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PubMed1962

Immunological specificity of delayed and immediate hypersensitivity reactions.

The effects of the following parameters on the immunologic specificity of delayed and immediate hypersensitivity reactions were investigated in the guinea pig using the picryl and p-toluenesulfonyl systems: (a) the contribution of the carrier protein, (b) the effect of the number of hapten groups per molecule of the immunizing and challenging antigens, and (c) the effect of interposing a 6 carbon chain (epsilon-aminocaproic acid) between the hapten and its usual attachment to the lysine epsilon-NH(2) groups of the carrier protein. It was found that induction of delayed hypersensitivity was accomplished equally well with both lightly and heavily coupled conjugates. Sensitized animals which gave strong delayed reactions to the immunizing conjugate cross-reacted poorly or not at all to (a) conjugates of the same hapten with a different carrier protein, or (b) conjugates differing from the immunizing conjugate by having an epsilon-aminocaproyl chain interposed between hapten and its attachment onto the carrier protein. Animals sensitized with either lightly or heavily substituted conjugates exhibited strong delayed reactions to both conjugates, but more intense reactions to the immunizing conjugate were always observed. In contrast to the marker carrier specificity exhibited by the delayed hypersensitivity reactions, immediate hypersensitivity reactions, (specific precipitation, Arthus, and PCA reactions) could be elicited equally well with hapten conjugates of all carrier proteins, as well as with conjugates containing epsilon-aminocaproyl chains interposed between hapten and the carrier protein, provided the number of hapten groups per molecule conjugate was sufficiently high. Both in inducing antibody response and in provoking immediate hypersensitivity reactions, heavily substituted conjugates were considerably more effective than were lightly substituted conjugates. Alternative explanations for these observed differences in specificity between immediate and delayed hypersensitivity reactions are discussed.

Animals↗
PubMed1967

Generation of chemotactic activity in rabbit serum by plasminogen-streptokinase mixtures.

The addition of plasminogen and streptokinase to rabbit serum results in appearance of chemotactic activity which is relatively heat-labile and dialyzable. Generation of this activity requires heat-labile factors in serum, but not the sixth component of complement. The optimal mole ratio for generation of chemotactic activity is 1:1 to 1:3 for plasminogen to streptokinase. Neither material alone is sufficient to generate the activity in fresh serum. Generation of chemotactic activity can be blocked by the presence of epsilon-aminocaproic acid. This plasmin-generated chemotactic factor sediments slowly in a sucrose density gradient during ultracentrifugation. The addition of plasminogen and streptokinase to rabbit serum containing the preformed chemotactic factor (activated trimolecular complex of C'5, C'6, C'7) causes destruction of the chemotactic factor and loss of hemolytic activity of the sixth component of complement. The same mole ratio of reactants for optimal expression of the phenomenon holds as for plasmin generation of chemotactic activity in untreated serum.

Animals↗
PubMed2003

Hemorrhage after coronary artery bypass graft procedures.

OBJECTIVES: To identify risk factors for excessive bleeding after coronary artery bypass graft (CABG) procedures and to quantify the outcomes related to this complication. DESIGN: We conducted a case-control study to identify risk factors for hemorrhage following CABG surgery and a historical cohort study to quantify outcomes of hemorrhage. SETTING: The cardiothoracic surgery service of a university hospital. RESULTS: Factors associated with excessive blood loss were recent catheterization (odds ratio [OR] = 0.44; 95% confidence interval [CI95], 0.21 to 0.91); age older than 65 years (OR = 1.94; CI95, 0.96 to 3.93); bypass time of 150 minutes or more (OR = 2.91; CI95, 1.09 to 7.81); and postoperative platelet count of 160,000/mm3 or less (OR = 2.36; CI95, 1.06 to 5.22). The attributable cost of a postoperative hemorrhage was $3,866 (P = .0002) overall, $9,912 (P = .0001) for patients who required reoperation, and $3,316 (P = .03) for those treated medically. The median attributable postoperative length of stay was 1 day longer for cases than for controls (P = .011). Postoperatively, patients who hemorrhaged received significantly larger volumes of packed red blood cells (P < .0001), fresh frozen plasma (P < .0001), platelets (P < .0001), plasminate (P = .007), protamine sulfate (P < .0001), desmopressin acetate (P < .0001), and epsilon-aminocaproic acid (P < .0001) than did controls. CONCLUSIONS: Age, duration of bypass, and postoperative platelet count were associated with excessive bleeding. Hemorrhage after CABG surgery significantly increased the length of stay and cost of care.

Age Factors↗
PubMed1977

Biochemically assisted antibiotic treatment of lethal murine Staphylococcus aureus septic shock.

Evidence has been sought for life-prolonging effects of a variety of chemicals given subcutaneously 1 hr after intraperitoneal challenge of mice with 10(9) Staphylococcus aureus cells. The chemicals were chosen to replace chemicals found to be missing in the blood or carcass at death or to treat biochemical or visible abnormalities in sick mice near death from infection. Nafcillin given subcutaneously in adequate amounts cure S. aureus infection. In these experiments nafcillin treatment was delayed until 40% of the time from challenge to death in the controls. Chemicals were given in addition to nafcillin subcutaneously 20% of the time from challenge to death. Cortisol, Dilantic, epsilon-aminocaproic acid, glucose, nicotinamide, olive oil, phentolamine-propanalol, sodium bicarbonate, sodium lactate, and reserpine each prolonged life compared to saline treatment. When nafcillin was added, only cortisol, Dilantin, nicotinamide and reserpine were found to prolong life significantly compared to nafcillin-saline treatment Fatality rates were significantly reduced with cortisol and Dilantin when they were given in association with nafcillin compared to nafcillin-saline treatment.

Animals↗
PubMed1992

Excessive fibrinolysis in amyloidosis associated with elevated plasma single-chain urokinase.

Severe bleeding resulting from excessive fibrinolysis has been observed in patients with primary amyloidosis. The authors studied a patient with this hemostatic disorder before and during therapy with epsilon-aminocaproic acid. Excessive fibrinolysis was associated with depressed plasma concentrations of coagulation Factors XII, XI, high-molecular-weight kininogen, and Factors VIII and V; and plasminogen and alpha-2-plasmin inhibitor. These deficiencies were corrected with treatment. The functional and antigenic concentrations of tissue plasminogen activator and plasminogen activator inhibitor in the patient's plasma were normal. Urokinase-type activator activity and antigen were three to five times elevated in the patient's plasma. Results of immunoprecipitation showed that single-chain urokinase-type activator was the primary urokinase-type activator species in the patient's plasma. Excessive fibrinolysis in patients with amyloidosis results from increased plasma single-chain urokinase-type activator activity.

Amyloidosis↗
PubMed1976

Coagulopathy in experimental sepsis with Streptococcus pneumoniae in rabbits: effect of drug therapy and splenectomy.

The cause of death in bacteremia due to Streptococcus pneumoniae remains unclear. The role of intravascular coagulation and splenectomy was investigated in rabbits with lethal pneumococcal bacteremia. The staphylococcal clumping titer in serum, a measure of fibrin degradation products, increased early and persisted until death. This titer correlated with the level of bacteremia. The partial thromboplastin time and platelet-rich plasma clotting time also increased as the disease worsened. However, the prothrombin time remained normal. 125I-labeled fibrinogen was cleared normally from the plasma of infected rabbits, whether intact or splenectomized. Similarly, the concentration of fibrogen in plasma remained normal, even though the level of fibrin degradation products increased, and no difference in these parameters was noted between intact and splenectomized rabbits. Fibrin deposition could not be detected in any of the organs studied. Neither the level of fibrin degradation products nor survival was affected by treatment with hydrocortisone, hexadimethrine, cytochrome c, carboxypeptidase B, epsilon-aminocaproic acid, or heparin. These data suggest that intravascular coagulation occurs in this experimental infection prior to the onset of shock but probably plays only a minor role in lethality.

Animals↗
PubMed1992

Binding of plasminogen to Neisseria meningitidis and Neisseria gonorrhoeae and formation of surface-associated plasmin.

Forty-two strains of Neisseria meningitidis and 17 of Neisseria gonorrhoeae were tested for their ability to interact with 125I-labeled Glu-plasminogen. All strains tested reacted substantially with plasminogen, resulting in uptake values of 20%-48%. Scatchard analysis with selected N. meningitidis strains demonstrated a dual-phase receptor interaction, one more avid receptor with a Kd of 50 nM and 3000-6000 receptors per bacterium and a second receptor with a Kd of 200 nM and 10,000-20,000 receptors per bacterium. Plasminogen uptake could be completely eliminated by low concentrations of epsilon-aminocaproic acid, suggesting that the lysine binding sites on the plasminogen molecule are involved in the receptor-ligand interaction. The binding of plasminogen to the bacterial receptor facilitates the tissue-type plasminogen activator-mediated conversion to Glu-plasmin, which also modifies itself to the Lys form. Receptor-associated plasmin is enzymatically active, monitored as a breakdown of the chromogenic substrate S-2251, and retains its activity in the presence of naturally occurring inhibitors in plasma.

Aprotinin↗
PubMed2003

Evidence of allosteric conformational changes in the antibody constant region upon antigen binding.

We have addressed the question of whether antigen binding induces a conformational change in the heavy chain constant (C(H)) domain of antibodies using staphylococcal protein A or streptococcal protein G as probes, since these proteins are known to bind to IgG domains such as C(H)1 and C(H)2-C(H)3 domains. Biosensor assays on interactions between these proteins and mouse IgG specific to (4-hydroxy-3-nitrophenyl)acetyl (NP) or their enzymatic fragments conducted in the presence or absence of the hapten, NP-epsilon-aminocaproic acid (NP-Cap), showed that the binding of IgG to these proteins was inhibited by the binding of NP-Cap. The results of isothermal titration calorimetry also revealed that the association constant for the interaction of protein A with IgG2b decreased by the addition of NP-Cap. These results suggested that antigen binding induced conformational changes in binding sites for protein G or protein A located at C(H)1 and C(H)2-C(H)3 domains, respectively.

Allosteric Regulation↗
PubMed1988

Synthesis and hybridization of a series of biotinylated oligonucleotides.

A series of oligonucleotides containing biotin-11-dUMP at various positions were synthesized and compared in quantitative, colorimetric hybridization-detection studies. A deoxyuridine phosphoramidite containing a protected allylamino sidearm was synthesized and used in standard, automated synthesis cycles to prepare oligonucleotides with allylamino residues at various positions within a standard 17-base sequence. Biotin substituents were subsequently attached to the allylamino sidearms by reaction with N-biotinyl-6-aminocaproic acid N-hydroxysuccinimide ester. These oligomers were hybridized to target DNA immobilized on microtiter wells (ELISA plates), and were detected with a streptavidin-biotinylated horseradish peroxidase complex using hydrogen peroxide as substrate and o-phenylenediamine as chromogen. We found that the sensitivity of detection of target DNA by biotin-labeled oligonucleotide probes was strongly dependent upon the position of the biotin label. Oligonucleotides containing biotin labels near or off the ends of the hybridizing sequence were more effective probes than oligonucleotides containing internal biotin labels. An additive effect of increasing numbers of biotin-dUMP residues was found for some labeling configurations.

Base Sequence↗
PubMed1986

Identification of the plasminogen-binding site of human alpha 2-plasmin inhibitor.

A plasminogen-binding site of human alpha 2-plasmin inhibitor was studied. The chromatogram of digest from the amidinated alpha 2-plasmin inhibitor (67K-daltons, plasminogen-binding form) with trypsin was almost identical with that obtained from the 65K-daltons derivative (non-plasminogen-binding form) treated with the same procedure, except for the three tryptic peptides. One of the three peptides, the deamidinated peptide T-11, was found to have a strong ability to inhibit the interaction of alpha 2-plasmin inhibitor with human plasmin. Moreover, the dissociation constant Kd for interaction between the peptide T-11 and plasmin was estimated to be 5.5 microM, indicating that Kd is about 10-fold lower than that of epsilon-aminocaproic acid. The sequence of the peptide T-11 was determined by the Edman method as follows: NH2-G-D-K-L-F-G-P-D-L-K-L-V-P-P-M-E-E-D-Y-P-Q-F-G-S-P-K-COOH. alpha 2-Plasmin inhibitor and its 65K-daltons derivative were found to have the same NH2-terminal sequence of Asn(Asp)-Gln-Glu-Gln-. These results indicated that the plasminogen-binding site(s) of alpha 2-plasmin inhibitor could be located in the COOH-terminal region of its molecule and that some of epsilon-NH2-groups in the deamidinated peptide T-11 may be involved in the lysine-binding site(s) of plasmin(ogen).

Amino Acid Sequence↗
PubMed1998

Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity.

Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.

Arteriosclerosis↗
PubMed2003

Pericellular plasmin induces smooth muscle cell anoikis.

Smooth muscle cell (SMC) rarefaction is involved in the development of several vascular pathologies. We suggest that the plasminogen activation system is a potential extracellular signal that can induce pericellular proteolysis and apoptosis of vascular SMCs. Using primary cultures of arterial SMCs, we show that plasmin generated from plasminogen on the cell surface induces cell retraction and fibronectin fragmentation, leading to detachment and morphological/biochemical changes characteristic of apoptosis (also called anoikis). The generation of cell-bound plasmin mediated by tissue-type plasminogen activator (t-PA), constitutively expressed by VSMCs, requires binding of plasminogen to the cell surface and is inhibited by epsilon-aminocaproic acid (IC50=0.9+/-0.2 mM), a competitor of plasminogen binding to membrane glycoproteins. Conversely, addition of alpha2-antiplasmin, which blocks free plasmin in the cell supernatant, could not fully prevent anoikis. Finally, an MMP inhibitor failed to prevent VSMC anoikis, arguing for a direct involvement of plasmin in this phenomenon. Indeed, similar changes are induced by plasmin directly added to VSMCs or to arterial rings, ex-vivo. We show for the first time that pathological anoikis can be triggered by a process that requires functional assembly of the plasminogen activation system on the surface of VSMCs.

Anoikis↗
PubMed2000

Platelet-rich plasma sequestration, with therapeutic platelet yields, reduces allogeneic transfusion in complex cardiac surgery.

UNLABELLED: Platelet dysfunction is the most common cause of nonsurgical bleeding after cardiopulmonary bypass (CPB). We hypothesized that reinfusion of a therapeutic quantity of platelets sequestered before CPB would decrease the need for allogeneic platelet transfusion, as well as decrease bleeding and total allogeneic transfusion, in cardiac surgery patients at moderately high risk for bleeding. Fifty-five patients undergoing either reoperative coronary artery bypass (CABG) or combined CABG and valve replacement were randomized to control or platelet-rich plasma sequestration (pheresis) groups. All patients received intraoperative epsilon-aminocaproic acid infusions. There was no significant difference between groups with respect to preoperative characteristics, duration of CPB, or target postoperative hematocrit. Mean platelet yields were 6.2 +/- 2.1 units (3.1 x 10(11) platelets). Mean pheresis time was 44 min. Allogeneic platelets (range = 6-12 units) were transfused to 28% of control patients, compared with 0% of pheresis patients (P < 0.01). Allogeneic packed red blood cells were transfused to 45% of control patients (1.2 units per patient) versus 31% of pheresis patients (0. 7 unit per patient) (P = 0.35). Total allogeneic units transfused were significantly reduced in the pheresis group (P < 0.02). Mediastinal chest tube drainage was not significantly decreased in the pheresis group. In this prospective, randomized study, therapeutic platelet yields were obtained before CPB. In contrast with recent studies with low platelet yields, these data support the conclusion that platelet-rich plasma sequestration is effective in reducing allogeneic platelet transfusions and total allogeneic units transfused in cardiac surgery patients at moderately high risk for post-CPB coagulopathy and bleeding. IMPLICATIONS: Transfusion of allogeneic blood products, including platelets, is common during complex cardiac surgical procedures. In the present prospective, randomized study, a significant reduction in allogeneic platelet transfusion and total allogeneic units transfused was observed after the reinfusion of a therapeutic quantity of autologous platelets sequestered before cardiopulmonary bypass.

Aged↗
PubMed2001

Intraoperative plateletpheresis and autologous platelet gel do not reduce chest tube drainage or allogeneic blood transfusion after reoperative coronary artery bypass graft.

Platelet-rich plasma (PRP) is postulated to decrease postoperative mediastinal chest tube drainage (MCTD) and allogeneic blood transfusions (ABT) after surgery with cardiopulmonary bypass. However, recent metaanalysis of the literature reveals that few good quality (therapeutic yield) trials that show a benefit have been published. The potential hemodynamic instability caused by plateletpheresis has not been emphasized. We studied the effect of plateletpheresis on MCTD, ABT, and hemodynamic stability in reoperative coronary artery bypass graft patients, a group perceived to be at high risk for ABT. Ninety patients were randomly assigned to Pheresis or Control groups. epsilon-Aminocaproic acid was given to all patients. Hemodynamic instability was assessed by degree of volume and inotrope resuscitation required. Part of the sequestered platelet volume was used to make autologous platelet gel, which was applied as a wound sealant. Mean pheresis yield was 30% +/- 7% of the circulating platelet mass or 6.4 +/- 2.2 allogeneic platelet unit equivalents. Total MCTD did not differ between the groups. There were no differences in mean packed red blood cell, platelet, and plasma transfusion rates. Overall, 52% of the Pheresis group received ABT, versus 55% of the Control group. Fifty-three percent of the Pheresis group patients exhibited significant hemodynamic instability, versus 27% of the Control group (P < 0.05). This study was unable to show any reduction in MCTD or ABT, although the plateletpheresis technique may offset platelet dysfunction caused by aspirin or increased blood exposure to nonbiologic surfaces, or it may compensate for lack of antifibrinolytic use. The significantly increased incidence of hemodynamic instability in the Pheresis group means that the risk/benefit ratio must be determined for individual cardiac surgical units.

Aged↗
PubMed1989

Skin graft survival--the bacterial answer.

An in vitro wound model was created to determine the mechanism by which bacteria cause skin graft failure. A wound surface was simulated by a human fibrin clot. Staphylococcus aureus or group A streptococcus was incubated over the clot. Either saline, human plasminogen, aprotinin, or epsilon-aminocaproic acid (EACA), or a combination of these, was added to the tubes. After 30 hours, the tubes were examined for the presence of the clot. The supernatant was then examined for the presence of fibrin degradation products (FDP). S. aureus was incapable of destroying the fibrin clot without the presence of plasminogen in the culture media. Group A streptococcus was capable of some clot degradation, but this was markedly improved in the presence of plasminogen. High FDP levels correlated with the destruction of the clot. Both aprotinin and EACA were capable of preserving the fibrin clots. In this study we carefully controlled the chemical and bacterial milieu on a simulated wound.

Antifibrinolytic Agents↗
PubMed1989

Autologous fibrin glue in full-thickness skin grafting.

Full-thickness skin grafts can be anchored to the recipient site using fibrin glue made from the patient's own blood and commercially available thrombin and epsilon aminocaproic acid. The technique works well for small grafts on irregularly contoured sites where suture fixation of a graft would be technically difficult. Full-thickness skin grafts anchored with autologous fibrin glue have been uniformly successful in 50 patients followed for a minimum period of four months.

Fibrin Tissue Adhesive↗
PubMed2000

More porous fibrin gel structure obtained by interaction with Lys-plasminogen than with Glu-plasminogen.

The effect of Glu1- and Lys78-plasminogen on the assembly and structure of fibrin gels was studied in purified fibrinogen-thrombin system and in plasminogen-free plasma, using turbidity, liquid permeation and three-dimensional (3D) confocal laser microscopy methods. In the purified fibrinogen system using the turbidity method, the final optical density of the fibrin gels increased with increasing concentrations of Lys-plasminogen. The fiber mass/length ratio mu increased with increasing concentrations of both Glu1- and Lys78-plasminogen, the effect of Lys78-plasminogen being much stronger. The permeability coefficient (Ks) analyzed with the permeation method revealed that fibrin gels formed in the presence of Lys78-plasminogen were more permeable (porous) than the control gels. The effect on the gel structure was inhibited by the fibrinolytic inhibitor epsilon-aminocaproic acid. The same results were obtained in plasma milieu for both mu and Ks as in the purified system, i.e. the gels became more porous with increasing concentrations of Lys78-plasminogen. 3D microscopy pictures of the gels verified the findings.

Blood Coagulation↗