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Dural substitute with polyglycolic acid mesh and fibrin glue for dural repair: technical note and preliminary results.

BACKGROUND: An ideal dural substitute that enables watertight closure, has sufficient strength, and can be absorbed without remnant materials that induce inflammation, adhesion, and infection is not available. The purpose of this study was to evaluate the efficacy of a bioabsorbable polyglycolic acid (PGA) mesh and fibrin glue as a substitute for dural repair. METHODS: Altogether, 10 patients with noted dural tears during extradural spinal surgery and 20 patients who underwent durotomy for intradural spinal surgery were included in this study. In a series of 20 consecutive cases, dural closure was performed by suture and fibrin glue. In the subsequent 10 consecutive patients, dural closure was performed by suture and fibrin glue with the use of absorbable PGA mesh. The medical records and magnetic resonance imaging (MRI) of the surgical site were retrospectively reviewed to evaluate the presence of a cerebrospinal fluid (CSF) fistula or leakage after the surgery. RESULTS: A CSF fistula occurred in five patients who underwent dural repair with fibrin glue alone, and postoperative MRI showed CSF leakage in two patients with incidental dural tears after laminectomy for ossification of ligamentum flavum. No CSF fistula was present in patients who underwent dural repair using PGA mesh and fibrin glue, and no adverse effects or complications were encountered postoperatively. Follow-up MRI revealed no evidence of CSF leakage around the reconstructed dura mater. CONCLUSIONS: The use of PGA mesh and fibrin glue for the repair of dura mater is a useful method of preventing CSF leakage in spinal surgery.

Adolescent↗

Early effects of fibrin sealant on colonic anastomosis in rats: an experimental and case-control study.

BACKGROUND: Leakage from colonic anastomoses leads to mortality and morbidity. Fibrin adhesives can be used to increase the strength of the anastomosis. In this study, we evaluated the early effects of fibrin sealant and hyaluronic acid-carboxymethylcellulose on colonic anastomosis in rats. METHODS: Anastomoses were made in the descending colon of 38 female Wistar-Albino rats, in three groups: control group (n = 12), group 1 treated with hyaluronic acid-carboxymethylcellulose (n = 16), and group 2 treated with fibrin sealant (n = 10). After 72 hours, adhesion scores, bursting pressure, rupture strength and histopathologic healing scores were evaluated. RESULTS: Due to postoperative mortality, we evaluated 10, 10 and 9 rats in the control group and in groups 1 and 2, respectively. Of these, we excluded 4, 5 and 4 rats that had macroperforations at autopsy. In the remaining rats, bursting pressure (123.2 +/- 14.8 mmHg) and rupture strength (400 +/- 16 mg) in the fibrin sealant group were significantly greater than in the two other groups ( CONTROL: 68.0 +/- 10.6 p = 0.006 and 325 +/- 52 p = 0.009; Group 1: 74.0 +/- 9.8 p = 0.03, 330 +/- 27 p = 0.016). However, we did not observe any significant difference between adhesion scores (2.5 +/- 0.6, 2.0 +/- 0.7, 2.0 +/- 0.7, p = 0.343). CONCLUSIONS: In this experimental study, fibrin sealant increased bursting pressure and rupture strength of colonic anastomoses while hyaluronic acid-carboxymethylcellulose had no effects in rats, but both of them showed no effect on adhesion scores. In order to use fibrin sealant to decrease the rate of early leakages from colonic anastomoses, further studies have to be performed.

Anastomosis, Surgical↗

Fibrin glue treatment of complex anal fistulas has low success rate.

PURPOSE: Fibrin glue has been used to treat anal fistulas in an attempt to avoid more radical surgical intervention. Reported success rates vary widely. The purpose of this study was to review the use of fibrin glue in the management of complex anal fistulas at a tertiary referral center. METHODS: This study was designed as a retrospective review of all patients treated with fibrin glue injection for complex anal fistulas in the Section of Colon and Rectal Surgery, Washington University School of Medicine/Barnes-Jewish Hospital. Demographics, previous treatment, operative information, and early follow-up were obtained from the patients' medical records. Phone interviews were conducted to determine successful healing or recurrence of fistulas requiring further treatment. Statistical analysis was by Fisher's exact test. The institutional review board approved the study. RESULTS: A total of 42 patients (19 males; median age, 44 (range, 20-76) years) were treated between 1999 and 2002. Three patients were lost to follow-up and were excluded from the study. Etiology of fistulas were cryptoglandular (n = 22), Crohn's disease (n = 13), or coloanal and ileal pouch-anal anastomotic (n = 4). Fistulas were classified as deep transsphincteric (n = 33), superficial transsphincteric (n = 1), supralevator (n = 2), or rectovaginal (n = 3). Initially, most patients had "closure" of the fistula but recrudescence was common. Durable healing was only achieved in 31 percent (12/39). Healing rates by etiology were cryptoglandular 23 percent (5/22), Crohn's disease 31 percent (4/13), and ileal pouch-anal anastomotic 75 percent (3/4; P = 0.14). Success rates by classification were deep transsphincteric 33 percent (11/33), superficial transsphincteric 0 percent (0/1), supralevator 0 percent (0/2), and rectovaginal 33 percent (1/3; P = 1). The success rate for patients with no previous treatment was 38 percent (8/21) vs. 22 percent (4/18) in those whose fistulas had been previously treated ( P = 0.32). Eight patients underwent a second fibrin glue treatment and only one of them healed (12.5 percent). Median follow-up for successfully healed fistula was 26 months. CONCLUSIONS: Fibrin glue treatment for complex anal fistulas has a low success rate and most recrudescences occurred within three months. However, given the low morbidity and relative simplicity of the procedure, fibrin glue should still be considered as a first-line treatment for patients with complex anal fistulas.

Adult↗

Efficacy of anal fistula plug vs. fibrin glue in closure of anorectal fistulas.

PURPOSE: Long-term closure rates of anorectal fistulas using fibrin glue have been disappointing, possibly because of the liquid consistency of the glue. A suturable bioprosthetic plug (Surgisis, Cook Surgical, Inc.) was fashioned to close the primary opening of fistula tracts. A prospective cohort study was performed to compare fibrin glue vs. the anal fistula plug. METHODS: Patients with high transsphincteric fistulas, or deeper, were prospectively enrolled. Patients with Crohn's disease or superficial fistulas were excluded. Age, gender, number and type of fistula tracts, and previous fistula surgeries were compared between groups. Under general anesthesia and in prone jackknife position, the tract was irrigated with hydrogen peroxide. Fistula tracts were occluded by fibrin glue vs. closure of the primary opening using a Surgisis anal fistula plug. RESULTS: Twenty-five patients were prospectively enrolled. Ten patients underwent fibrin glue closure, and 15 used a fistula plug. Patient's age, gender, fistula tract characteristics, and number of previous closure attempts was similar in both groups. In the fibrin glue group, six patients (60 percent) had persistence of one or more fistulas at three months, compared with two patients (13 percent) in the plug group (P < 0.05, Fisher exact test). CONCLUSIONS: Closure of the primary opening of a fistula tract using a suturable biologic anal fistula plug is an effective method of treating anorectal fistulas. The method seems to be more reliable than fibrin glue closure. The greater efficacy of the fistula plug may be the result of the ability to suture the plug in the primary opening, therefore, closing the primary opening more effectively. Further prospective, long-term studies are warranted.

Bioprosthesis↗

Fibrin glue as an adjunct to flap repair of anal fistulas: a randomized, controlled study.

PURPOSE: Both flap repair and fibrin glue are accepted sphincter-preserving techniques for managing anal fistulas. Additionally, the two techniques are not mutually exclusive and can be combined. This trial was undertaken to determine whether the combination of flap repair and fibrin glue resulted in better outcomes than flap repair alone. METHODS: Between July 2000 and March 2004, patients with trans-sphincteric anal fistulas were randomly assigned to advancement flap repair alone or flap repair combined with fibrin glue obliteration of the fistula tract. Data regarding age, gender, fistula anatomy, race, and previous repairs were collected. Fistulas managed by fistulotomy or caused by Crohn's disease, acute obstetric trauma, or radiation were excluded from this study. RESULTS: There were 58 patients randomized to flap repair alone or flap repair with fibrin glue (47 males; median age, 47 (range, 29-68) years). Mucosal advancement flap was performed in 36 patients and anodermal advancement flap was performed in 22. The median follow-up was 22 (range, 12-36) months. Total fistula recurrence rate for all patients was 32.6 percent. The recurrence rate for fistulas repaired by advancement flap alone was 20 percent, whereas the recurrence rate for fistulas repaired by advancement flap with fibrin glue was 46.4 percent (P < 0.05). CONCLUSIONS: The data fail to show improved outcomes when fibrin sealant is used in combination with an advancement flap compared with advancement flap alone for the management of complex anal fistulas.

Adult↗

Detection of intracoronary fibrin degradation after coronary balloon angioplasty.

Intracoronary thrombus formation may be involved in the pathogenesis of arterial closure after coronary angioplasty and may contribute to restenosis. It is hypothesized that, unlike markers of platelet activation and fibrin formation, D-dimer, a product of plasmin-mediated proteolysis of cross-linked fibrin, is not subject to significant catheter-induced artifact and could be used to study intracoronary fibrin degradation during angioplasty. No significant difference in D-dimer levels was noted in serial plasma samples obtained from an 8Fr arterial sheath and the wire lumen of an angioplasty balloon catheter, indicating that sampling through the catheter lumen did not induce artifactual D-dimer elevations. Translesion (proximal and distal to the lesion) coronary blood samples were collected in 31 patients undergoing elective coronary angioplasty pretreated with aspirin, dipyridamole and heparin. In 20 of those in whom translesion coronary samples for plasma D-dimer levels (mean +/- standard deviation) were collected before balloon dilation, there was no evidence of ongoing intracoronary fibrinolysis (proximal D-dimer levels, 289 +/- 145 ng/ml; distal, 299 +/- 156 ng/ml; difference not significant). After coronary angioplasty (n = 31), there was a relatively small, but significant (p less than 0.001) increase (45 +/- 71 ng/ml) in translesional D-dimer levels (proximal, 396 +/- 223 ng/ml; distal, 441 +/- 257 ng/ml). The results from this study suggest (1) D-dimer levels are not subject to significant catheter-induced artifact and may be useful for assessment of intracoronary fibrin metabolism, and (2) intracoronary degradation of fibrin can be detected after (but not before) routine coronary angioplasty despite pretreatment with antithrombotic therapy, presumably in response to balloon-induced arterial injury and fibrin formation.

Aged↗

Gold labeling of thrombin and ultrastructural studies of thrombin-gold conjugate binding by fibrin.

Monodispersed thrombin-gold (T-Au) conjugates were prepared by the absorption of a monolayer (3.8 nm thick) of human alpha-thrombin around individual monodispersed colloidal gold particles (16.5 +/- 1.8 nm). Like free molecular thrombin, T-Au conjugates can cause platelet aggregation, plasma clotting, and the release of fibrinopeptides A and B from fibrinogen. At the same thrombin concentration, T-Au conjugates have only one-tenth the fibrinogen-clotting activity of free thrombin and one-third the amidolytic activity of free thrombin. Hirudin can completely inhibit the fibrinogen-clotting activity of both T-Au conjugates and free thrombin, but can inhibit only half of the amidolytic activity of the conjugates. Diisopropyl fluorophosphonate can completely inhibit the fibrinogen-clotting activity and the amidolytic activity of both T-Au conjugates and free thrombin. T-Au conjugates were further characterized by studying the mechanism of their binding to fibrin and the location of the binding site on fibrin. The results of electron microscopic studies showed that T-Au conjugates, but not albumin-Au conjugates, are bound by fibrin. Increasing T-Au conjugate concentrations are associated with an increase in the number of T-Au conjugates binding to fibrin. At 0.1 microM thrombin, 73% of the T-Au conjugates are bound to branch points of the fibrin network with 27% of the T-Au conjugates present in the fibrin strands. At higher thrombin concentration (e.g., 0.5 microM) the percentage of T-Au conjugates bound to locations other than branch points increases to 62%.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗

Effect of routine fibrin glue use on the duration of air leaks after lobectomy.

The effectiveness of fibrin glue as a sealant to reduce postoperative air leaks after pulmonary lobectomy was evaluated in 28 consecutive patients between November 1988 and May 1989. A fibrin glue spray was used in 14 patients, and 14 patients served as controls. Assignment of either group was made before thoracotomy. Nine male and 5 female patients with a mean age of 63.8 years were in the fibrin glue experimental group, and 8 male and 6 female patients with a mean age of 59 years, in the control group. An equal number of complete and incomplete fissures were in each group. All fissures were handled in the same way (stapled). Two milliliters of fibrin glue was applied through a double-syringe delivery system and sprayed on the staple line and any cut surface of the inflated lung just before thoracotomy closure. The fibrin glue-treated group had a mean air leak duration of 2.3 +/- 3.7 days, chest tube drains for 6 +/- 4.1 days, and a postoperative hospitalization of 9.8 +/- 3.1 days. The control group had a mean air leak duration of 3.3 +/- 3.3 days (p = 0.94), chest tube drains for 5.9 +/- 3.9 days (p = 0.95), and a postoperative hospitalization of 11.5 +/- 3.9 days (p = 0.21). We conclude that the routine use of a fixed quantity of fibrin glue is not effective in reducing the duration of air leaks, chest tube drainage, or hospitalization after uncomplicated pulmonary lobectomy.

Air↗

Zinc binding to fibrinogen and fibrin.

Zinc binding to fibrinogen and fibrin was studied by two techniques. Scatchard analysis of ultrafiltration eluates reveals that fibrinogen has multiple Zn(II)-binding sites, KD (fibrinogen) = 18 microM; n = 6. The zinc content of the "collapsed" fibrin gel supernatant was also determined by atomic absorption spectroscopy and analyzed by a Scatchard plot (KD (fibrin) = 8 microM, n = 6). In other experiments, Zn(II) did not displace 45Ca(II) from fibrin. It appears that the binding of zinc to fibrinogen or fibrin is distinct from that of calcium, and that the zinc-binding characteristics of fibrinogen and fibrin are not significantly affected by the transformation of one into the other.

Calcium↗

Repair of experimental atrial rupture with fibrin glue.

Ten cases of experimental atrial rupture were created in five pigs by cutting into both atria. The defects measured approximately 3.0 x 1.0 cm. Bleeding was stopped by applying a tangential clamp and the defect in the atrium was sealed with fibrin glue (mean volume 2.0 ml, range 1.5-2.5 ml) with a mean fibrin concentration of 23 mg/ml. The mean pressures in the atria were 11 cmH2O in the left and 10 cmH2O in the right atrium. The clamp was released after 5 min and the atria were observed for bleeding for 30 min. In four animals, immediate haemostasis was obtained. In one animal, both atria leaked after release of the clamp because too little fibrin glue was applied, but complete haemostasis was obtained at a second attempt. All experimental atrial defects could be sealed with fibrin glue (P = 0.03), and we believe, based on our experimental results, that fibrin glue may have a place in emergency cases to improve the management of atrial injury. In conclusion successful repair of experimental atrial rupture was performed by the use of fibrin glue.

Animals↗

A solid-phase fibrin immunoassay for the specific detection of monoclonal antibodies against different epitopic determinants of tissue-plasminogen activators.

The selective detection of hybridomas producing monoclonal antibodies against tissue-plasminogen activators (t-PA) by means of a solid-phase fibrin immunoassay (SOFIA) is described. The screening method is based on the specific and high affinity binding of t-PA for fibrin solid phase. This, as in the physiological fibrin-t-PA interaction, provides a molecular structure conserving its antigenic and functional properties. The solid-fibrin-state support is prepared by thrombin proteolysis of fibrinogen coupled to a poly-glutaraldehyde activated polyvinylchloride plate. This procedure avoids fibrinogen desorption and provides a uniform fibrin network onto which t-PA from crude extracts or purified preparations, can be specifically absorbed. The fibrin-t-PA solid-phase support is able to fix anti-t-PA antibodies which can be subsequently revealed by a second enzyme- or radiolabelled anti-mouse Ig antibody. The results demonstrate the effectiveness of the SOFIA method for the selection of hybridomas producing anti-t-PA antibodies against different epitopic determinants of t-PAs.

Animals↗

Mechanical strength in rat skin incisional wounds treated with fibrin sealant.

The biomechanical strength of skin incisional wounds of rats treated with fibrin sealant was assessed by in vitro determination of maximum tensile strength and relative failure energy. Wounds adapted without application of fibrin sealant served as control. Both types of wounds were fixed with surgical tape for the first 8 days of healing. Measurements were performed after 0, 2, 4, 8, 20, and 42 days of healing. After 2 days of healing, wounds treated with fibrin sealant possessed increased maximum tensile strength and relative failure energy. This increase corresponds to the initial strength of the fibrin sealed wounds (0 day values). After 4 and 8 days of healing, no differences were found between the sealed and unsealed groups. After 20 days, the pattern had changed showing increased tensile strength and relative failure energy in wounds not treated with fibrin sealant. A similar trend was reported after 42 days of healing. In both sealed and control wounds, an increase in strain at maximum stress during healing was most pronounced in the first 8 days. After 2 days of healing the strain at maximum stress was increased in wounds treated with fibrin sealant.

Animals↗

The effect of fibrin on cultured vascular endothelial cells.

The normal cobblestone monolayer architecture of cultured vascular endothelium becomes rapidly disorganized after contact of the cell layer with a fibrin clot. The cells of a confluent endothelial monolayer separate into individual migratory cells in 4--6 hr after contact with fibrin. The effect is reversible in that removal of the fibrin clot results in resumption of the normal morphology within about 2 hr. No other cell type tested exhibits the same change in organization when exposed to fibrin. A similar morphological change in endothelium does occur after the cell layer is overlaid with a collagen fibril gel but a gel of methylcellulose has no effect. It is proposed that the change in behavior of endothelial cells in response to contact with fibrin may represent a cellular component of fibrinolysis. The implications of this finding for the pathophysiology of disease states involving intravascular fibrin deposition are discussed.

Animals↗

Effects of tranexamic acid and local fibrin deposition of fibrinolysis and granulation tissue formation in preformed cavities.

The effects of locally deposited fibrin and of tranexamic acid-induced antifibrinolysis on forming granulation tissue were studied in the light of a recently developed method for treatment of postoperative fistulas by occlusion with a fibrin clot. Perforated teflon cylinders, either empty or fibrin-filled, were implanted subcutaneously in rats and extracted after 2 weeks. Fibrin deposition was found to stimulate granulation tissue ingrowth into the cylinders but it did not change the fibrinolytic activity in the granulation tissue. A significantly higher fibrinolytic activity was, however, found in the tissue fluid collected from the space between the granulation tissue and the implanted fibrin clot compared to tissue fluid from cylinders implanted empty. Tranexamic acid significantly reduced the fibrinolytic activity on the granulation tissue and delayed lysis of the implanted fibrin clot. It also reduced granulation tissue ingrowth but it did not abolish the positive effects of the clot on granulation tissue formation.

Animals↗

Effects of fibrin on the enhanced activation of plasminogen by urokinase and tissue plasminogen activator: role of cross-link.

When human plasma was activated by urokinase (UK) in the presence of thrombin, thrombin plus Ca++, Ca++ or in their absence and the plasmin activity was measured by the hydrolysis of S-2251, plasmin activity was higher in the presence of cross-linked or non cross-linked plasma clot. The results of similar experiments utilizing plasma after severe exercise indicated that the hydrolysis of S-2251 by plasma containing tissue plasminogen activator (t-PA) was also higher in cross-linked or non cross-linked plasma clot. Fibrinolysis was faster in thrombin-induced plasma clot, but was later shown significantly in plasma clot induced by thrombin and Ca++, whereas practically no fibrinogenolysis was shown in plasma. When Glu-plasminogen (Glu-plg) was activated by UK in the presence of cross-linked or non cross-linked fibrin and alpha 2 antiplasmin (alpha 2AP), fibrinolysis was faster in cross-linked fibrin than non cross-linked fibrin in the presence of alpha 2AP. No fibrinogenolysis was shown either. Plasmin activity measured by the hydrolysis of S-2251 was also higher in cross-linked or non cross-linked fibrin than in fibrinogen in the presence of alpha 2AP. These results indicate that enhanced activation of Glu-plg by UK or t-PA in the presence of fibrin was a more significant event than the inactivation of plasmin in the plasma clot or purified clot by alpha 2AP cross-linked to fibrin.

Calcium↗

Binding and internalization of soluble fibrin by thrombocytes.

Binding of soluble 125I-fibrin to platelets was investigated with thrombocytes separated by gelfiltration or by sedimentation as well as in a thrombocyte concentrate. Gelfiltered platelets failed to retain 125I-fibrin within 16 hours unless they had been pretreated with factor XIIIa. In addition, a 30 kDa-component derived from the N-terminal fibronectin domain was required as a mediator. Platelets isolated by sedimentation bound some 125I-fibrin even in the absence of those cofactors. The 30 kDa-component improved binding and only this increase was sensitive to putrescine inhibition. Evidently, centrifuged platelets unlike gelfiltered ones express two pathways of fibrin binding. In a thrombocyte concentrate with platelets in their plasmatic environment 125I-fibrin was partially internalized. Engulfed radioactivity was detectable only for a limited period between 4-6 hours after substrate application suggesting that 125I-fibrin was intracellularly degraded followed by release of the fragments. The 30 kDa-component promoted internalization, while factor XIIIa improved the capacity. Thrombin inhibitors suppressed the uptake.

Blood Platelets↗

Suppression of plasminogen activator inhibitor 1 release by fibrin from human umbilical vein endothelial cells.

The effect of fibrin stimulation on the fibrinolytic potential in cultured human umbilical vein endothelial cells (HUVEC) was investigated in the normal state and aged state. The amount of antigen of the two fibrinolytic factors, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), was determined using ELISA and the ABC method, respectively. When a fibrin clot was overlayered on the normal HUVEC, the secretion of t-PA or PAI-1 from the HUVEC was greatly changed. That is, PAI antigen was decreased 3-fold and t-PA antigen increased slightly in the conditioned medium. On the other hand, when the aged HUVEC were stimulated by a fibrin clot, PAI antigen was increased 3-fold and t-PA antigen did not change in the conditioned medium. When the level of fibrinolytic activity in the conditioned medium was expressed as the molar ratio of PAI and t-PA (PAI/t-PA), the value in the fibrin-stimulated normal HUVEC was markedly reduced (a 3.5-fold decrease) when compared with that of the non-stimulated normal HUVEC, reflecting a profibrinolytic state. On the other hand, the value in the fibrin-stimulated aged HUVEC was markedly increased (a 5-fold increase) when compared with that of the non-stimulated aged HUVEC, reflecting an antifibrinolytic state. Actinomycin D- or cycloheximide-treated HUVEC showed no response to the fibrin stimulation. We conclude that the level of HUVEC-mediated fibrinolytic activity was regulated mainly by the production and secretion of PAI from the HUVEC to protect against the generation of thrombi. In the aged HUVEC, the regulatory mechanism acts in an opposite manner and a thrombotic process may be induced.

Cell Survival↗

On the molecular interactions between fibrin, tissue-type plasminogen activator and plasminogen.

The molecular interactions involved in the fibrin-mediated stimulation of plasminogen activation by tissue-type plasminogen activator (t-PA) were studied using natural human plasminogen (nPlg) and rPlg-Ala740, a recombinant human plasminogen in which the catalytic site is destroyed by mutagenesis of the active site Ser740 to Ala. Using this rPlg-Ala740 moiety, the dissociation constant of the interaction between plasminogen and CNBr-digested fibrinogen was determined to be 0.40 microM. In addition, conversion of 125I-labeled single chain plasminogen to two chain plasmin by single chain recombinant t-PA (rt-PA) in the absence or the presence of CNBr-digested fibrinogen was quantitated on reduced SDS-gel electrophoresis, combined with autoradiography and radioisotope counting of gel bands. In the absence of fibrin, the activation rate of nPlg and rPlg-Ala740 by single-chain rt-PA was comparable. In the presence of fibrin, however, the activation rate of rPlg-Ala740 was about 20-fold lower than that of nPlg. These results with rPlg-Ala740 may be explained by an impaired formation of the stable cyclic ternary complex between plasminogen, t-PA and fibrin, which mediates the fibrin stimulation of plasminogen activation by t-PA or, alternatively, by impaired conversion of single chain rt-PA to two chain rt-PA at the fibrin surface.

Animals↗