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PubMed2004

Use of the affinity chromatography principle in creating new thromboresistant materials.

The principle of affinity chromatography was used for preparation of thromboresistant bilayer coatings. The outer biospecific layer containing epsilon-aminocaproic acid residues (from 2.2 up to 5.5 nmol/cm2) was synthesized using a copolymer of maleic anhydride with N-vinylpyrrolidone and L-lysine dihydrochloride or N-epsilon-tert-BOC-L-lysine. This surface can selectively adsorb plasminogen (fibrinolytic zymogen) from blood. The biospecific layer (from 2.0 up to 3.6 microg/cm2) was applied for covering chitosan (native or modified) or albumin interlayer. Such bilayer coatings (BCs) were stable and represented the insoluble polyelectrolyte complexes. BCs were proposed for bilayer modification of synthetic vascular grafts, polyethylene, and other materials contacting with blood. This technique allowed us to significantly reduce thrombogenic properties of polyethylene surfaces.

Albumins↗
PubMed2006

The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis.

BACKGROUND: Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. METHODS: Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system. RESULTS: Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner. CONCLUSION: Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain.

Aminocaproic Acid↗
PubMed2001

Regulation of urokinase plasminogen activator/plasmin-mediated invasion of melanoma cells by the integrin vitronectin receptor alphaVbeta3.

The integrin vitronectin receptor alphavbeta3 is a mediator of cellular migration and invasion and has been identified as a marker of progression in malignant melanoma. Using a human melanoma model, we have previously shown that this receptor was coordinately expressed with the receptor for the urokinase plasminogen activator (uPAR). In our present study, the link between these receptors was further investigated by assessing the effect of alphavbeta3 ligation on uPAR transcription and function. Using the reverse transcription-polymerase chain reaction, we found that receptor ligation by immobilized monoclonal antibodies (MAbs) induced a rapid increase (up to 4.5 fold) in uPAR mRNA levels, which was maximal 4 hr after cell attachment. An increase was also noted in plasminogen activator inhibitor type-1 (PAI-1) mRNA levels (2.7-fold), but none was noted in uPA levels. In addition, ligation of alphavbeta3 resulted in a significant increase in cell surface-associated plasmin levels, which coincided with a 2- to 3-fold increase in cell invasion as measured in the Matrigel invasion assay. This increase in invasion could in turn be abolished by antibodies directed to uPA and uPAR and by the plasmin inhibitors epsilon-aminocaproic acid and aprotinin. Furthermore, ligation of the integrin alphavbeta3 triggered a rapid increase of up to 12-fold in total cellular PKC activity, and this coincided with the redistribution of PKCbeta, but not PKCalpha, from the cytosol to the membrane. Treatment of the cells with the PKCbeta-specific inhibitor LY379196 blocked uPAR and PAI-1 mRNA induction and reduced the increase in cell invasion due to alphavbeta3 ligation, confirming the involvement of this isoform in the response. The results provide evidence that the vitronectin receptor can enhance invasion by regulating the uPAR/uPA/plasmin system of proteolysis and implicate PKCbeta as an intermediate in the activation pathway.

Aminocaproic Acid↗
PubMed1987

Phorbol ester induces cultured endothelial cells to invade a fibrin matrix in the presence of fibrinolytic inhibitors.

We have previously shown that the tumor promoter 4 beta-phorbol 12-myristate 13-acetate (PMA) induces capillary endothelial cells grown to confluency on the surface of three-dimensional collagen gels to invade the underlying matrix and to form capillary-like tubular structures, a phenomenon mimicking angiogenic processes that occur in vivo (Montesano and Orci: Cell, 42:469-477, 1985). Since angiogenesis frequently occurs within a fibrin-rich extracellular matrix, we have examined the ability of PMA-treated endothelial cells to invade fibrin gels. Control endothelial cells grown on fibrin gels formed a confluent monolayer on the gel surface and did not invade the underlying matrix. Treatment of the cultures with PMA resulted in a progressive lysis of the substrate without invasion of the fibrin matrix. However, if the cells were treated with PMA either in the presence of fibrinolytic inhibitors (Trasylol, epsilon-aminocaproic acid) or in the absence of detectable plasminogen, dissolution of the substrate was prevented, and the endothelial cells invaded the fibrin gel, forming vessel-like tubular structures similar to those previously observed with collagen gels. These results demonstrate that the invasive and morphogenetic events induced by PMA do not necessarily require an interaction between endothelial cells and collagen fibrils but can also occur with other biologically relevant substrata. They also suggest (1) that invasion may occur via a plasmin-independent mechanism and (2) that in vivo, neutralization of excess proteolytic activity may play an important permissive role in angiogenesis and other invasive processes by preventing uncontrolled matrix degradation.

Aminocaproic Acid↗
PubMed2005

Antifibrinolytics in orthotopic liver transplantation: current status and controversies.

This article reviews the current status and controversies of the 3 commonly used antifibrinolytics-epsilon-aminocaproic acid, tranexamic acid and aprotinin-during liver transplantation. There is no general consensus on how, when or which antifibrinolytics should be used in liver transplantation. Although these drugs appear to reduce blood loss and decrease transfusion requirements during liver transplantation, their use is not supported uniformly in clinical trials. Aprotinin has been studied more extensively in clinical trials and appear to offer more advantages compared to two other antifibrinolytics. Because of the diverse population of liver transplant recipients and the potential adverse effects of antifibrinolytics, especially life-threatening thromboembolism, careful patient selection and close monitoring is prudent. Further studies addressing the risks and benefits of antifibrinolytics in the setting of liver transplantation are warranted.

Aminocaproic Acid↗
PubMed1981

A method for monitoring antifibrinolytic therapy in patients with ruptured intracranial aneurysms.

A rapid fluorometric assay technique has been utilized to assess the degree of fibrinolytic inhibition in 20 patients with ruptured intracranial aneurysms treated with epsilon-aminocaproic acid (EACA). This method quantitates the available plasminogen activity (APA) of plasma, and has proven to be a reliable means of monitoring antifibrinolytic therapy. Determination of the plasma APA also permits correlation of the level of fibrinolytic activity with putative complications of EACA therapy. Normal control plasma APA was 3.1 +/- 0.7 CTA units/ml, but in patients with subarachnoid hemorrhage (SAH), pretreatment fibrinolytic activity was supranormal at 3.78 +/- 0.88 CTA units/ml. During continuous intravenous administration of EACA (1.5 gm/hr) in patients with SAH, the plasma fibrinolytic activity was decreased to 0.9 +/- 0.31 CTA units/ml. A case described which examplifies the use of this assay. In addition, an approach to monitoring antifibrinolytic therapy using the plasma APA is proposed.

Aminocaproates↗
PubMed1977

The effect of antifibrinolytic therapy in experimental spinal cord trauma.

The efficacy of antifibrinolytic therapy with epsilon aminocaproic acid (EACA) in experimental spinal cord injury is assessed by use of a standardized trauma model at both nonparaplegic and paraplegic trauma doses. Evaluation of neurologic parameters, cortical evoked response and histopathology of the injured spinal cord demonstrated that within the contusion range studied, EACA has no significant therapeutic effect. The ability of the animal to walk was the most reliable criterion indicative of functional recovery, and was closely paralleled by return of the cortical evoked response. Spinal cord cavitation in excess of 60% uniformly resulted in paraplegia. The data from this experiment show no evidence of a significant secondary injury occurring after spinal cord trauma that is amenable to posttraumatic antifibrinolytic therapy.

Aminocaproates↗
PubMed2002

Fibrin as an alternative biopolymer to type-I collagen for the fabrication of a media equivalent.

We report here on studies examining the use of fibrin as an alternative to collagen for the entrapment of neonatal aortic rat smooth muscle cells (SMCs) in the fabrication of media equivalents. The studies show increased collagen production by fibroblasts entrapped in fibrin, which suggests that fibrin may be used in the fabrication of tissue equivalents to promote increased protein synthesis and remodeling. However, one of the challenges of working with fibrin is the rapid degradation by SMCs. This degradation was effectively inhibited with the addition of epsilon-aminocaproic acid (EACA) to the culture medium in concentrations ranging from 0.25 to 1 mg/mL. We also present results showing that fibrin stimulates collagen production by SMCs. SMCs in fibrin produced 3.2 and 4.9 times the amount of collagen produced by SMCs in collagen when supplemented with 1 and 0.25 mg/mL EACA, respectively. More than half of the collagen produced appeared in the medium rather than the matrix. The collagen in the medium appeared to be processed beyond the proform and may be in an aggregate form. In addition, the presence of type-III collagen or a type-I trimer was indicated by the results of an analysis of the medium by autoradiography.

Aminocaproic Acid↗
PubMed1990

Interaction of plasminogen and fibrin in plasminogen activation.

Glu1-, Lys77-, miniplasminogens, kringle 1-3, kringle 1-5A, and kringle 1-5R were able to bind with fibrin, while microplasminogen and kringle 4 did not bind significantly. Kringle 1-5A, but not kringle 1-3, effectively inhibited the binding of Glu1-, Lys77-, and miniplasminogens with fibrin. Miniplasminogen also inhibited the binding of Glu1-plasminogen with fibrin. The binding of kringle 1-3 with fibrin was blocked by mini- or Glu1-plasminogen. It is therefore evident that there are two fibrin-binding domains in plasminogen and that the one in kringle 5 is of higher affinity than that in kringle 1-3. CNBr cleavage products of fibrinogen effectively enhanced the activation of Glu1-, Lys77-, or miniplasminogens, but not microplasminogen, by tissue-type plasminogen activator. Kringle 1-5, but not kringle 1-3, dose-dependently inhibited the enhancement by fibrinogen degradation products of Glu1-plasminogen activation by the activator. Lysine and epsilon-aminocaproic acid could inhibit the binding of plasminogens and plasminogen derivatives with fibrin and block the enhancement effect of fibrinogen degradation products on plasminogen activation. The data clearly illustrate that the binding of plasminogen with fibrin, mainly determined by kringle 5, is essential for effective activation by tissue-type plasminogen activator. However, the presence of kringle 1-4 in the plasminogen molecule is required for the full enhancing effect since the kcat/Km of miniplasminogen activation in the presence of fibrinogen degradation products was 8.2 microM-1 min-1 which is significantly less than 52.0 microM-1 min-1 of Glu1-plasminogen.

Aminocaproic Acid↗
PubMed2007

Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis.

Although several randomized controlled trials (RCTs) have shown the efficacy of antifibrinolytic drugs in liver transplantation, their use remains debated due to concern for thromboembolic complications. None of the reported RCTs has shown a higher incidence of these complications in treated patients; however, none of the individual studies has been large enough to elucidate this issue completely. We therefore performed a systematic review and meta-analysis of efficacy and safety endpoints in all published controlled clinical trials on the use of antifibrinolytic drugs in liver transplantation. Studies were included if antifibrinolytic drugs (epsilon-aminocaproic acid, tranexamic acid (TA) or aprotinin) were compared with each other or with controls/placebo. Intraoperative red blood cell and fresh frozen plasma requirements, the perioperative incidence of hepatic artery thrombosis, venous thromboembolic events and mortality were analyzed. We identified 23 studies with a total of 1407 patients which met the inclusion criteria. Aprotinin and TA both reduced transfusion requirements compared with controls. No increased risk for hepatic artery thrombosis, venous thromboembolic events or perioperative mortality was observed for any of the investigated drugs. This systematic review and meta-analysis does not provide evidence for an increased risk of thromboembolic events associated with antifibrinolytic drugs in liver transplantation.

Adult↗
PubMed2006

Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: possible association with antifibrinolytic therapy.

BACKGROUND: Maintaining hemostasis in patients with end-stage heart failure undergoing cardiac surgery is always challenging. These patients have chronic hepatic insufficiency, resulting in derangement of coagulation. In addition, they are commonly receiving both systemic anticoagulation (warfarin or heparin) and antiplatelet therapy. The introduction of antifibrinolytics has had a significant effect on postoperative coagulopathy. We report fatal pulmonary microthrombi in patients receiving antifibrinolytics who developed suprasystemic pulmonary artery pressures and right heart failure that was impossible to overcome despite insertion of a right ventricular assist device. METHODS: We reviewed the surgical procedure and autopsy reports to identify patients with high pulmonary artery pressures caused by pulmonary microthrombi after a cardiac surgical procedure for end-stage heart failure. Patient demographics and preoperative, intraoperative, and postoperative variables were collected from a retrospective review of the patients' medical records. RESULTS: We identified 9 patients (7 men and 2 women; mean age, 45 +/- 16 years) who died of pulmonary microthrombi after cardiac surgery between January 1997 and January 2004. Surgical procedures included 5 left ventricular assist device implantations, 2 heart transplantations, and 2 left ventricular reconstructions with mitral valve repair or replacement. Eight patients received aprotinin, and 1 patient received epsilon-aminocaproic acid immediately before and during cardiopulmonary bypass. All patients had severe suprasystemic pulmonary artery pressures after protamine administration for heparin reversal, a complication that proved fatal in all cases. Intraoperative wedge biopsy of the lungs revealed multiple microthrombi within capillaries and in the small- and medium-sized pulmonary arterioles. CONCLUSION: We report 9 cases for which fatal pulmonary microthrombi might be associated with the use of prophylactic antifibrinolytic therapy. Mortally ill patients with multiorgan failure who are receiving systemic anticoagulation and undergoing surgical procedures require careful perioperative monitoring to identify potential hazards. Anticoagulation and antifibrinolytic therapy protocols may require adjustment in such patients.

Adult↗
PubMed1986

Effects of EACA on thrombin generation as measured by the chromagen S2238.

In the presence of epsilon aminocaproic acid (EACA) thrombin generation in recalcified platelet rich plasma (PRP) was markedly stimulated, as measured by the cleavage of the synthetic substrate S2238. However, thrombin activity remaining after 30 minutes incubation was reduced when compared with control values. The residual activity was shown to be hirudin insensitive and to be associated with a species of higher molecular weight than free thrombin. These results suggested an inhibition of thrombin binding to the antithrombin, alpha 2-macroglobulin (alpha 2M). Preincubation of PRP with EACA reduced the concentration at which EACA elicited its dual effects. Similar results were obtained with the alpha 2M inhibitor, hydrazine. These experiments indicated that alpha 2M may play a more important role in regulating thrombin generation than has been previously recognized.

Aminocaproates↗
PubMed1984

Suppression of influenza virus replication in infected mice by protease inhibitors.

Administration of the protease inhibitors, epsilon-aminocaproic acid or aprotinins, to mice infected with mouse-adapted influenza virus strain A/PR/8/34 (HON1) and A/Aichi/2/68 (H3N2) reduced virus replication in the lungs. Up to 100-fold reduction of virus titre and virus-induced neuraminidase activity were revealed in mouse lungs under protease inhibitor treatment. As a result, drug-treated mice rapidly cleared the virus from their lungs. The predominant synthesis was of non-infectious virions with uncleaved haemagglutinin in the lungs of drug-treated mice, in contrast to the production of highly infectious virions with proteolytically cleaved haemagglutinin in untreated mice. These observations suggest that protease inhibitors suppress influenza virus replication in mouse lungs due to prevention of haemagglutinin cleavage and virus proteolytic activation.

Aminocaproic Acid↗
PubMed2006

Clinical impact of oral health indexes in dental extraction of hemophilic patients.

PURPOSE: Periodontal disease in patients with hemorrhagic disorders may lead to severe bleeding during dental treatment. This study evaluated the clinical impact of oral health indexes in hemophilic patients undergoing tooth extraction. PATIENTS AND METHODS: Thirty-one hemophilic patients underwent teeth extractions using autologous fibrin glue and an oral antifibrinolytic drug (epsilon-aminocaproic acid). Oral health indexes (plaque, PI; gingival, GI; and decay-missing-filling-teeth, DMFT index) were evaluated before tooth extraction. RESULTS: Postsurgical bleeding episodes were observed in 6 hemophilic patients (1 severe, 3 moderate, and 2 mild type). The PI and GI index in the bleeding group were 1.8 and 1.7, respectively, and 1.8 for both of the non-bleeding groups (PI, P = .8; GI, P = .56). The global DMFT index was 18 in the bleeding group and 19.6 in the non-bleeding group (P = .67). CONCLUSION: The status of oral health did not interfere with bleeding caused by dental extraction of hemophilic patients.

Adolescent↗
PubMed2001

[Enhancement of bacillus Calmette-Guerin attachment to the bladder wall: experimental study].

OBJECTIVE: To provide experimentally a scientific basis for enhancement of bacillus Calmette-Guerin (BCG) antineoplastic effect. METHODS: Thirty rabbits were equally divided into five groups (groups A, B, C, D, and E) and the bladder mucosa of every rabbit was injured by electrocautery, cryocautery and incision on the left lateral wall, right lateral wall and posterior wall respectively. Then different drugs were instilled into bladders. Group A: pure phosphate-buffered sodium instillation (PBS); group B: PBS and radiolabeled BCG (3H-BCG) instillation; group C and group D: epsilon-aminocaproic acid or para-aminomethyl benzoic acid and 3H-BCG instillation; group E: heparin and 3H-BCG instillation. After instillation, every injured bladder wall and non-injured wall (anterior wall of bladder) were surgically removed and digested. The quantity of BCG adherence was determined by liquid scintillation counter. RESULTS: The quantity of BCG attached to injured bladder wall was significantly higher than that of non-injured wall (P < 0.001). The mean level of group C or group D was significantly higher than that of group B (P < 0.001) while the mean level of group E was significantly lower than that of group B (P < 0.001). CONCLUSION: For experimental rabbits, intravesical instillation of fibrin clot stabilizer EACA or PAMBA can enhance BCG attachment to the bladder wall while fibrin clot inhibitor heparin inhibits it.

Administration, Intravesical↗
PubMed1985

Perfusion outflow facility in the rabbit eye. Stabilization by EACA.

The time-dependent increase in apparent facility of outflow (washout effect) that occurs with prolonged perfusion of the eye has imposed limitations on the study of aqueous humor dynamics. The washout effect in postmortem in situ rabbit eyes, undergoing constant pressure perfusion with a saline perfusate, can be attenuated dramatically by adding to the perfusate the serine protease inhibitor and antifibrinolytic agent epsilon-aminocaproic acid (EACA) at a concentration of 3.8 X 10(-3) molar. Washout curves from 13 pairs of rabbit eyes, plotted as outflow facility versus time, were fitted by linear regression, and their washout slopes calculated. The washout slope of all of the 13 eyes perfused with normal saline + EACA was lower in magnitude (less washout) than the paired control eye in the same animal, perfused with a control perfusate of normal saline + leucine. Wilcoxon signed rank test yielded P less than 0.001. This suggests that a significant component of the washout effect may be mediated by fibrinolytic activity, or by some EACA sensitive component of the aqueous drainage pathway, and that addition of EACA to a saline perfusate may be useful for blunting the washout effect in prolonged perfusion studies.

Aminocaproates↗
PubMed2006

Haemostatic drug therapies for acute primary intracerebral haemorrhage.

BACKGROUND: Because primary intracerebral haemorrhage (PICH) volume influences its outcome and a third of PICHs enlarge by a third within 24 hours of onset, early haemostatic drug therapy might improve outcome. OBJECTIVES: To examine the clinical effectiveness and safety of haemostatic drug therapies for acute PICH in a randomised controlled trial (RCT) design. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched May 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to August 2005) and EMBASE (1980 to August 2005). In an effort to identify further published, ongoing and unpublished studies we scanned bibliographies of relevant articles, searched international registers of clinical trials and research, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We sought RCTs of any haemostatic drug therapy for acute PICH, compared against placebo or open control, with relevant clinical outcome measures. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, reviewed the relevant studies, and extracted data from them. MAIN RESULTS: We found four phase II RCTs, involving adults aged 18 years or over, within four hours of PICH: 116 received placebo and 373 participants received haemostatic drugs (two received epsilon-aminocaproic acid (EACA) and 371 received recombinant activated factor VII (rFVIIa)). Haemostatic drugs appeared to reduce the risk of death or dependence on the modified Rankin Scale (grades 4 to 6) within 90 days of PICH (risk reduction 0.79 (95% confidence intervals (CI) 0.67 to 0.93)), but not when assessed by the extended Glasgow Outcome Scale (risk reduction 0.90 (95%CI 0.81 to 1.01)). There was a statistically significant excess of arterial thromboembolism at 160 mcg/kg rFVIIa. AUTHORS' CONCLUSIONS: Current evidence for the use of haemostatic drugs in the treatment of acute PICH cannot provide clear guidelines for clinical practice. Adults with acute PICH may benefit from haemostatic therapy with rFVIIa, but the evidence on major clinical outcomes is neither robust nor precise. Large phase III RCTs of rFVIIa - and other less costly drugs - are necessary.

Aminocaproic Acid↗
PubMed1999

The additive effects of antifibrinolytics: dangers in the OR.

The use of antifibrinolytic agents in recent years had been heralded as a major breakthrough in the prevention of postoperative bleeding. However, whenever the delicate balance between coagulation and fibrinolysis is altered, the potential exists for disaster. There have been a number of complications reported in the literature related to the use of antifibrinolytics. With the availability of oral epsilon aminocaproic acid (EACA) as treatment for the symptoms of hemophilia and other secondary bleeding disorders, the possibility exists that a patient presenting for heart surgery may already be receiving antifibrinolytic therapy. A 72 year-old female underwent double valve replacement which was complicated by postoperative bleeding. Her medical history included gastrointestinal bleeding which was being treated with oral EACA. The patient was heparin resistant with a dose response of 55 sec/unit/ml. Heparin was administered during cardiopulmonary bypass to maintain the ACT between 400-500 seconds using a heparin-coated bypass circuit. In spite of this, the patient became thrombocytopenic and bled excessively in the postoperative period. Administration of additional antifibrinolytic agents in the operating room may be contraindicated when the patient is receiving this therapy preoperatively, and may contribute to the development of a procoagulant state during bypass.

Aged↗