 18 micrograms kg-1 h-1), diltiazem (100 and 200 micrograms kg-1 h-1) and verapamil (19 micrograms kg-1 h-1) continuously infused during haemodialysis on granulocyte and complement activation was investigated. Plasma levels of lactoferrin, elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) and C3a were measured in patients dialysed with dialysers made of cuprophane, polymethylmethacrylate (PMMA) and polyacrylonitrile (PAN). Calcium channel blockers caused no change of blood pressure during haemodialysis in all patients. There was no effect of nifedipine, diltiazem or verapamil on plasma lactoferrin, E-alpha 1PI or C3a levels in patients dialysed with cuprophane. However, plasma lactoferrin and E-alpha 1PI values were significantly reduced by all calcium channel blockers in patients dialysed with PMMA, and also by nifedipine and verapamil in patients dialysed with PAN. Our data indicate that calcium channel blockers inhibit granulocyte activation occurring in dialysers with very little anaphylatoxin formation. These drugs, however, are ineffective in patients dialysed with cuprophane where complement activation takes place. Therefore, granulocyte activation during haemodialysis in the absence of complement activation seems to be mediated by calcium ions.

Aged↗
PubMed1988

Abnormal clearance of soluble aggregates of human immunoglobulin G in patients with systemic lupus erythematosus.

In the present study, we tested mononuclear phagocyte system function in nine healthy controls and 15 SLE patients with complement activating 123I-labelled aggregates of human IgG (AIgG). Clearance half-time of AIgG was 26 +/- 8 min in controls, compared to 58 +/- 27 min in patients (P less than 0.005). Binding of AIgG to erythrocytes was significantly lower in patients, 9.3 +/- 8.1 vs 24 +/- 20% (P less than 0.05). The increase of C3a-levels in plasma was significantly lower in patients than in controls (P less than 0.05 at 3 and 8 min), suggesting less complement activation. Liver and spleen uptake of 123I-AIgG was measured with a gamma camera and expressed as liver/spleen uptake ratios. In patients, the liver/spleen uptake ratios were significantly higher than in controls at 15 min, 3.8 +/- 2.0 vs 2.31 +/- 0.7 (P less than 0.05), due to less splenic uptake of AIgG. Correlations between clearance half-time or liver/spleen uptake ratios and immune complex levels or disease activity were not found. This study indicates that clearance of soluble AIgG is abnormal in patients with SLE, due to decreased splenic uptake of AIgG.

Adult↗
PubMed1975

The pathogenesis of arthritis associated with acute hepatitis-B surface antigen-positive hepatitis. Complement activation and characterization of circulating immune complexes.

Circulating immune complexes were identified in cryoproteins isolated from serial samples of serum from six patients with acute viral hepatitis with and without arthritic symptoms. Cryoprecipitates were analyzed for the presence of hepatitis-B surface antigen (HBsAg) and hepatitis-B surface antibody (anti-HBs) by hemagglutination inhibition and hemagglutination. Complement components were detected by counter electrophoresis, and immunoglobulins were detected by gel diffusion. HBsAg, IgG, and IgM were identified in cryoprecipitates from all hepatitis patients, but were higher in concentration in patients with arthritis. Only cryoprecipitates from hepatitis patients with arthritis contained IgA and complement components C3, C4, and C5 as well as IgG and IgM, which disappear with resolution of the arthritis. The subtypes of IgG in these cryoprecipitates were predominantly the complement-fixing IgG1 and IgG3, HBsAg and anti-HBs were concentrated several-fold in the cryoprecipitates when compared to the serum concentration. Sequential studies in two patients demonstrated that the initial appearance of anti-HBs in the cryoprotein complex was associated with the detection in the complex of IgM suggesting a primary immune response to HBsAg. The C3 activator fragment (C3A) of the properdin complex was found in fresh serum obtained from three hepatitis patients with arthritis and not in uncomplicated hepatitis. The cryoprecipitable immune complexes from patients with arthritis converted C3PA in fresh normal sera to C3A in vitro whereas cryoprotein isolated from patients with uncomplicated hepatitis had no such effect. Thus, the transient appearance of circulating complement-fixing immune complexes in patients with the arthritis of acute hepatitis is associated with activation of both classical and alternate complement pathways and suggests that they play an important role in the pathogenesis of these serum sickness-like extrahepatic symptoms.

Acute Disease↗
PubMed1973

Formation of C3a and C5a anaphylatoxins in whole human serum after inhibition of the anaphylatoxin inactivator.

Two biologically and chemically distinct anaphylatoxins (ATs) could be generated in whole human serum after removal of the AT inactivator (AI) by immune-absorption or after inhibition of AI with 1 M epsilon-aminocaproic acid (EACA). Both human ATs could be generated by treatment of serum with antigen-antibody complexes, which activate the classical complement pathway, and with inulin or yeast, both of which trigger the alternate pathway. The ATs were isolated from serum in active form and characterized as C3a and C5a. Although human C3a had been characterized previously, C5a had not. The molecular weight of human C5a AT was 17,500; its electrophoretic mobility at pH 8.5 was -1.7 x 10(-5) cm(2) V(-1) s(-1). The minimal effective concentration in vitro was 7.5 x 10(-10) M. The minimal effective doses of human C5a in producing a wheal and erythema in the human skin was 1 x 10(-15) mol. The results strongly suggest a biological function for both ATs and indicate that the expression of their activity is controlled by the AI of normal blood plasma.

Adsorption↗
PubMed2005

The impact of two whole blood inline filters on markers of coagulation, complement and cell activation.

BACKGROUND AND OBJECTIVES: There exists a current lack of information about the impact of different inline filters, used for the leucoreduction of whole blood (WB), on the levels of clotting factors and markers of coagulation, complement and cell activation in plasma. Only a few small comparisons of different types of WB inline filters have been published to date. MATERIALS AND METHODS: This study compared two plasma types of 200 units each. Both study groups were derived from WB, inline-filtered and held for 2 h at 20 degrees between donation and filtration. Then, 200 units (Group A) were filtered using a positively charged polyester filter (Baxter RZ2000) and the other 200 units (Group B) were filtered using an uncharged polyester filter (Fresenius). After filtration, both groups were analysed for fibrinogen, factors V and VIII:C (FV and FVIII:C, respectively), immunoglobulin G (IgG), residual leucocytes and platelets, and markers of coagulation, complement and cell activation. Predonation plasma samples from CPDA1-anticoagulated blood were obtained from 100 different individuals and served as controls. RESULTS: WB inline filtration did not influence fibrinogen, FV, FVIII:C or IgG levels. Neither filter induced thrombin or fibrin formation. The charged filter caused substantial complement activation and neutrophil elastase and platelet factor 4 release. In contrast, the plasma filtered through the uncharged filter showed markedly lower levels of C3a-desArg, C5a, neutrophil elastase and platelet factor 4, and moderately reduced levels of prothrombin fragments 1+2 and D-dimer, compared with controls. CONCLUSIONS: Filter type has a significant impact on the quality of plasma derived from WB filtered through inline filtration systems. Some filters produce substantial coagulation and complement activation and cell release, while others appear to reduce the plasma levels of activation markers. The clinical significance of these findings remains to be determined.

Adolescent↗
PubMed1994

Abrupt complement activation and transient neutropenia in patients with acute myocardial infarction treated with streptokinase.

BACKGROUND: Whether and to what extent complement is activated in acute myocardial infarction (AMI) and how it contributes to inflammation of the ischemic area are not yet clear. Fibrinolytic agents used for thrombolysis are known to activate complement in vitro and may contribute to its activation in vivo. The aim of this study was to measure the extent of complement activation in AMI patients, some treated and some not treated with streptokinase. In addition, because abrupt complement activation in vivo is usually associated with leukocyte margination, plugging of cells in the microcirculation, and hypotension, we correlated complement activation with leukocyte numbers and mean arterial pressure. METHODS AND RESULTS: Forty AMI patients were studied: 20 were treated with streptokinase (1.5 million IU IV over 60 minutes), and 20 were not given any fibrinolytic agent. The extent and severity of AMI were not significantly different in both groups. Blood samples were drawn on arrival at the hospital, during streptokinase infusion, and then daily for 1 week. Time-matched samples were also drawn from patients not treated with streptokinase. We measured plasma levels of anaphylatoxin C4a, C3a, and C5a by radioimmunoassay and membrane attack complexes SC5b-9 by enzyme immunoassay. Leukocytes and arterial pressure also were measured when samples were obtained. C4a, C3a, and SC5b-9 levels increased about 10-fold (P < .0001) during infusion of streptokinase. There were no significant increases in complement catabolic products in AMI patients not treated with streptokinase. There was a significant transient leukopenia (mean +/- SEM, -29.5 +/- 7.0%; P = .001) and decreases in systolic and diastolic pressures (systolic, -29.3 +/- 3.2%, P < .0001; diastolic, -27.5 +/- 3.4%, P < .0001) after 15 minutes of streptokinase infusion in coincidence with the peak of anaphylatoxins in plasma. CONCLUSIONS: Streptokinase treatment of AMI causes abrupt activation of the complement system, whereas no significant complement activation can be detected in plasma of AMI patients not treated with fibrinolytic agents. Complement activation causes a transient leukopenia, as reported for such other clinical conditions as dialysis and cardiopulmonary bypass, and possibly contributes to the hypotension observed during streptokinase treatment.

Aged↗
PubMed2002

Potentiation of liposome-induced complement activation by surface-bound albumin.

Large anionic multilamellar liposomes containing 71% membrane cholesterol (MLV) caused complement (C) activation in human serum in vitro, as reflected in significant rises in S protein-bound terminal complex (SC5b-9) and C3a-desarg levels. Increasing the albumin content in serum by 1-4 g/100 ml led to 50-100% further increase in MLV-induced C activation, while higher amounts of exogenous human serum albumin (HSA) gradually lost the capability to potentiate liposomal C activation. HSA alone had no influence on SC5b-9 formation at any level below 12%. Complement activation by liposomes and the potentiating effect of supplemental HSA were greatly reduced or eliminated in the absence of C1q or in the presence of 10 mM EGTA/2.5 mM Mg(2+), pointing to the involvement of the classical pathway. Potentiation of C activation by supplemental HSA was not unique to MLV-induced activation, as deposition of HSA on the membrane of "Centricon" ultrafiltration units also potentiated the C-activating effect of the polycarbonate membrane. Fatty acid (FA) or non-monomeric protein contamination in HSA were unlikely to be playing a role in the described effects, as 96% pure, FA-rich (Buminate) and 99% pure, FA-free HSA had identical effects on liposomal C activation. While highlighting a new modulatory mechanism on liposomal C activation, the above data raise the possibility that deposition of extravasated HSA at sites of tissue injury may serve a hitherto unrecognized proinflammatory function.

Carbonates↗
PubMed1988

Complement activation in patients with renal failure as detected through the quantitation of fragments of the complement proteins C3, C5, and factor B.

Using sensitive and highly specific enzyme-linked immunosorbent assays fragments of the complement proteins C3, C5, and factor B were quantitated in patients with renal failure. During hemodialysis on new cuprophan membranes raised levels not only of C3a, but in addition of activated C3, C5a, and Ba were demonstrated. In patients with chronic renal failure and end-stage renal disease plasma concentrations of Ba and activated C3 were markedly elevated independent of hemodialysis. This finding is taken as an indication of a continuous recruitment of the alternative pathway of complement in these patients. As the detected complement protein fragments are known to exert immune regulatory functions these findings may imply that these peptides are involved in the maintenance of the immune suppressed state in renal failure.

Acute Kidney Injury↗
PubMed2004

Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells.

Mice deficient in complement C3 (C3(-/-)) are hematologically normal under steady-state conditions, and yet displayed a significant delay in hematopoietic recovery from either irradiation or transplantation of wild-type (WT) hematopoietic stem/progenitor cells (HSPC). Transplantation of histocompatible WT Sca-1(+) cells into C3(-/-) mice resulted in a (i) decrease in day 12 CFU-S, (ii) 5-7-day delay in platelet and leukocyte recovery, and (iii) reduced number of BM CFU-GM progenitors at day 16 after transplantation. Nevertheless, HSPC from C3(-/-) mice engrafted normally into irradiated WT mice, suggesting that there was a defect in the hematopoietic environment of C3(-/-) mice. Since C3(-/-) mice cannot activate/cleave C3, the C3 fragments C3a, C3a(des-Arg), and iC3b were examined for a role in HSPC engraftment. Liquid-phase C3a and C3a(des-Arg) increased CXCR4 incorporation into membrane lipid rafts (thus potentiating HSPC responses to SDF-1 gradients), whereas iC3b was deposited onto irradiated BM cells and functioned to tether CR3(CD11b/CD18)(+)HSPC to damaged stroma. The activity of C3a(des-Arg) suggested that C3aR(+)HSPC also expressed the C5L2 (receptor for C3a and C3a(des-Arg)) and this was confirmed. In conclusion, a novel mechanism for HSC engraftment was identified, which involves complement activation and specific C3 fragments that promote conditioning for transplantation and enhance HSPC engraftment.

Animals↗
PubMed1991

Increases in circulating level of platelet-activating factor lag behind transient neutropenia during hemodialysis with cuprophane membranes.

The significance of the level of circulating 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine (C16-PAF, platelet-activating factor) in relation to transient neutropenia during hemodialysis with cuprophane membranes was examined. The neutrophil count was transiently and significantly decreased at 30 min after the start of hemodialysis, and it then gradually recovered during the period from 60 to 240 min after the start. Mirror image changes were observed in the circulating levels of C3a and C5a, suggesting that the decrease in the neutrophil count was triggered by activation of the complement factors. The circulating level of C16-PAF, although being similar to the basal level after 30 min of hemodialysis, was significantly increased after 60 and 120 min of hemodialysis. These data indicate that the increase in the circulating PAF level is not a direct cause of the transient decrease in the neutrophil count, but may be the result of activated neutrophils during hemodialysis with cuprophane membranes.

Adult↗
PubMed1980

Double immunofluorescence studies on IgA-associated immune-complexes in glomerular deposits in patients with IgA nephropathy.

A study on double immunofluorescent staining of immunoglobulins and complement in IgA-associated immune-complexes of glomerular deposits in patients with IgA nephropathy is described. The components of immune-complexes deposited in kidney tissues included IgA, IgG, IgM, IgE, C3, C3A, properdin, Clq and C4. Although the majority of the deposits consisted of IgA and C3, some deposits showed the coexistence of other classes of immunoglobulins and C3 as well as other types of complement. It was suggested that the immune-complexes deposited in the glomeruli of patients with IgA nephropathy have a polyclonal nature.

Antigen-Antibody Complex↗
PubMed2003

Inflammatory mediators in autotransfusion drain blood after knee arthroplasty, with and without leucocyte reduction.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether leucocyte-reducing filters influenced complement activation and the formation of pro-inflammatory cytokines in autotransfusion drain blood after knee arthroplasty. MATERIALS AND METHODS: Twenty-three patients undergoing knee arthroplasty were divided into two groups. All patients were given salvage blood postoperatively. In Group A, a leucocyte filter was connected between the wound and the drain blood container. In Group B the drain blood was not leucocyte filtered. Complement split products and cytokines were analysed in circulating blood and in drain blood, together with blood-cellular differential counts. RESULTS: Drain blood showed activation vs. venous blood, with elevated concentrations of C3a, SC5b-9, interleukin (IL)-6, IL-8, polymorphonuclear (PMN) elastase and tumour necrosis factor-alpha (TNF-alpha) (P<0.05 to P<0.001). The leucocyte filter reduced TNF-alpha (P<0.01), but triggered complement activation (P<0.05). Room-temperature incubation increased the concentration of IL-8 (P<0.01), which was seen in both venous and drain blood. The leucocyte filter prevented formation of IL-8 (P<0.01). In drain blood at 24 h the inflammatory reactions accelerated (P<0.05-0.001), although the filter reduced the leucocyte counts and TNF-alpha concentrations. CONCLUSIONS: The leucocyte filter reduced IL-8 and TNF-alpha in drain blood, but at the same time triggered complement activation. Incubation affected the inflammatory spectrum of both drain blood and control venous blood, and the filtering reduced this activation.

Aged↗