Fibrin sealants

INTRODUCTION — Various electrosurgical instruments are available and are used for dissection and sealing vascular structures, while topical hemostatic agents, including fibrin sealants, are used to manage bleeding from surfaces or cavities that are not amenable to suturing, electrosurgery, or other specialized instruments (eg, argon plasma coagulator).

Fibrin sealants are two-component systems that are approved for use as hemostatics, tissue sealants, and tissue adhesives. These can be used in a variety of surgical situations. However, there are no reliable guidelines about when fibrin sealants are best used or which products are optimal for specific indications.

The use of fibrin sealants is reviewed here. The use of other topical hemostatic agents and tissue adhesives or sealants, including topical thrombin as a single-component topical agent, is discussed separately (table 1) [1,2]. (See "Overview of topical hemostatic agents and tissue adhesives".)

BACKGROUND AND PHYSIOLOGY — The search for the perfect operative sealant began in the first decade of the 20^th century. By the 1940s, fibrinogen and thrombin were combined in operative settings. Once Cohn fractionation led to the ability to generate highly concentrated fibrinogen preparations (in the 1960s), fibrin sealants were used to promote wound healing, skin grafting, and dural sealing; to provide hemostasis in microvascular surgery and parenchymal injury; and to serve as a matrix for bony chips and fragments in the repair of bone defects [3].

Fibrin sealants simulate the final stage of the clotting cascade (figure 1 and figure 2 and figure 3). (See "Overview of hemostasis".)

Fibrin sealants are a two-component system comprised of a solution of concentrated fibrinogen and factor XIII that is combined with a solution of thrombin and calcium to form a coagulum. Once combined, a fibrin clot forms in seconds, or somewhat more slowly if a more diluted form of thrombin is used. Because fibrin sealants have fibrinogen concentrations that are higher than physiologic concentrations at the site of bleeding (particularly for commercial preparations), clot formation with fibrin sealants is faster than the native coagulation process [4]. The contribution of flow to clot retraction was discovered using a microfluidic device capable of flowing human blood over a side channel plugged with collagen [5]. This device was used in one study to measure thrombus permeability and contraction in the presence of platelet binding to collagen alone or in the presence of thrombin and fibrinogen. Collagen supported formation of a 20-micrometer thick platelet layer, which retracted significantly upon cessation of flow but resulted in a 5.34-fold increase in permeability because of reconfiguration of the supporting collagen. The presence of thrombin and fibrinogen allowed isotropic contraction of platelets, creating an impermeable clot. Although not the purpose of this study, these results would seem to predict that applying a combination of thrombin and fibrinogen promotes a more hemostatic clot than using a collagen alone as a mechanical barrier to flow.

Different fibrin sealants (table 1) have different adhesive properties. In one study, the tensile strengths of four different fibrin sealants were measured [6]. Tisseel/Tissucol provided the best adhesion of a small wooden cylinder to liver cross-section in a canine model of hepatectomy. (See 'Formulations and use' below.)

Components — Fibrin sealant preparations (table 1) contain fibrinogen, thrombin, and other components such as ionized calcium, as a coagulation protein cofactor, factor XIII, fibronectin, and often, but not always, an antifibrinolytic agent (eg, aprotinin) [1,7].

Fibrinogen — Fibrinogen, which provides the adhesive and hemostatic capabilities of fibrin sealant, is the most important component. The tensile or adhesive strength of the sealant correlates directly with the fibrinogen concentration, but the presence of activated platelets, which generate contractile force through actin and myosin II fibers, increases contractile force/area to 1500 dynes/cm² compared with less than 100 dynes/cm² in a platelet-free clot [8,9].

Commercial preparations have the major advantage over locally prepared (operating room or blood bank) fibrin sealants in that they have a highly concentrated fibrinogen component that is more uniform. As an example, both Tisseel and Evicel have fibrinogen concentrations of 70 and 55 to 85 mg/mL, respectively [10,11], compared with 2.5 to 25 mg/mL for cryoprecipitate (unmanipulated). Other published methods for producing sealant generate fibrinogen levels intermediate between the cryoprecipitated and lyophilized methods. (See "Cryoprecipitate and fibrinogen concentrate".)

Thrombin — Thrombin is the other important component of fibrin sealant preparations. The rapidity of the clot formation and the tensile strength of the fibrin seal are related to the concentration of thrombin. Thrombin also activates factor XIII, which facilitates the bonding of the fibrin polymer and helps stabilize the clot [4].

●When rapid clot formation (5 to 10 seconds) is desired, thrombin concentrations of 500 to 1000 NIH units should be used (eg, Tisseel; 500 IU/mL, Evicel; 800 to 1200 IU/mL) [10,11].

●If slower clot formation is desirable (eg, in plastic surgery procedures when close approximation of tissues is sought), thrombin concentrations of 4 to 10 NIH units should be used (eg, Artiss; 4 IU/mL) [12].

Virtually all earlier fibrin sealant preparations used bovine thrombin, but this has largely been supplanted by human thrombin in currently available preparations. In addition to other benefits, use of human thrombin eliminates acquired factor V deficiency (and concomitant bleeding diathesis) that occasionally results when patients make antibodies to bovine factor V (a common contaminant of bovine thrombin) that cross-react with endogenous factor V to produce a functional deficiency of that clotting factor [13-16]. (See 'Complications' below and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)" and "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

A recombinant human thrombin preparation has been developed [17]. Results from eight clinical trials have indicated that this preparation is well tolerated in numerous surgical settings when used as a topical adjunct to hemostasis [18]. Less than 1 percent of the patients developed antibodies to human recombinant thrombin; these antibodies did not neutralize native human thrombin.

Others — The contributions of the other components are important, although in some cases controversial. Ionized calcium is critical to the action of thrombin. Factor XIII, or fibrin stabilizing factor, is felt by some to be important in the fibrin crosslinking that determines the sealant's breaking strength or mechanical properties [3,19,20]. Fortunately, most methods of preparation that isolate fibrinogen also generate adequate amounts of factor XIII.

In some preparations, or for selected indications, an antifibrinolytic agent (eg, aprotinin) is also included, presumably to prevent lysis of the clot [21,22]. Chromatographic filtering techniques can also be used to reduce the amount of plasminogen in the product, eliminating the need for an antifibrinolytic. However, antifibrinolytic agents may or may not be desirable. For certain anatomic sites (eg, the middle ear), rapid lysis of the sealant is considered essential. For this indication, antifibrinolytic agents, which can promote a tissue seal lasting three to four weeks rather than several days, would be less useful. On the other hand, for surgical procedures on tissues that have high levels of fibrinolysins (eg, prostate, lung, uterus), antifibrinolytic agents would be a valuable adjunct.

CONTRAINDICATIONS — Fibrin sealants made from donor plasma or cryoprecipitate should not be used in patients with a history of prior anaphylactic reactions to plasma products or in those with IgA deficiency. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Adverse effects and complications'.)

Fibrin sealants should never be injected intravenously or allowed to enter cell saver or cardiopulmonary bypass circuits because of the risks of thrombosis [23]. (See "Surgical blood conservation: Intraoperative blood salvage".)

FORMULATIONS AND USE — Data are limited regarding the comparative efficacy of topical hemostatic agents in clinical practice. We prefer to use a commercially prepared fibrin sealant because of its ease and timeliness of use and reliable action. When not available, a cryoprecipitate-based preparation can be used.

Some of the fibrin sealant products (eg, Tisseel, Beriplast, Biocol) have been used extensively in Europe for over 30 years. During much of this time, these products were not commercially available in the United States due to the reluctance of the Food and Drug Administration (FDA) to approve fibrinogen prepared from pooled human plasma, given the previously demonstrated increased risk of hepatitis transmission [24]. American surgeons relied on cryoprecipitate-based preparations until the first commercial fibrin sealant (ie, Tisseel) was approved for use in the United States in 1998.

Commercially prepared — Commercially prepared fibrin sealant products are most commonly used in liquid form (table 1). Other commercially available preparations include patches (eg, TachoSil, Veriset, Evarrest) and pads (eg, Fibrin Pad) that are composed of fibrin sealant combined with other hemostatic agents (eg, polyglactin, oxidized regenerated cellulose [ORC]) [25-27]. A spray-dried fibrin sealant formulation is also available (Raplixa) [28]. Patches, which are indicated for cardiovascular and hepatic surgery, obtain hemostasis faster than ORC alone. The manufacturer of Tachosil states that placement near bowel can lead to bowel obstruction from adhesion formation. A recombinant fibrinogen in a dry formulation is also under study [29,30].

Solvent (tri-n-butyl phosphate) detergent (Tween 80; ie, S-D) treatment of pooled plasma results in a fibrin sealant with predictable and measurable hemostatic/adhesive qualities and minimal infectious disease risk, as this treatment inactivates lipid-enveloped viruses [31]. One pooled human plasma fibrin sealant (Artiss) incorporates S-D treatment of the pooled human plasma that provides the source of the fibrinogen in its system [32]. One of the S-D plasma products (Octaplas) is used primarily in Europe; however, due to cost, it is not widely used in the United States.

Cryoprecipitate-based — Cryoprecipitate prepared from a single (autologous or allogeneic) donor most often serves as the fibrinogen source when commercially prepared fibrin sealants are not available or prohibited by cost.

In spite of its low (and variable) fibrinogen content, cryoprecipitate remains in use because it is readily available in most communities, needs little handling after preparation, and has the low infectious disease risk of a single-donor component. When time for planning is available, autologous cryoprecipitate can be prepared, virtually eliminating any infectious disease risk [33]. Preparation of fibrin sealant from platelet-rich or platelet-poor plasma harvested in the operating room at the start of surgery has also been described [34,35], and a commercial product (Vitagel) was approved by the US Food and Drug Administration in 2006.

Vitagel comes as a kit containing bovine collagen and thrombin as well as the materials required to obtain plasma from the patient's blood [36]. Clinical trials in cardiac, hepatic [37], general surgical, and orthopedic patients have led to its broad regulatory approval for surgical hemostasis [38]. Concern about the potential immune-mediated coagulopathy associated with bovine thrombin and the labor-intensive collection and separation of donor plasma are impediments to widespread adoption.

At institutions with special interest in fibrin sealant, alternative preparations have been evaluated, including twice-precipitated, or twice-centrifuged, or chemically modified (ammonium sulfate or polyethylene glycol [PEG]-precipitated) cryoprecipitate to enhance the fibrinogen concentration of the final product. Also, an alternative product dubbed "French glue", which contains a gelatin-resorcinol-formaldehyde-glutaraldehyde (GRFG) mixture, has excellent adhesive qualities in an animal model [39]. GRFG has been advanced to clinical use for sealing pulmonary air leaks during video-assisted thoracoscopic surgical procedures [40] and to aid repair of thoracic aortic dissection [41].

Application in the operating room — Fibrin sealant is applied very much like epoxy glue, using a two-syringe technique. When the two components (fibrinogen/factor XII and thrombin/calcium) are mixed together, a fibrin clot forms quickly at the application site [42]. In some preparations, an antifibrinolytic agent is included to prevent lysis of the clot [1,21,22]. For the various commercial products, we suggest adhering to the instructions for use contained within the packaging insert.

Commercially available preparations consist of a combination plunger, side-by-side syringes, and a dual needle-tip to facilitate even application of each component. The two components are applied simultaneously using a two-syringe technique. Tisseel and Evicel (table 1) come fully mixed and assembled in dual-syringe applicators. Prior to use, the frozen product must be thawed completely, which takes approximately 15 minutes.

When allogeneic or autologous cryoprecipitate is used as the source of fibrinogen, application devices are commercially available that contain all the essential components (side-by-side syringes, Y-connector and tubing, needle-tip or spray applicator). (See 'Cryoprecipitate-based' above.)

●In the operating room, the fibrinogen/factor XIII source (eg, cryoprecipitate) is thawed, if necessary, and drawn into one syringe, and the thrombin/calcium drawn into the other.

●Depending upon the clinical application (eg, suture line stabilization versus achieving hemostasis of a diffusely oozing surface), one would select either the needle-tip or the spray applicator.

●At the appropriate time, the contents of the syringes are simultaneously expressed and allowed to mix (in a 1:1 ratio) in either a concentrated or aerosol form, proceed to fibrin generation, and achieve hemostasis.

Fibrin sealants/glue preparations can also be used in laparoscopy but require a long dual-lumen applicator [43-45]. The application is frequently complicated by obstruction of the applicator tip. (See "Instruments and devices used in laparoscopic surgery", section on 'Devices for hemostasis'.)

The clinician must take care not to apply an overly thick layer, which can lead to infection and poor healing. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Adverse effects and complications'.)

Fibrin sealants should be gently applied near vessels and should not be injected into a vessel or allowed to enter blood salvage or cardiopulmonary bypass circuits [46]. We discontinue the use of blood-salvaging suction tips immediately before use of fibrin sealant because of the risk of thrombosis. (See "Surgical blood conservation: Intraoperative blood salvage" and "Overview of topical hemostatic agents and tissue adhesives", section on 'Adverse effects and complications'.)

EFFICACY — Much of the literature generated during the past 30 years has come from Europe, but later studies have also been performed in the United States as well as Asia. Although many early studies were anecdotal or lacking a reasonable control group, it appeared that fibrin sealant systems were effective for controlling slowly bleeding foci, diffuse oozing, bleeding from needle puncture sites, lymphatic leaks, serous fluid collections, and diffuse parenchymal organ hemorrhage [47,48].

Most fibrin sealant products shorten bleeding times in both animal and human studies, but there is little information linking the use of these products to improved patient outcomes. In the absence of an ideal measure of the effectiveness for topical hemostatic agents, attainment of hemostasis within 10 minutes of application has been the standard measure for product approval [4,49]. Other outcome measures used include operating room time, transfusion rates, and overall cost of care for surgical admissions.

Virtually every surgical discipline has found an application for fibrin sealant. Depending upon the nature of the surgery, fibrin sealant is utilized primarily for either its hemostatic, sealant, or adhesive properties.

Hemostasis — Fibrin sealant has been used to control bleeding in a variety of surgical applications (suture hole bleeding, bleeding from raw surfaces). The use of fibrin sealants appears to reduce the need for transfusion, though the effect varies widely depending upon the type of surgery. In a systematic review, the proportion of patients receiving transfusion was reduced (relative risk 0.40, 95% CI 0.26-0.61; five trials with 275 subjects), as was overall blood loss (weighted mean difference [WMD] -151.68 mL, 95% CI -251.91 to -51.46; seven trials with 391 subjects) and the number of units of blood transfused (WMD -0.56, 95% CI -0.84 to -0.29) [50].

Because the process of clot formation with fibrin sealant is independent of earlier steps in the coagulation cascade, fibrin sealants remain effective in patients with coagulation defects [4].

The use of fibrin sealants for hemostasis has been studied in the listed clinical scenarios. The efficacy for controlling bleeding from suture holes and from raw cut surfaces is reviewed in more detail below.

●Bleeding associated with cardiac, thoracic, or vascular surgery [51-56]

●Hemorrhage associated with trauma, including liver and spleen lacerations [57]

●Dental extractions in general, and in hemophiliacs [58-60]

●Burn wound debridement and skin donor harvesting [61]

●Hemostasis at cannulation sites in ECMO (extracorporeal circulating membrane oxygenation) [62]

●During orthopedic surgery, including knee and hip replacement [63-70]

●As a replacement for nasal packing in endonasal operations [71]

●Endoscopic treatment of bleeding peptic ulcers and postsphincterotomy bleeding [72-74]

●As an alternative to surgery for fistula-in-ano [75]

Suture holes — Fibrin sealant can be used to control bleeding from needle holes in vascular anastomotic sites [52,53,76,77]. In a systematic review, 19 trials were identified, mostly comparing fibrin sealant with control hemostatic measures [77]. Pooled analysis suggested that surgical sealants reduced the time to hemostasis (mean difference 243.3 seconds, 95% CI 183.9-302.5 seconds), improved hemostasis at five minutes, and were associated with less treatment failure and blood loss, and also a shorter duration of surgery.

Cut surfaces — Fibrin sealants are useful for managing bleeding from raw surfaces (eg, liver, spleen, peritoneum) and for managing smaller blood vessels that can be difficult to suture due to their location. Fibrin sealants are best studied for reducing bleeding associated with liver resection and appear to reduce blood transfusion associated with liver resection when compared with other agents (eg, oxidized regenerated cellulose) [78-81]. The liquid formulation is more commonly used; however, a fibrin sealant patch may be equally effective [78,81].

Systematic reviews have compared fibrin sealant with other topical hemostatic agents or no sealant during liver surgery [79,80]. In one of these, the time to hemostasis was reduced (mean difference -208.46 seconds, 95% CI -228.22 to -88.70), and the rate of hemostasis success was increased. There were no differences in the amount of drainage or drainage duration when comparing fibrin sealant with no fibrin sealant.

Tissue sealing and adhesion — Tissue sealants prevent the leakage of body fluids such as blood, lymph, cerebrospinal fluid (CSF), gastrointestinal contents, and air, with the aim of reducing complications. Sealants can have a hemostatic effect by functioning as a barrier preventing the leakage of blood from vessels even if they do not cause blood to clot [4]. Agents that act as tissue adhesives can be used to achieve tissue fixation and attachment, allowing for easier and more rapid performance of operative procedures.

Fibrin sealant is best studied for minimizing wound hematoma/drainage, aiding graft or flap adhesion, and promoting a seal between bowel ends that have been anastomosed. These are reviewed below.

It has also been used for sealing of dural leaks [82], promoting union of middle ear bones [83], sealing bronchopleural fistulas, as an alternative to sutures in plastic surgery [84], and providing a matrix for the repair of bony defects.

Minimizing wound hematoma/drainage — A systematic review identified 186 trials across 14 surgical specialties. Among 32 trials in nonemergency surgical specialties, the use of fibrin sealant compared with standard reduced the development of hematoma (OR 0.62, 95% CI 0.44-0.86, 24 trials) but did not reduce the risk of seroma (odds ratio 0.84, 95% CI 0.68-1.04) [85].

Fibrin sealant has also been applied during axillary and groin lymph node dissection as a means to decrease the risk for wound leakage [86-88]. In a systematic review that identified six trials comparing the use of fibrin sealant with standard care during groin dissection for malignant disease, there were no differences in the rate of seroma or postoperative wound infection between the groups [88]. Separate reviews evaluated the effectiveness of fibrin sealants for reducing postoperative drainage and seroma formation after breast cancer surgery [89,90]. Fibrin sealant did not reduce the rate of postoperative seroma (relative risk 1.14, 95% CI 0.88-1.46; 10 trials), or the volume of drainage (weighted mean difference -117.7, 95% CI 259.2-23.8 mL; five trials) [90].

Gastrointestinal anastomosis — One fibrin sealant, Tisseel, has been approved for use in the United States for prevention of anastomotic complications in colon surgery [91]. In a phase II trial (unpublished trial), 118 patients were randomly assigned to standard care (58 patients) or standard of care plus fibrin sealant (60 patients) for closure of temporary colostomy placed for traumatic colon injury. Tisseel plus standard care significantly reduced the incidence of anastomotic complications (leakage, intra-abdominal abscess, reoperation, septic shock, death) [92,93]. (See "Bowel resection techniques".)

Fibrin sealant has also been studied for efficacy in reducing pancreatic fistula following pancreatic resection [94,95]. (See "Surgical resection of lesions of the body and tail of the pancreas", section on 'Pancreatic transection and closure'.)

Graft or flap adhesion — Fibrin glue may aid in the adhesion of skin flaps or grafts placed for reconstructive or cosmetic reasons [89,96,97], or for skin grafting following burn injury [98,99].

Fibrin glue has also been used to promote adhesion of synthetic grafts used in hernia repair instead of placing sutures with similar outcomes compared with other forms of fixation [90,100,101]. (See "Laparoscopic inguinal and femoral hernia repair in adults", section on 'Mesh placement and fixation'.)

Other experimental uses — Experimental applications of fibrin sealant technology include the following:

●Fibrin sealant impregnated with antibiotics may be able to concentrate the antibiotic at the site of an infection and promote wound healing [102,103].

●It is possible that fibrin sealant could also be used for the local delivery of chemotherapeutic agents [104].

●Fibrin sealant may be used in combination with cytokines capable of promoting endothelialization of vascular grafts in vivo.

●Fibrin sealant has also been tried as a filler as a nonsurgical method to treat lumbar disc herniation [105].

COMPLICATIONS — Despite a very good safety record, there are both documented and theoretical problems associated with the use of topical hemostatic agents, including fibrin sealant. These are listed here and reviewed separately. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Adverse effects and complications'.)

●Air/gas embolism

●Hypotension  

●Surgical infection or poor wound healing

●Blood-borne disease

●Immune-mediated coagulopathy

●Anaphylaxis

SUMMARY AND RECOMMENDATIONS

●Topical hemostatic agents – Topical hemostatic agents, including fibrin sealants, are used to manage bleeding from surfaces or cavities that are not amenable to suturing, electrosurgery, or other specialized instruments (eg, argon plasma coagulator). (See 'Introduction' above and "Overview of topical hemostatic agents and tissue adhesives".)

●Fibrin sealants – Fibrin sealant preparations are a two-component system comprised mainly of a solution of concentrated fibrinogen and factor XIII, which is combined with a solution of thrombin and calcium, to form a coagulum. Clot formation with fibrin sealants is faster than the native coagulation process. Some commercial preparations include an anti-fibrinolytic agent (eg, aprotinin) to aid in clot stabilization. (See 'Components' above and 'Formulations and use' above.)

•The tensile or adhesive strength of the sealant correlates directly with the fibrinogen concentration. Commercial fibrin sealant preparations have a highly concentrated fibrinogen component that is more uniform compared with cryoprecipitate-derived preparations.

•The rapidity of the clot formation as well as tensile strength are also related to the concentration of thrombin. Higher concentrations of thrombin (500 to 100 IU/mL) should be used if rapid clot formation (5 to 10 seconds) is desired.

•Depending upon the nature of the surgery, fibrin sealants are used primarily for their hemostatic, sealant, or adhesive properties. Fibrin sealants can also be used in laparoscopy but require a long dual-lumen applicator.

●Selection and efficacy – There are no reliable guidelines about when fibrin sealants are best used or which products are optimal for specific indications. The choice of fibrin sealant should be based on the individual's preference, experience, cost, and institutional or hospital acceptance. Fibrin sealants do appear to be effective hemostatic and/or adhesive agents capable, in some settings, of contributing to a decrease in allogeneic blood exposure, but there is little information linking the use of these products to improved patient outcomes. (See 'Efficacy' above.)

●Complications – Complications of topical hemostatic agents, including fibrin sealants, include air/gas embolism, hypotension, wound healing problems, the potential for blood-borne disease, and immune-mediated coagulopathy. For those who have received bovine thrombin-based preparations and have developed anti-factor V antibodies, anaphylaxis can occur. (See "Overview of topical hemostatic agents and tissue adhesives", section on 'Adverse effects and complications'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arthur Silvergleid, MD, who contributed to an earlier version of this topic review.