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PubMed2003

Influence of PMEA-coated bypass circuits on perioperative inflammatory response.

BACKGROUND: Poly(2-methoxyethylacrylate) (PMEA) is a new coating material, and several experimental studies have revealed excellent biocompatibility of PMEA-coated cardiopulmonary bypass circuits. The clinical utility of the PMEA-coated circuits was compared with that of uncoated circuits, focusing on perioperative inflammatory response. METHODS: Twenty-two patients were randomized to PMEA-coated (group P; Capiox RX25; n = 11) or uncoated (group U; Capiox SX10; n = 11) circuit group, and underwent coronary artery bypass grafting and/or valve operations. The following markers, as well as clinical outcomes, were analyzed perioperatively: (a) complement activation by C3a (including C3a-desArg) concentrations; (b) leukocyte activation by polymorphonuclear-elastase concentrations; (c) acute phase inflammatory response by interleukin-6 concentrations; and (d) platelet preservation by number of platelets. RESULTS: The maximal values of C3a and polymorphonuclear-elastase were significantly lower in group P than in group U. The intergroup difference of interleukin-6 was not significant. Although preservation of platelets was significantly better in group P until 1 hour after initiating cardiopulmonary bypass, no significant intergroup difference was observed thereafter. The duration of postoperative mechanical ventilation revealed no significant intergroup difference. CONCLUSIONS: The PMEA-coated circuits exhibited better suppression of perioperative complement and leukocyte activation than the uncoated circuits. In addition, the price of the PMEA-coated circuits is the same as that of the uncoated circuits. Therefore, we judged that the clinical utility of the PMEA-coated circuits is superior to those of the uncoated circuits.

Aged↗
PubMed1994

Influence of Pall Pl-50 platelet filters on lactate dehydrogenase, platelet factor 4, and complement factor 3 in stored platelet concentrates.

BACKGROUND: The study examines Pall Pl-50 platelet filters with respect to their influence on some biochemical properties of platelet concentrates. MATERIAL AND METHODS: Ten pairs of pooled platelet preparations, each consisting of 3 platelet concentrates, were studied. On day 1, one of the preparations was filtered and the other served as an identical non-filtered control. Immediately after filtration platelet counts, the levels of desarginated activated complement factor 3 (C3a), extracellular levels of lactate dehydrogenase (LDH) and extracellular and total concentrations of platelet factor 4 (PF4) were determined in both concentrates. After 5 days sterility testing and determination of extracellular levels of PF4 and LDH were performed. RESULTS: Extracellular concentrations of PF4 and C3a decreased immediately after filtration (p < 0.01). Furthermore, Pall Pl-50 filters caused cellular instability reflected by an increased release of PF4 (p < 0.01) during subsequent storage. CONCLUSION: Platelet concentrates filtered with Pall Pl-50 would not appear suitable for storage.

Blood Preservation↗
PubMed1994

Blood compatibility of two different types of membrane oxygenator during cardiopulmonary bypass in infants.

The contact of blood with the artificial extracorporeal circuit causes a systemic inflammatory response due to blood activation. In this study, we compared two different paediatric membrane oxygenators used for extracorporeal circulation: a hollow fibre membrane oxygenator (Dideco Masterflo D-701, n = 10), and a flat sheet silicone membrane oxygenator (Avecor Kolobow 800-2A, n = 10). Blood compatibility was indicated by measuring complement activation as well as leukocyte and platelet activation. In patients perfused with a flat sheet membrane oxygenator, concentrations of complement split products C3a were significantly increased 30 minutes after the start of bypass (p < 0.01), whereas only a mild increase of C3a was found in patients perfused with a hollow fibre membrane oxygenator. Leukocyte and platelet counts dropped uniformly in both groups after the start of bypass mainly due to hemodilution. Activation of leukocytes and platelets identified by both plasma beta-glucuronidase and beta-thromboglobulin was similar in both groups. Infants perfused with a flat sheet membrane oxygenator received significantly more donor blood than those perfused with a hollow fibre oxygenator (p < 0.05). These results indicate that when used during paediatric cardiopulmonary bypass, a flat sheet membrane oxygenator has a higher complement activity than a hollow fibre membrane oxygenator, which is probably due to the relatively larger blood-surface contacting area of the oxygenator.

Biocompatible Materials↗
PubMed1998

Formation of complement split products and proinflammatory cytokines by reinfusion of shed autologous blood.

1. The purpose of this study was to determine whether shed autologous blood collected postoperatively contains complement split products (C3a and SC5b-9) and proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6 and IL-8) and whether transfusion of shed blood increases the concentrations of inflammatory mediators in the circulation. 2. Twenty consecutive patients undergoing total hip replacement surgery under spinal anaesthesia were studied. The patients were transfused with whole blood collected postoperatively. 3. The median volume shed blood returned to the patients was 350 ml (25-75% range = 300-450). Before transfusion of shed blood was filtered using a 40 microm filter (Solcotrans). Samples for complement and cytokine determinations were drawn from the collected blood. 4. Venous blood samples were drawn 1 min before transfusion, 1 and 60 min after completed transfusion. High concentrations of C3a, SC5b-9, TNF-alpha, IL-1beta, IL-6 and IL-8 were found in shed blood. The concentrations were higher than the circulating levels (P < 0.05). The filtration procedure did not significantly reduce the concentrations. 5. Transfusion of the shed blood did not significantly alter the circulating concentrations of C3a, SC5b-9, TNF-alpha, IL-1beta, and IL-8. The plasma concentrations of IL-6 were increased both 1 and 60 min after completed transfusion compared to before (P < 0.05). 6. This study shows that whole blood collected from a surgical wound contains large concentrations of complement split products and proinflammatory cytokines. Transfusion of shed blood leads to elevated plasma levels of IL-6.

Aged↗
PubMed1992

Effect of labor and delivery on neonatal polymorphonuclear leukocyte number and function.

The ability of the neonate to mount an adequate polymorphonuclear leukocyte (PMN) response, either quantitatively or functionally, is impaired. To assess whether neonatal PMN number and function are altered by labor and delivery, three groups of infants were studied: cesarean section without labor (10), cesarean section after labor (10), and vaginal delivery (11). PMN counts were higher in the groups undergoing labor (p less than 0.01) compared with the cesarean section without labor group. Similarly, the labor groups had evidence of complement activation (increased C3a desarg) compared with the cesarean section without labor group. No differences were noted between the groups in measures of PMN motility (chemokinesis or chemotaxis) or PMN degranulation (plasma lysozyme), suggesting that normal labor and delivery does not contribute to the general PMN dysfunction of the neonate.

Cesarean Section↗
PubMed1998

[Activation of astrocytes of by anaphylatoxins of the complement system].

It has been shown that astrocytes (human glioblastoma U118 cell line) release reactive oxygen species (ROS), including superoxide O2.- and hydrogen peroxide H2O2 following the action of C5a complement component C5a (but not C3a). The effect of C5a (1 nM) is accompanied with hyperpolarization of the astrocyte plasma membrane. Component C3a (100 nM), which is not an inducer of ROS, caused a prolonged depolarization of astrocytes. However, both the agents induced a transient increase in intracellular Ca2+ concentration. The data obtained permit a conclusion that O2.- participates in the intracellular signal transduction, and is involved in the mechanism of hyperpolarization response of astrocytes to the effect of the inducer of ROS, complement component C5a.

Astrocytes↗
PubMed2001

Storage of single donor platelet concentrates: paired comparison of storage as single or double concentrates.

Modern cell separators allow the collection of two plateletpheresis concentrates (PCs) at one session. This study evaluates the quality of PCs stored as double concentrates in standard storage containers of two manufacturers. We collected 20 PCs that contained 4.5 x 10(11) platelets in 375 ml plasma (10 using the COBE Spectra and 10 using the Fresenius AS.TEC 204 with 500 ml bags) that were split into one unit of 3.0 x 10(11) platelets in 250 ml (3.0-PC) and one of 1.5 x 10(11) platelets in 125 ml (1.5-PC). Storage of one 3.0-PC per bag of a two-bag system corresponded to storage conditions for double PCs and storage of one 1.5-PC per bag to storage conditions of single PCs. Cell counts, blood gas analysis, glucose and lactate levels, platelet aggregation, and activation and plasma levels of beta- thromboglobulin (beta-TG) and complement factor 3a (C3a) were measured before storage and again on days 3 and 5. COBE 3.0-PCs demonstrated less pH rise, lactate production, CD 62P expression and beta-TG plasma levels, and better aggregability after storage than COBE 1.5-PCs. Fresenius 1.5-PCs had similar platelet quality to COBE 3.0-PCs. Fresenius 3.0-PCs showed a fall of pH (day 5: 6.22 +/- 0.56), the highest amount of anaerobic glycolysis compared to all other storage conditions investigated, high CD 62P- expression and beta-TG plasma levels, and impaired aggregability on days 3 and 5. The highest C3a levels were found in COBE 1.5-PCs. 3.0 x 10(11) platelets in 250 ml plasma should be stored either in one bag of the COBE system or in two 500 ml bags of the Fresenius system. The COBE two-bag system allows the storage of two PCs without loss of platelet quality. Two PCs should not be stored in the Fresenius C4L 500 ml storage containers.

Blood Chemical Analysis↗
PubMed1992

Regulation of pulmonary resistance during cardiopulmonary preservation.

To characterize the neural and vasoactive mediators of pulmonary vasoconstriction and determine whether the beneficial effect of isoproterenol could be mimicked by other agents that increase cyclic adenosine monophosphate, heart and lung organ blocks were harvested from calves and studied in a normothermic autoperfusion circuit. In the experimental protocol, measurements were obtained (A) after sternotomy but before autoperfusion (in vivo); (B) during stimulation of in vivo control with tert-butyl hydroperoxide (t-BuOOH), a lipid peroxide; (C) after cannulation and institution of in situ autoperfusion (innervated preparation); (D) following denervation and explanation (ex vivo); (E) during stimulation of ex vivo preparation with t-BuOOH; and (F,G) after administration of isoproterenol, aminophylline and prostaglandin E1 to the ex vivo preparation with (time G) and without (time F) stimulation using t-BuOOH. Plots of transpulmonary pressure gradient versus cardiac output were generated for each animal, and an index of pulmonary vascular resistance was obtained from the slope of the linear relationship. Blood samples were collected for measurement of thromboxane-B2, 6-keto-prostaglandin-F1 alpha, and complement activation products C3a and C5a. Pulmonary vasoconstriction occurred during in situ autoperfusion prior to denervation and increased further following denervation and ex vivo autoperfusion; vasoconstriction correlated with increased levels of circulating vasoactive mediators. The pulmonary vasoconstrictor response was greater in the denervated vascular bed compared with the innervated state. All agents reduced postexplant pulmonary vasoconstriction. We conclude that agents that increase cyclic AMP modulate the pulmonary vasoconstrictor response and thus may enhance lung preservation in the autoperfusion model as well as with other current preservation methods.

Alprostadil↗
PubMedDate not supplied

PMEA coating of pump circuit and oxygenator may attenuate the early systemic inflammatory response in cardiopulmonary bypass surgery.

We investigated the effects of coating a cardiopulmonary bypass (CPB) circuit and oxygenator with poly-2-methoxy-ethyl acrylate (PMEA) on the systemic inflammatory response during and after CPB. Thirty patients undergoing elective cardiac surgery were randomized into three groups (each group n = 10): noncoated (group N), heparin coated (group H), and PMEA coated circuit and oxygenator (group X). Bradykinin (BK), complement 3 activation (C3a) and interleukin-6 (IL-6) levels were measured as early phase indicators of inflammatory response, as were maximum C reactive proteins (CRP) and white blood cell (WBC) levels. The alveolar-arterial oxygen gradient (A-a DO2) was measured as a parameter of respiratory function. IL-6 levels after CPB were significantly higher in group N than in groups H and X (p < 0.05). Serum BK and C3a levels showed similar patterns in all groups. A-a DO2 was lower at the end of and 3 hours after CPB in groups H and X than in group N (p < 0.05). Maximum CRP levels were lower in group X than in groups N (p < 0.05). This prospective study suggests that PMEA coated CPB may improve respiratory function and decrease systemic inflammatory response after cardiac surgery, possibly because this circuit is as biocompatible as heparin coated CPB circuit.

Acrylates↗
PubMed1992

Investigation of how different filters affect some biochemical properties of stored platelet concentrates.

The aim of the present study was to investigate how four different filters, i.e. Imugard IG500 (Terumo, Japan), Miropore (Miramed, Italy), Pall P1-100 (Pall, USA) and Sepacell P1-10A (Asahi, Japan) affect some biochemical properties of platelet concentrates. The work was conducted using 42 pairs of platelet concentrates. After 2 days of storage, one of the preparations was filtered and the other served as an unfiltered control. Immediately after filtration, determination of the platelet count, desarginated activated complement factor 3 (C3a des arg) and the extracellular and total concentrations of platelet factor 4 (PF4) and lactate dehydrogenase (LDH) were carried out on both these platelet concentrates. After an additional storage period of 3 d, extracellular concentrations of PF4 and LDH were determined on both concentrates. A significant decrease of extracellular PF4 concentration was found immediately after filtration when Pall P1-100 and Imugard IG500 were used. During the 3-d storage after filtration, the concentrates filtered with Imugard IG500 and Pall P1-100 demonstrated significantly higher platelet lysis as compared to the unfiltered controls. It is concluded that the present work demonstrates storage instability after filtration with Imugard IG500 and Pall P1-100. Therefore, platelet concentrates filtered with these filters would not appear to be suitable for storage.

Blood Platelets↗
PubMed1991

Levels of complement factor C3 and its activated product, C3a, in operatively salvaged blood.

In intra-operative blood salvage the collected blood is exposed to traumatized tissue and a synthetic circuit. Because of this exposure it was expected that the complement system, which is a contact system present in plasma, would be activated in salvaged blood. To determine whether this occurs, the plasma levels of the complement factor C3 and its activated fragment, C3a, were measured in intra-operative salvaged blood before and after washing. Samples were obtained from patients undergoing aortic surgery where intra-operative salvage was used. In the unwashed salvaged blood, the level of C3 fell (mean C3: 0.33 g/L) and the level of C3a increased (mean C3a: 1994 ng/mL) compared with the patient circulating levels of C3 and C3a (mean C3: 0.70 g/L, mean C3a: 855 ng/mL) respectively. Washing of the collected blood reduced the C3a level (mean: 346 ng/mL) to the patient's level and reduced C3 to the lower detection limit of the test (less than 0.2 g/L). The raised level of C3a and the reduced level of C3 confirm that the complement system is activated and imply that other complement factors are also activated.

Blood Loss, Surgical↗
PubMed1994

Systemic blood activation during and after autotransfusion.

To evaluate the extent of shed blood activation in two autotransfusion systems and the effect of circulating blood activation upon autotransfusion, we performed a prospective study in 18 patients undergoing internal mammary artery bypass operation and a control group of 10 patients. The autotransfusion systems were from Sorin (n = 9) consisting of a hard shell reservoir with a filter having a small contact area (0.32 m2), and from Dideco (n = 9) consisting of a hard shell reservoir with a filter having a larger contact area (4.64 m2). We found high concentrations of thromboxane, fibrinogen degradation products, complement split product C3a, and elastase in the shed blood and, with the exception of C3a, in the circulating blood of autotransfused patients. There was no such activation in control patients. The degree of the systemic inflammatory reaction was determined by the type of autotransfusion system and by the amount of infused shed blood. The Dideco system provoked more inflammatory response than did the Sorin. This was reflected by the larger shed blood loss during autotransfusion in the Dideco patients than in Sorin patients, resulting in infusion of more shed blood (means, 737 mL versus 566 mL; not significant). After autotransfusion, Dideco patients shed significantly more blood than did Sorin or control patients (p < 0.05). Dideco patients also needed more colloid/crystalloid solution per 24 hours than Sorin patients (p < 0.05). This became clinically relevant only after infusion of more than 800 mL of shed blood (p < 0.001): hemodilution indicated the need for packed cells in 4 Dideco patients and in 1 Sorin patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Loss, Surgical↗
PubMed1990

Activation of the complement system during immunotherapy with recombinant IL-2. Relation to the development of side effects.

Therapy with high doses of rIL-2 is complicated by the occurrence of hypotensive reactions and the development of a vascular leakage syndrome (VLS). In four patients, who together received seven cycles of high doses of IL-2 (up to 12 x 10(6) U per m2 per day), and who developed these side effects, we observed an unexpected increase in plasma levels of C3a, indicating activation of the complement system. C3a levels markedly increased during IL-2 therapy from 4 nmol/liter (mean level) before therapy to 23 nmol/liter at the end of the cycle. Activation of C3 occurred via the classical pathway inasmuch as C4a levels also increased during therapy. Mean daily C3a levels correlated with signs of the VLS, such as daily weight gain (p less than 0.001) and albumin levels (inverse correlation, p less than 0.001). In five additional patients, who together received seven cycles of lower doses of IL-2 (2 x 10(6) U per m2 per day) and who did not develop a VLS, only moderate increases in C3a levels (up to 13 nmol/liter) were observed. The highest levels at the first day of the regimen (mean: 7 nmol/liter) occurred 8 h after the IL-2 infusion. Thus, administration of IL-2 induces a dose-dependent activation of the complement system in vivo, which appeared to be related to the development of side effects of this therapy, such as the VLS.

Adult↗
PubMed2004

Purification and functional assessment of C3a, C4a and C5a of the common carp (Cyprinus carpio) complement.

Promotion of inflammatory response is an important role of the complement system, but this kind of function is poorly documented for the lower vertebrates. Here we report chemotactic activity of purified anaphylactic fragments derived from the complement components C3, C4 and C5 of the common carp. The purified anaphylatoxins are two C5a-desArg peptides derived from the C5-I isotype, an intact form and a desArg form of C4a from C4-2 isotype, and an intact form and a desArg form of C3a from C3-H1 isoform. These were identified by N-terminal sequencing, mass spectrometry, and peptide mass fingerprinting. In the chemotaxis assay using carp kidney neutrophils, the two C5a-desArg fragments, which are probably allotypic variants, showed a potent chemotactic activity at 0.5-1 nM, whereas C3a or C4a showed no significant activity. The results suggest that C3a, C4a and C5a of bony fish have functionally diverged to the state similar to their mammalian homologs.

Amino Acid Sequence↗
PubMed1990

Preliminary report: complement activation in wasp-sting anaphylaxis.

The generation of the anaphylatoxin C3a was measured after a wasp-sting challenge in eight patients with previous anaphylactic reactions to wasp stings. Whereas there was no change in C3a in one patient who showed no reaction and only a slight rise in three patients with mild reactions, C3a rose substantially in the four patients with severe anaphylactic reactions. This complement activation is the first in-vitro variable which correlates with the severity of wasp-sting anaphylactic reactions. A role for complement activation in the pathophysiology of wasp-sting anaphylaxis is therefore suggested.

Adult↗
PubMed1988

Detection of native human complement components C3 and C5 and their primary activation peptides C3a and C5a (anaphylatoxic peptides) by ELISAs with monoclonal antibodies.

Monoclonal antibodies (mAbs) were raised against human C3a, C3b, C5a, and C5b after immunization of BALB/c mice with the native components C3 and C5. Using different combinations of these mAbs we have developed four sensitive sandwhich-enzyme-linked immunosorbent assays (ELISAs) for the detection of native C3 or C5 in samples with low concentrations of these proteins, e.g., in cell culture supernatants or synovial fluids and cerebrospinal fluids (CSF) and for the detection of the anaphylatoxic peptides (AT-peptides) C3a or C5a in human EDTA-plasma. The C3- and C5-ELISAs were found to be specific for the uncleaved complement proteins. Two different anti-C3a or anti-C5a mAbs were combined for the C3a- and C5a-ELISA. Before assaying a sample in the C3a- or C5a-ELISA a precipitation step to eliminate uncleaved C3 and C5 was necessary. The sensitivity and specificity of the four ELISAs were tested with purified antigens and EDTA-plasma or Cobra venom factor-activated EGTA-plasma samples as a source of C3a and C5a. The detection limits were 1 ng/ml for C3, 1 ng/ml for C3a, 2 ng/ml for C5, and 100 pg/ml for C5a. Plasma samples from patients undergoing cardiopulmonary bypass (CPB) surgery were used as a source of pathological material.

Anaphylaxis↗
PubMed1995

The value of complement activation products in the assessment of systemic lupus erythematosus flares.

Complement activation products (CAP) have been reported as sensitive markers of disease activity in systemic lupus erythematosus (SLE). We have measured seven parameters of the complement system (C3, C4, factor B, C3a, C4a, iC3b, and the terminal complement complex-TCC-) in 61 SLE patients to study their interrelationship and relative efficacy as diagnostic indicators of lupus activity. Disease activity was judged according to a clinical index (SLEDAI) to be active in 22 and inactive in 39 patients. Subjects with active SLE showed increased levels of C3a, C4a, and TCC compared with those of stable lupus and normal controls, and plasma concentrations of these CAP manifested a positive correlation with disease activity scores. However, values of factor B and iC3b did not correlate with lupus flares. Serum C3 levels were a better reflection of the degree of SLE activity than were C4 levels. The anaphylatoxins were extremely sensitive markers of disease activity but they lacked enough specificity, and iC3b was not at all informative for this purpose. On the whole, TCC concentration was the most useful parameter (77% sensitivity, 80% specificity) to monitor lupus activity, correlating the best with the activity scoring system, and thus offers a better laboratory marker of lupus severity than conventional measurements of complement.

Adolescent↗
PubMed2001

Trimeresurus flavoviridis (habu snake) venom induces human erythrocyte lysis through enzymatic lipolysis, complement activation and decreased membrane expression of CD55 and CD59.

Trimeresurus flavoviridis (habu snake) bites can be fatal to man because of its virulent venom, which is clinicopathologically classified as haemorrhagic, necrotic, and haemolytic toxins. Trimeresurus flavoviridis venom causes lysis of human erythrocytes in conditions where plasma is present as well as in plasma-free conditions in a dose-dependent manner. The haemolytic process requires Ca2+ and Mg2+ ions in the solution. Additionally, the venom initiates activation of the human complement cascade as evidenced by C3a and C5a releases, complement consumption indicated by CH50 and formation of soluble membrane attack complex. The insertion of membrane attack complex into the erythrocyte membranes is morphologically identified by electronmicroscopy. Immunofluorescence analysis reveals that incubation of erythrocytes with the venom decreased cell-surface expression of CD55 (decay accelerating factor) and CD59 (protectin), which renders erythrocyte more vulnerable to adherent C3 and C5 convertases and to polymerization of C9 into membranes, and may enhance autologous complement-mediated haemolysis triggered by the venom. Our data demonstrate that Trimeresurus flavoviridis venom induces haemolysis in the presence of plasma by three distinct mechanisms, direct lipolysis through PLA2 activity, activation of the human complement system, and cleavages of CD55 and CD59 from erythrocyte membranes.

Animals↗