Fibrin Sealants 

Fibrin Sealants – Introduction

• Fibrin sealants are topical hemostatic agents most commonly used to manage intraoperative bleeding or prevent bleeding from bodily surfaces or wounds for which suturing, electrosurgery, or other surgical methods (such as argon plasma coagulation devices) may not be appropriate or adequate⁽³⁾
• fibrin sealants (also known as fibrin glue) are classified as hemostats (allowing blood to clot), sealants (creating sealing barrier to prevent leakage of gas or liquid from structure), or adhesives (gluing together tissues)^(3,4)
  • hemostats are typically used as adjunct for hemostasis, such as in surgical procedures
  • sealants are typically used to prevent leakage, such as from colonic anastomoses
  • adhesives are typically used to adhere skin grafts to surgically prepared wounds
• fibrin sealants are useful because they provide faster clot formation than body’s own coagulation processes, and provide fibrinogen concentrations 15-25 times greater than physiologic concentrations at bleeding sites⁽²⁾
• fibrin sealants are available in several different formulations (including patches, drips, or sprays) to match clinical need⁽³⁾

Also Called

• fibrin glues
• fibrin adhesives
• topical hemostats
• topical hemostatic materials or agents

Components of Fibrin Sealants

• fibrin sealants typically consist of high concentrations of human fibrinogen with human, bovine, or recombinant thrombin
  • thrombin
    • thrombin concentrations positively correlated with
      •  time to polymerization/clot formation⁽⁴⁾
      •  time to achieve maximum adhesive strength (J Biomed Mater Res B Appl Biomater 2016 Apr;104(3):626)
    • in general, fibrin sealants with higher thrombin concentrations (such as 500-1,000 units/mL) have more rapid polymerization rates (about 15-20 seconds)⁽³⁾
    •  fibrin sealants with lower concentrations of thrombin (such as 4 units/mL) have slower polymerization rates (about 60 seconds) which allows for additional time to properly position grafts or flaps⁽³⁾
    • higher thrombin concentrations useful for circumstances requiring rapid wound sealing; lower concentrations useful for procedures requiring time and precision (such as skin grafting)⁽³⁾
  • fibrinogen concentration may be positively correlated with adhesive strength of fibrin sealant (J Biomed Mater Res B Appl Biomater 2016 Apr;104(3):626)
• some fibrin sealant products may also contain other ingredients, such as^(2,3)
  • aprotinin, antifibrinolytic agent to promote maintenance of stable fibrin clots (for example, Tisseel)
  • calcium chloride, a coagulation protein cofactor which counteracts effects of sodium citrate, a compound often added to harvested plasma to prevent clotting (for example, Evarrest)
• differences in concentrations of factor XIII and collagen in each product is also suggested to potentially affect adhesion strength⁽³⁾

Mechanism of Action

• physiologic process of hemostasis⁽¹⁾
  • tissue injury triggers process by which platelets form primary plug at the bleeding site and coagulation cascade is activated
  • human body converts unstable platelet plug into stable fibrin through primary and secondary hemostasis
  • primary hemostasis
    • vessels contract to reduce blood loss from wound; procoagulant proteins and factors are secreted
    • activated platelets form initial platelet plug in injured vascular wall, and additional platelets may be recruited in blood to form hemostatic plug which prevents hemorrhage
  • secondary hemostasis (coagulation cascade)
    • process of clot formation at site of injury follows 3 pathways: intrinsic, extrinsic, and common pathway
    • in intrinsic pathway, coagulation factor X is activated in presence of calcium and platelet-secreted phospholipid membrane
    • in extrinsic pathway, in the presence of calcium, tissue factor combines with active coagulation factor VII to form factor VII-tissue factor complex
    • in common pathway, activated factor X synthesizes fibrin in presence of calcium, platelet-secreted phospholipid membrane, and activated factor XIII; fibrin is then formed to strengthen platelet plug produced in primary hemostasis stage
• mechanism of fibrin sealants
  • fibrin sealants form hemostatic plug and matrix to help facilitate wound healing⁽²⁾
  • effect exerted at end of coagulation cascade (when fibrinogen is converted to fibrin in presence of thrombin and calcium); thrombin cleaves fibrinogen to fibrin, which serves as cross-linked scaffold for platelet aggregation and clot formation⁽²⁾
  • clot formation is purportedly enhanced or more rapid due to fibrinogen concentrations that are higher than physiologic concentrations at the site of bleeding (particularly for commercial preparations)⁽³⁾
  • thrombin also activates factor XII to help stabilize clot⁽³⁾

Indications

Head and Neck Procedures

• dental surgery such as periodontal flap closure, traumatic alveolar bone loss, and other indications⁽³⁾
• ophthalmologic procedures (such as to assist with intraocular lens fixation)⁽³⁾
• rhytidectomy and other soft tissue surgery of neck and head (Clin Otolaryngol 2017 Dec;42(6):1141)
• fibrin sealant might not reduce risk of hematoma or seroma formation that requires invasive treatment in adults having head and neck soft tissue surgery (level 2 [mid-level] evidence)
  •  based on systematic review with confidence interval that cannot exclude differences that may be clinically important
  • systematic review of 11 randomized trials evaluating fibrin sealants in 522 patients having head and neck soft tissue surgery
    • indications included rhytidectomy (5 trials), central or lateral neck dissection (3 trials), thyroidectomy (2 trials), and parotidectomy (1 trial)
    • wound drainage included closed suction drain (10 trials) and pressure bandage (1 trial)
  • comparing fibrin sealant to standard of care
    • no significant differences in
      • risk of hematomas or seroma formation requiring invasive treatment (risk ratio 0.49, 95% CI 0.22-1.07) in analysis of 11 trials with 522 patients, not significant, but CI cannot exclude differences that may be clinically important
      • adverse events (risk ratio 0.69, 95% CI 0.35-1.38) in analysis of 11 trials with 522 patients
      • retention time of drain or length of hospital stay in analysis of 3-4 trials
    • fibrin sealant associated with
      • reduced mean total drainage volume (mean difference 26.86 mL, 95% CI 43.41-10.31 mL) in analysis of 8 trials with 545 patients
  • consistent results reported in subgroup analyses by surgery type
  • Reference – Clin Otolaryngol 2017 Dec;42(6):1141

Neurosurgical Procedures

• fibrin sealants are reported to be used in neurosurgery (including spinal surgery, cranial surgery, and endoscopic endonasal/trans-sphenoidal surgery) for a variety of indications, including
  • dural sealing, such as in postoperative surgery after both cranial and spinal repair, or for cerebrospinal fluid leaks after transsphenoidal or skull base surgery (although 1 review failed to show benefit for prophylactic use after skull base repair)⁽³⁾
  • sealing of ventricular chambers (Neurosurg Rev 2022 Apr;45(2):1217)
  • sealing craniotomy edges, plate holes, and cortex, as well as general hemostasis after resection (Neurosurg Rev 2022 Apr;45(2):1217)
  • reinforcement of vascular and nerve grafts (Neurosurg Rev 2022 Apr;45(2):1217)
  • noted to be more effective in a dry field and better at preventing bleeding compared to stopping bleeding (Neurosurg Rev 2022 Apr;45(2):1217)

Cardiac and Vascular Surgery

• cardiac and cardiovascular surgery
  • use of topical sealants
    • although topical sealants should not be used routinely (EACTS/EACTA Class IIb, Level C), they may be considered for persistent bleeding problems that are more local than global
    • Reference – European Association for Cardio-Thoracic Surgery (EACTS) and the European Association of Cardiothoracic Anaesthesiology (EACTA) guidelines on blood management for adult cardiac surgery (Eur J Cardiothorac Surg 2018 Jan 1;53(1):79)
  • fibrin sealants associated with decreased blood loss compared to standard surgical hemostatic control in adults having vascular or cardiac surgical procedure (level 2 [mid-level] evidence)
    •  based on systematic review limited by heterogeneity
    • systematic review of 21 studies (13 randomized trials, 5 retrospective, and 3 prospective cohort studies) comparing fibrin- or thrombin-based sealant vs. active or standard surgical hemostatic control in 7,622 patients > 17 years old having major open vascular or cardiac surgical procedure
    • fibrin sealants used varied including Evicel, Tachosil, Vivostat, or unspecified; most common control used was manual compression or surgical swabs
    • patients having percutaneous intervention or pacemaker placement were excluded
    • sealant associated with (all results limited by significant heterogeneity)
      • shorter time to hemostasis (mean difference -2.52 minutes, 95% CI -3.96 to -1.09 minutes) in analysis of 4 trials with 649 patients
      • decreased total blood loss at ≤ 48 hours after surgery (mean difference -144.25 mL, 95% CI -177.46 to -111.03 mL) in analysis of 9 studies (5 trials and 4 cohort studies) with 3,636 patients
      • increased successful hemostasis in analysis of 8 trials with 1,340 patients
        • risk ratio 1.81 (95% CI 1.27-2.59)
        • NNT 2-9 with successful hemostasis in 44% of control group
    • no significant differences in
      • need for blood transfusion in analysis of 6 studies (4 trials and 2 cohort studies) with 2,075 patients, results limited by significant heterogeneity
      • reoperation due to bleeding in analysis of 7 studies (4 trials and 3 cohort studies) with 4,877 patients
      • 30-day mortality in analysis of 6 studies (4 trials and 2 cohort studies) with 4,810 patients, results limited by significant heterogeneity
    • postoperative adverse events reported in 8 trials and 1 cohort study include hemothorax, wound infection, mediastinitis, stroke, shock, sepsis, myocardial infarction, renal failure, respiratory insufficiency, atrial flutter, pleural effusion, and mild pyrexia
    • Reference – Eur J Vasc Endovasc Surg 2020 Sep;60(3):469full-text
• anastomoses in vascular surgery
  • sealants may reduce time to hemostasis and reduce risk of failure to control anastomotic bleeding compared to standard care in patients having vascular surgery with creation of anastomosis (level 2 [mid-level] evidence)
    •  based on Cochrane review of trials with methodologic limitations
    • systematic review of 24 randomized trials comparing fibrin or synthetic sealant vs. standard care in 2,376 patients who had creation of anastomosis during vascular surgery
      • types of sealants and follow-up duration not reported
      • standard care included oxidized cellulose, gelatin sponge, or manual compression
    • all trials had ≥ 1 methodologic limitation including unclear allocation concealment and lack of blinding of patients, clinicians, or outcome assessors
    • sealants associated with
      • shorter mean time to hemostasis (mean difference -230 seconds, 95% CI -329 to -131 seconds) in analysis of 7 trials with 498 patients
      • reduced risk of failure to control anastomotic bleeding within 30 minutes in analysis of 17 trials with 2,120 patients
        • risk ratio 0.46 (95% CI 0.35-0.61)
        • NNT 5-8 with failure of hemostatic intervention in 33% of standard care group
      • increase in likelihood of achieving hemostasis at 4 minutes, 5 minutes, or 10 minutes in analysis of 2-4 trials with 254-623 patients
      • nonsignificant reduction in operating time (mean difference -18.72 minutes, 95% CI -40.18 to +2.73 minutes) in analysis of 4 trials with 436 patients
      • nonsignificant reduction in risk of postoperative bleeding up to 30 days (risk ratio 0.78, 95% CI 0.59-1.04) in analysis of 9 trials with 1,216 patients
    • no significant differences in intraoperative blood loss or 30-day risk of unplanned return to operating room for bleeding complications in analyses of 3-8 trials
    • Reference – Cochrane Database Syst Rev 2024 May 2;5(5):CD013421
  • compared to control hemostatic measures, use of surgical sealants as adjunct to arterial-to-prosthetic graft anastomoses may reduce suture-hole bleeding and decrease time to hemostasis (level 2 [mid-level] evidence)
    • based on systematic review limited by clinical heterogeneity and without assessment of allocation concealment
    • systematic review of 19 randomized trials evaluating use of various types of surgical sealants as adjunct after arterial anastomoses vs. control hemostatic measures in 1,560 patients
      • all patients had continuous sutured vascular anastomosis between artery and prosthetic graft or vein requiring tissue adhesive to seal anastomosis
      • 12 studies randomized all patients to use of surgical sealant; 7 studies randomized those with suture-hole bleeding at time of clamp release
      • studies varied in
        • type of surgical sealant used, which included fibrin sealants (14 studies), and gelatin-resorcin-formol, polyethylene glycol, bovine gelatin and thrombin, cyanoacrylate, or bovine serum albumin/polyaldehyde (1 study each)
        • control hemostatic measures, which included ≥ 1 of manual compression (9 studies), gelatin and thrombin (5 studies), and oxidized cellulose (2 studies); unspecified/multiple methods (3 studies)
    • comparing surgical sealants to control treatment, surgical sealant associated with
      • shorter time to anastomotic hemostasis (mean difference [MD] 243.26 seconds, 95% CI 184 to 303 seconds; p < 0.001) in analysis of 16 studies, results limited by significant heterogeneity
      • improved likelihood of hemostasis at 5 minutes (odds ratio 4.5, 95% CI 2.59 to 7.81 minutes; p < 0.001) in analysis of 9 studies, results limited by significant heterogeneity
      • lower likelihood of treatment failure (lack of hemostasis at 10 minutes) in analysis of 7 studies (odds ratio 3.2, 95% CI 1.78 to 5.75 minutes; p < 0.05), results limited by significant heterogeneity
      • reduction in operative blood loss (MD 14.26 mL, 95% CI 2.38 to 26.15 mL; p < 0.001) in analysis of 6 studies, results limited by significant heterogeneity
      • reduction in duration of surgery (MD 9.85 minutes, 95% CI 2.37 to 17.34 minutes; p < 0.05) in analysis of 5 studies
    • Reference – Br J Surg 2016 Dec;103(13):1758
• peripheral vascular surgery
  • Vistaseal, Evicel, and Tisseel fibrin sealants each associated with improved hemostasis compared to manual compression in adults having peripheral vascular surgery (level 3 [lacking direct] evidence)
    •  based on network meta-analysis of nonclinical outcomes from trials with unclear blinding of outcome assessors
    • systematic review and network meta-analysis of 5 randomized trials evaluating fibrin sealants among each other and compared to other methods of hemostasis in 693 adults having peripheral vascular surgery
    • all patients received heparin during surgical procedure; most common surgery was bypass grafting
    • fibrin sealant treatment arms were stratified by clotting time (2 minutes [2C] or 1 minute [1C])
    • primary outcome was proportion of patients achieving hemostasis by 4 minutes after treatment application
    • meta-analysis used Bayesian methods with uncertainty of effects expressed by 95% credible intervals (CrI)
    • in network meta-analysis including indirect comparisons
      • compared to manual compression, improved hemostasis by 4 minutes associated with
        • Vistaseal 2C (relative risk [RR] 2.67, 95% CrI 2.13-3.34)
        • Evicel 1C (RR 2.58, 95% CrI 2.04-3.23)
        • Vistaseal 1C (RR 2, 95% CrI 1.45-2.65)
        • Tisseel 2C (RR 1.99, 95% CrI 1.48-2.6)
      • Vistaseal 2C associated with improved hemostasis by 4 minutes compared to
        • Tisseel 1C (RR 1.9, 95% CrI 1.18-3.74)
        • Tisseel 2C (RR 1.34, 95% CrI 1.05-1.77)
        • Vistaseal 1C (RR 1.33, 95% CrI 1.02-1.82)
      • no significant difference in hemostasis by 4 minutes comparing
        • Tisseel 1C to manual compression
        • Vistaseal 2C to Evicel 1C
    • adverse events reported in 4 trials
      • nonserious adverse event possibly related to fibrin sealant in 0.5%-2%
      • serious adverse event possibly related to fibrin sealant in 0% -1.2%
    • consistent results in analyses for hemostasis achieved by 10 minutes
    • Reference – Ann Med Surg (Lond) 2021 Jan;61:161full-text
    • CLINICIANS’ PRACTICE POINT: The extent to which decreasing time to hemostasis (either at 4 minutes or at 10 minutes) affects clinical or patient-oriented outcomes has yet to be fully elucidated.

Pulmonary and Breast Procedures

• seroma prevention (breast surgery), although this is controversial and there are reports of increased seroma formation after mastectomy or other breast procedures, possibly related to variations in technique (⁽³⁾, BMC Infect Dis 2020 Jun 20;20(1):430, Ann Plast Surg 2020 Jul;85(S1 Suppl 1):S41)
• noncardiac thoracic surgery (³, Pharmacotherapy 2013 Sep;33(9):935)

Abdominal Procedures

Common Indications

• colonic/intestinal anastomosis
  • intestinal anastomoses coated or reinforced with fibrin sealant or collagen-based laminar biomaterial may decrease rate of postoperative anastomotic leakage, major surgical complications, reoperation rate, and length of stay (level 2 [mid-level] evidence)
    • based on systematic review of observational studies and randomized trials with allocation concealment not described
    • systematic review of 15 studies comparing intestinal anastomosis coated or reinforced with collagen-based laminar biomaterial or fibrin sealant vs. control (intestinal anastomoses not coated or reinforced with product) in 3,630 patients having intestinal surgery
      • studies included 5 randomized trials, 3 nonrandomized interventional studies, 4 retrospective cohort studies, 2 prospective cohort studies, 1 abstract
      • all patients had surgery requiring the creation of an intestinal anastomosis
      • intestinal surgery indications included for malignant tumors (such as colorectal cancer), benign lesions (such as diverticulitis, inflammatory bowel disease), or morbid obesity (bariatric surgery)
    • comparing coated or reinforced intestinal anastomosis vs. control
      • coated or reinforced intestinal anastomosis associated with
        • lower rate of postoperative anastomotic leakage in analysis of 14 studies in 3,024 patients
          • odds ratio [OR] 0.37 (95% CI 0.27-0.52)
          • NNT 15-22, with anastomotic leakage in 10% of control group
        • lower postoperative reoperation rate in analysis of 7 studies with 1,068 patients
          • OR 0.21 (95% CI 0.1-0.47)
          • NNT 19-33, with postoperative reoperation in 6% of control group
        • lower incidence of postoperative major complications (according to Clavien-Dindo classification) in analysis of 2 studies in 833 patients
          • OR 0.54 (95% CI 0.35-0.84)
          • NNT 10-44, with postoperative major complications in 17% of control group
        • shorter length of hospitalization (weighted mean difference -1.96, 95% CI -3.21 to -0.71) in analysis of 7 studies, results limited by significant heterogeneity
      • no significant difference in postoperative mortality rate
    • Reference – Front Surg 2022;9:882173full-text
• hernia repair (such as open inguinal hernia repair, ventral hernia repair)⁽³⁾
  • fibrin glue (fibrin sealant) and staple for mesh fixation may have similar hernia recurrence, seroma or hematoma formation, and operating time in patients having laparoscopic transabdominal preperitoneal (TAPP) repair of inguinal hernia (level 2 [mid-level] evidence)
    •  based on systematic review of trials with statistical limitations
    • systematic review of 10 studies (4 randomized trials and 6 observational studies) comparing fibrin glue (fibrin sealant) vs. staple for mesh fixation in 9,067 patients having laparoscopic TAPP repair of inguinal hernia
    • follow-up ranged from 6 to 12 months in randomized trials and 1 to 40 months in observational studies
    • in analysis of randomized trials, no significant differences in
      • hernia recurrence (odds ratio 2.1, 95% CI 0.61-7.22) in analysis of 4 trials with 430 patients, but CI includes possibility of benefit or harm
      • seroma or hematoma formation (odds ratio 0.55, 95% CI 0.27-1.14) in analysis of 3 trials with 341 patients, analysis included 2 trials with CI that includes possibility of benefit or harm and 1 trial with CI that includes differences that may not be clinically important
      • operating time (standardized mean difference 0.8, 95% CI -0.34 to +1.94) in analysis of 4 trials with 430 patients, results limited by significant heterogeneity
    • adverse events not reported
    • Reference – Surg Endosc 2017 Feb;31(2):527
• pancreatic fistula prevention
  • fibrin sealant to reinforce pancreatic stump closure after distal pancreatectomy may not reduce risk of pancreatic fistula and might increase risk of postoperative morbidity (level 2 [mid-level] evidence)
    •  based on Cochrane review with wide confidence intervals
    •  systematic review of 12 randomized trials comparing fibrin sealant (fibrin glue or fibrin sealant patch) vs. control (no fibrin sealant or placebo) in 1,602 patients having pancreatic surgery
    •  7 trials evaluated fibrin sealants to reinforce pancreatic stump closure after distal pancreatectomy
    • comparing fibrin sealant to no fibrin sealant at 30 days
      • no significant differences in
        •  postoperative pancreatic fistula (risk ratio [RR] 0.96, 95% CI 0.68-1.35) in analysis of 4 trials with 755 patients, CI includes possibility of benefit or harm
        •  postoperative mortality (odds ratio 0.52, 95% CI 0.05-5.03) in analysis of 6 trials with 804 patients
        •  reoperation rate (RR 0.51, 95% CI 0.15-1.71) in analysis of 2 trials with 376 patients
      •  fibrin sealant associated with nonsignificant increase in risk of overall postoperative morbidity (RR 1.23, 95% CI 0.97-1.58) in analysis of 3 trials with 646 patients, CI includes both clinically important and unimportant differences
    •  Reference – Cochrane Database Syst Rev 2020 Mar 11;3:CD009621full-text
  • fibrin sealant for pancreatic anastomosis reinforcement after pancreaticoduodenectomy may not reduce risk of postoperative pancreatic fistula (level 2 [mid-level] evidence); insufficient evidence to assess effect of fibrin sealant for pancreatic duct occlusion on risk of fistula
    •  based on Cochrane review with wide confidence intervals
    •  systematic review of 12 randomized trials comparing fibrin sealant (fibrin glue or fibrin sealant patch) vs. control (no fibrin sealant or placebo) in 1,602 patients having pancreatic surgery
    • 4 trials evaluated fibrin sealants for pancreatic anastomosis reinforcement after pancreaticoduodenectomy
    • comparing fibrin sealant for pancreatic anastomosis reinforcement to no fibrin sealant at 30 days
      • no significant differences in
        • postoperative pancreatic fistula (risk ratio [RR] 1.14, 95% CI 0.28-4.69) in analysis of 2 trials with 199 patients, CI includes possibility of benefit or harm
        •  postoperative mortality (odds ratio 0.26, 95% CI 0.05-1.32) in analysis of 4 trials with 393 patients
        •  postoperative morbidity (RR 1.04, 95% CI 0.87-1.24) in analysis of 3 trials with 323 patients
        •  reoperation rate (RR 0.74, 95% CI 0.33-1.66) in analysis of 3 trials with 323 patients
      • serious adverse events not reported
    • 2 trials with 351 patients evaluated fibrin sealants for pancreatic duct occlusion after pancreaticoduodenectomy
      • postoperative pancreatic fistula not reported in either trial
      • no significant differences comparing fibrin sealant to no sealant in 30-day mortality, morbidity, or reoperation in analysis of both trials
      •  diabetes mellitus at 12 months in 33.7% with fibrin sealant vs. 14.5% with no fibrin sealant (no p value reported) in 1 trial with 169 patients
    •  Reference – Cochrane Database Syst Rev 2020 Mar 11;3:CD009621full-text
• hepatic surgery
  • fibrin sealant may reduce time to hemostasis, but not risk of blood transfusion or bile leak in adults having hepatic surgery or transplantation (level 2 [mid-level] evidence)
    •  based on systematic review of trials limited by clinical and statistical heterogeneity
    • systematic review of 22 studies (16 randomized trials, 5 retrospective cohort studies, and 1 case-control) comparing carrier-bound fibrin sealant vs. control in 2,468 adults having open or laparoscopic hepatic surgery or transplantation
    • carrier-bound fibrin sealants (defined as products/devices containing fibrinogen, coagulation factors such as thrombin, and anti-thrombolytic agents plus matrix components) included matrix with fibrin and thrombin in 11 studies, matrix with fibrin only in 1 study, and matrix with thrombin only in 1 study
    • control varied across studies and included simple (manual) compression or other types of topical hemostatic agent (matrix for endogenous coagulation including collagen, cellulose, or gelatin without active components such as thrombin)
    • carrier-bound fibrin sealant associated with reduced time to hemostasis (mean difference -2.33 minutes, 95% CI -3.52 to -1.15 minutes) in analysis of 5 studies with 429 patients, results limited by significant heterogeneity
    • no significant differences in risks of
      • receiving blood transfusion in analysis of 4 studies with 354 patients
      • postoperative collection requiring intervention in analysis of 3 studies with 298 patients
      • bile leak in analysis of 9 studies with 708 patients, results limited by significant heterogeneity
    • Reference – J Hepatobiliary Pancreat Sci 2016 Oct;23(10):609
  • fibrin sealant may not reduce risk for blood transfusion in patients having liver resection (level 2 [mid-level] evidence)
    •  based on Cochrane review of trials with methodologic limitations
    •  systematic review of 67 randomized trials evaluating methods to reduce blood loss during liver resection in 6,197 patients
    •  17 trials evaluated fibrin sealant
    •  all trials assessing risk of blood transfusion with fibrin sealant compared to control had unclear allocation concealment or no blinding of outcome assessors
    • comparing fibrin sealant to control, no significant differences in
      •  blood transfusion in analysis of 2 trials with 392 patients
      •  perioperative mortality in analysis of 2 trials with 380 patients
      •  serious adverse events in analysis of 3 trials with 457 patients
    •  comparing fibrin sealant plus collagen vs. control, no significant differences in blood transfusion, perioperative mortality, and serious adverse events in 1 trial with 300 patients
    • comparing fibrin sealant to oxidized cellulose, no significant differences in
      •  blood transfusion in 1 trial with 30 patients
      •  perioperative mortality in 1 trial with 50 patients
      •  serious adverse events in 2 trials with 80 patients
    •  comparing fibrin sealant to cyanoacrylate, no significant differences in blood transfusion and serious adverse events in 1 trial with 30 patients
    •  effect on blood transfusion not evaluated in trials comparing fibrin sealant to collagen or argon beam
    •  Reference – Cochrane Database Syst Rev 2016 Oct 31;(10):CD010683
• bariatric surgery
  • fibrin sealant may reduce risk of postoperative bleeding in adults having bariatric surgery (level 2 [mid-level] evidence)
    • based on systematic review with confidence interval that includes differences that may not be clinically important
    • systematic review of 9 randomized trials evaluating fibrin sealants in 2,136 adults with obesity having bariatric surgery
      • mean age ranged from 35 to 44 years across trials
      • body mass index ranged from 42 to 49 kg/m²across trials
    • surgery included laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass
    • fibrin sealants used included Tisseel or Tissucol fibrin in 5 trials, Evicel fibrin sealant in 2 trials, Tachosil fibrin sealant patch in 1 trial, and Floseal in 1 trial; control methods to which they were compared varied including no reinforcement, suture reinforcement, continued oversewing, and/or other adhesive materials applied
    • comparing fibrin sealant to no reinforcement
      • fibrin sealant associated with reduced risk of postoperative bleeding in analysis of 7 trials with 1,555 patients, significant, but CI includes differences that may not be clinically important
        • risk ratio (RR) 0.42 (95% CI 0.18-0.97)
        • NNT 43-1,150 with bleeding in 2.9% of control group
      • no significant differences in
        • postoperative leakage (RR 0.93, 95% CI 0.39-2.22) in analysis of 6 trials with 1,455 patients
        • gastric stricture (RR 1.25, 95% CI 0.52-3.02) in analysis of 5 trials with 1,406 patients
        • length of hospital stay, total operation time, or reoperation rate in analysis of 4-6 trials
    • comparing fibrin sealant to suture reinforcement, no significant differences in bleeding or leakage in analysis of 4 trials with 678 patients
    • Reference – Obes Surg 2021 Mar;31(3):1158

Other Reported Indications

• perianal fistula, where it has been reported to close some fistulas without the need for surgery (⁽³⁾, Surg Innov 2022 Feb;29(1):50)
• splenic injuries (Pharmacotherapy 2013 Sep;33(9):935)
• closure of colostomies (Pharmacotherapy 2013 Sep;33(9):935)
• urologic surgery (Pharmacotherapy 2013 Sep;33(9):935)
• pancreatic surgery⁽³⁾
• renal surgery⁽³⁾

Orthopedic Procedures

• joint replacement surgery (including total knee arthroplasty)
  • topical fibrin sealants may be associated with decreased need for blood transfusion and total blood loss in patients after total hip arthroplasty (level 2 [mid-level] evidence)
    • based on systematic review limited by clinical heterogeneity
    • systematic review of 7 randomized trials comparing topical fibrin sealant to placebo after total hip arthroplasty in 679 patients (mean age 60-75.1 years)
    • all patients received 5-10 mL of topical fibrin sealant (all of which were either noncommercialized and/or not made in the United States)
    • trials varied in product used and its origin (autologous blood vs. commercialized product)
    • compared to no fibrin sealants, topical fibrin sealant associated with
      • decreased need for transfusion in analysis of 5 trials with 336 patients
        • risk ratio 0.69 (95% CI 0.48-0.99; p = 0.05)
        • NNT 8-385 with transfusion needed in 26% of controls (patients not treated with fibrin sealant)
      • reduction in
        • total blood loss in analysis of 4 trials with 295 patients (mean difference [MD] 137.66 mL, 95% CI 212.11-63.20; p = 0.0003)
        • blood loss after drainage in analysis of 3 trials in 190 patients (MD 43.79, 95% CI 71.47-16.11; p = 0.002)
        • intraoperative blood loss in analysis of 4 trials in 156 patients (not significant)
    • topical fibrin sealants did not help prevent postoperative anemia in analysis of 2 trials in 142 patients (p = 0.06)
    • no significant differences in occurrence of deep vein thrombosis, fever, pain, anemia, hematoma, and oozing in analyses of 1-3 trials each; however, data too limited to adequately assess most of these parameters
    • Reference – Sci Rep 2018 Jan 8;8(1):78full-text
  • bone repair (Pharmacotherapy 2013 Sep;33(9):935)
  • trauma (such as laceration management)⁽³⁾

Skin Grafting

• fibrin tissue sealant may slightly improve rate of complete engraftment at 1 week or wound closure at 1 month compared to standard care in patients requiring skin graft (level 2 [mid-level] evidence)
  • based on systematic review limited by clinical heterogeneity
  • systematic review of 7 studies (3 randomized trials, 2 prospective cohort studies, and 2 case-controls) comparing fibrin tissue sealant vs. standard care in 538 patients requiring 751 skin grafts
    • population included patients with burns in 5 studies, chronic leg ulcers in 1 study, upper and lower extremity defects from pedestrian or bike accidents in 1 study, or reconstructive wounds from skin cancer excision in 1 study
    • standard care included staples in 5 studies, sutures in 2 studies , and no adhesive was specified in 1 study
  • no significant differences in
    • rate of 100% engraftment at 1 week (odds ratio [OR] 1.45, 95% CI 0.95-2.2, p = 0.086) in analysis of 7 studies with 404 patients, but CI cannot exclude differences that may be clinically important
    • rate of complete wound closure by 1 month in analysis of 7 studies with 501 patients
    • risk of hematoma or seroma in analysis of 7 studies with 443 patients
    • risk of infections in analysis of 7 studies with 540 patients
  • Reference – J Plast Reconstr Aesthet Surg 2019 Jun;72(6):871

Contraindications and Precautions

Contraindications

• general contraindications of all fibrin sealants include
  • history of or potential hypersensitivity to fibrin sealants
    • some fibrin sealants contain additional components that are associated with hypersensitivity, such as
      • those that include animal components (such as horse protein)
      • those that include aprotinin (which is associated with anaphylactic reactions)
  • injecting directly into circulatory system, intravascularly, or into highly vascularized tissues, as may cause life-threatening thromboembolic events
  •  patches should not be used to treat bleeding from large defects in arteries or veins due to risk of thromboembolic events
  • References – ⁽³⁾, FDA DailyMed 2019 Dec 17 (Evicel), FDA DailyMed 2022 Dec 12 (Evarrest), FDA DailyMed 2022 Aug 9 (Tachosil), FDA DailyMed 2019 Dec 26 (Tisseel), FDA DailyMed 2022 Jun 9 (Artiss), FDA Label 2015 May (Raplixa), FDA DailyMed 2022 Dec 12 (Vistaseal)

Precautions

• general precautions and complications of fibrin sealants may include
  • risk of transmitting infectious diseases (such as Creutzfeldt-Jakob disease, viral hepatitis) because products contain human plasma⁽³⁾
  • risk of thrombosis if fibrin sealant enters cell saver or cardiopulmonary bypass circuits⁽³⁾
  • risk of thrombosis, hypotension, and death if injected intravascularly⁽³⁾
  • impaired wound healing if sealant application thickness is excessive⁽³⁾
  • increased risk of infection as fibrin protein is a potential bacterial growth medium⁽³⁾
  • increased risk of tissue necrosis from application of thick layer of fibrin sealant (due to diffusion of nutrients and fibroblast ingrowth)⁽³⁾
  • patch-specific precautions
    • do not apply to contaminated areas as may increase susceptibility to infection
    • use least amount of patches required to cover entire bleeding area
    • do not overpack, which may lead to migration of excess material
    • References – FDA DailyMed 2022 Dec 12 (Evarrest), FDA DailyMed 2022 Aug 9 (Tachosil)
  • spray/liquid-specific precautions
    • avoid use in treatment of severe or brisk arterial bleeding
    • carry risk of air or gas emboli when air from gas powered spray applicator enters central veins; risk is particularly high when used at higher than recommended pressures or with shorter separation distance; therefore, operate only according to manufacturer’s instructions
    • References – ⁽³⁾, FDA DailyMed 2019 Dec 17 (Evicel), FDA DailyMed 2019 Dec 26 (Tisseel), FDA DailyMed 2022 Dec 12 (Vistaseal), FDA Label 2015 May (Raplixa)

Products Available for Use

Overview

• fibrin sealants may be prepared from cryoprecipitate-based blood products, autologously obtained blood products, or as self-contained commercial products (from human pooled plasma)
• platelet-rich fibrin, autologous platelet therapy that combines fibrin with platelets rather than thrombin, is used mainly to enhance tissue healing, may be prepared from centrifuged whole blood

Fibrin Sealant Products Commercially Available in the United States

• fibrin sealants are available commercially in the United States as patches and sprays or drips

Table

Table 1: Available Hemostat Fibrin Sealant Products

Citation: Abbreviations: BAC2, biological active component 2; N/A, not applicable; ORC, oxidized regenerated cellulose.* Hemostats are generally FDA approved as adjunct to hemostasis for bleeding not controlled by standard techniques (such as sutures, ligatures, or cautery) in patients having surgery.** All commercially available fibrin sealants contain thrombin and fibrinogen and are made from pooled human plasma.*** Some fibrin sealant products may denature when exposed to alcohol, iodine, or heavy metals. If any of these are used to clean wound area, thoroughly rinse and dry area before application of fibrin sealant.Reference -FDA DailyMed 2019 Dec 17FDA DailyMed 2022 Dec 12FDA DailyMed 2022 Aug 9FDA DailyMed 2019 Dec 26FDA Label 2015 May PDFFDA Product Information 2024 SepFDA Supplement Approval 2024 Sep 27

Table

Citation: * All commercially available fibrin sealants contain thrombin and fibrinogen and are made from pooled human plasma.** Some fibrin sealant products (including Artiss and Tisseel) may denature when exposed to alcohol, iodine, or heavy metals. If any of these are used to clean wound area, thoroughly rinse and dry area before application of fibrin sealant.Reference -FDA DailyMed 2019 Dec 26FDA DailyMed 2022 Jun 9

Cryoprecipitate-based Preparations

• cryoprecipitate is a blood product derived from plasma
  • cryoprecipitate is prepared by slowly thawing fresh frozen plasma, forming precipitate high-molecular-weight proteins, and then centrifuged to remove supernatant
  • resulting product is resuspended in plasma and contains fibrinogen, Factors VIII and XIII, von Willebrand factor, and fibronectin
  • Reference – Blood Coagul Fibrinolysis 2021 Mar 1;32(2):87, Br J Anaesth 2014 Dec;113(6):922
• cryoprecipitate may be used during trauma resuscitation, surgery, and other major bleeding events to replenish fibrinogen levels in patients with acquired coagulopathy (fibrinogen replacement therapy) (Br J Anaesth 2014 Dec;113(6):922)
• cryoprecipitate has also been leveraged for its fibrinogen content to make hemostatic surgical adhesive to bind sutures together when used together with calcium and thrombin; typically applied on areas that require hemostasis, where suturing may be ineffective or impractical and where the injury is slow to clot (for example, raw surface of traumatically injured liver) (Fung MK, Grossman, BJ, Hilyer CD, Westhoff, CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014)
• noncommercial fibrin sealants may be extemporaneously prepared with cryoprecipitate serving as the source of fibrinogen
  • thrombin component sourced from either commercial sources of thrombin (such as bovine thrombin) or automated devices for production of thrombin from single donor plasma
  • resulting concentration of fibrinogen around 20 g/L, and resulting concentration of thrombin around 50-60 units/mL
  • time to formation of fibrin clot (upon mixture with thrombin) about 2-10 seconds
  • advantages
    • eliminates risk of transmission of infectious agents, especially if autologous
    •  may result in higher tensile strength than with other methods
  • disadvantages
    • may not be suitable in patients who cannot give blood (such as patients with coagulation disorders)
    • requires advanced planning, so likely not suitable for patients requiring emergency procedures
    • contains relatively low concentration of fibrinogen, resulting in weaker clot strength compared to commercial fibrin sealants (which have higher fibrinogen concentrations)
  •  virus-inactivated allogeneic sealant or autologous fibrin sealant products and kits (such as Cryoseal or Vivostat systems, the latter not available in the United States) may be preferred over cryoprecipitate due to improved safety and efficacy for topical use (American Red Cross. A Compendium of Transfusion Practice Guidelines. American Red Cross 2021 PDF)
  • References – Transfus Apher Sci 2011 Dec;45(3):305, Fung MK, Grossman, BJ, Hilyer CD, Westhoff, CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014

Platelet-rich Fibrin Preparations

• CLINICIANS’ PRACTICE POINT: Although platelets are traditionally considered solely responsible for clotting, they also play a role in healing. The growing use of platelet-rich fibrin, often in the form of fibrin matrix gelatinous clots, may initially sound as if it is a form of fibrin sealant. In some ways this may be true, but the primary use for platelet-rich fibrin is to enhance wound or injury recovery.
• platelet-rich fibrin (PRF) is an autologous platelet therapy (Facial Plast Surg Clin North Am 2019 Aug;27(3):331)
• PRF involves placement of a fibrin clot directly onto a wound, but is primarily used to enhance tissue or wound regeneration and healing through the direct application of growth factors (Dent Clin North Am 2020 Apr;64(2):291)
• PRF is prepared by centrifuging whole blood without any additives (including anticoagulants), which allows for formation of a fibrin matrix gelatinous clot, allowing for delayed release of contents and confining growth factor secretion to the clotting site (Facial Plast Surg Clin North Am 2019 Aug;27(3):331, Dent Clin North Am 2020 Apr;64(2):291)
• mechanism of action of PRF during injury/wound healing
  • targeted release of growth factors and secretion of coagulation factors from platelets combined with stimulation of fibroblast proliferation and gene expression work to promote type I collagenesis and tissue regeneration
  • blood components that promote wound healing are suspended in the fibrin matrix for preservation and slow release during healing
  • during surgery and injections, PRF enhances body’s natural regenerative processes by recruiting and stimulating macrophages and also mesenchymal stem cells (MSC) cells, which give rise to tissues such as bone, cartilage, adipose
  • leukocytes present within PRF secrete signaling factors that stimulate further tissue repair and MSC cell recruitment
  • Reference – Facial Plast Surg Clin North Am 2019 Aug;27(3):331, Dent Clin North Am 2020 Apr;64(2):291
• centrifuge duration and speed provides for 2 types of PRF
  • injectable PRF (clot formation occurs around 15 minutes after centrifugation), known as I-PRF
    • prepared at higher centrifugation force for less time, providing a suspension that lacks anticoagulants
    • allows formation of slow release matrix that can be applied to tissue
    • may be injected into deep tissue spaces, onto open wounds, or mixed with other graft materials to create “sticky bone”
  • PRF that coagulates during centrifugation, known as A-PRF
    • a solid-like PRF that contains a higher concentration of leukocytes (due to slow centrifugation) and a more porous fibrin matrix (which allows for greater release of contents and more blood vessel penetration during angiogenesis)
    • may be shaped into pellets, cut into smaller pieces (which may be useful for bone grafting), or pressed flat and used as membrane
    • may be used when biological membrane or physiologic glue is required
  • References – Facial Plast Surg Clin North Am 2019 Aug;27(3):331, Dent Clin North Am 2020 Apr;64(2):291
• clinical uses reported include
  • bone grafting (such as in oral and maxillofacial surgery)
  • muscle repair and regeneration (such as in orthopedic and sports injuries)
  • cartilage grafting (such as in cartilage injuries)
  • rotator cuff repair
  • Reference – Medicina (Kaunas) 2019 May 15;55(5):141full-text
• other uses include fistula repairs (such as perianal fistula)
  •  persistent fistula closure reported in 67% of patients at median 2-year follow-up after surgical treatment with tract sealed with platelet-rich fibrin (level 3 [lacking direct] evidence)
    • based on case series
    • 60 patients (mean age 47 years, 68% male) with perianal fistula who were treated surgically with tract sealed with platelet-rich fibrin through catheter between 2010 and 2013 were evaluated at a median follow-up of 24 months
      • patients were included if they had single-tract transsphincteric perianal fistula (middle or high), low transsphincteric perianal fistula, suprasphincteric perianal fistula, or intersphincteric fistula with sphincter dysfunction
      • patients had 120 mL of blood removed before surgery to create autologous fibrin sealant
    • results in all 60 patients
      • 41 patients (68.33%) achieved fistula closures at initial treatment
        • 31 patients (51.6%) achieved fistula closure with primary treatment
        • 10 of 15 patients with persistent fistula achieved fistula closure after second application
        • 3 patients had relapse, with 2 patients achieving fistula closure with second application
      • 40 patients (66.6%) had persistent fistula closure and remained asymptomatic
    • Reference – J Gastrointest Surg 2015 Feb;19(2):360
  • autologous platelet-rich fibrin glue therapy may be effective for fistula closure in some patients with low-output enterocutaneous fistula (ECF) (level 2 [mid-level] evidence)
    •  based on nonrandomized trial
    • 145 patients with low-output ECF assigned to autologous platelet-rich fibrin glue therapy vs. no fibrin glue therapy and were followed for 180 days
    • analysis adjusted for age, sex, fistula length, fistula duration, medication, baseline laboratory values, and comorbidities
    • comparing fibrin glue therapy vs. no fibrin glue therapy
      • fistula closure within 28 days in 77% vs. 57% (p = 0.0127)
      • mean time to fistula closure 7 vs. 23 days (p = 0.001)
    • fibrin glue therapy associated with increased fistula closure compared to no fibrin glue therapy (adjusted hazard rate 3.13, 95% CI 1.82-5.36)
    • Reference – Surgery 2014 Mar;155(3):434
  • fibrin glue therapy reported to result in 68% fistula closure rate in 34 patients with abscess associated enteric fistula in case series (Tech Coloproctol 2016 Sep;20(9):641)
  • platelet-rich plasma and platelet-rich fibrin glue reported to improve urinary symptoms in women with vesicovaginal fistula (VVF) refractory to conservative management (level 3 [lacking direct] evidence)
    •  based on case series
    • 12 patients (mean age 39 years) with VVF refractory to conservative management (continuous bladder drainage with catheterization and anticholinergic medication for about 3 weeks) had autologous platelet-rich plasma and platelet-rich fibrin glue as minimally invasive approach for fistula closure
      • fistula due to difficult cesarean section in 50%
      • fistula due to hysterectomy in 50%
    • mean time between fistula formation and treatment 9.3 months
    • follow-up to 6 months
    • transvaginal physical exam performed at 3- and 6-months follow-up and cystography performed at 3-months follow-up
    • total dryness reported in 11 patients (91.7%), with 1 patient rejecting second injection and receiving open surgery instead
    • no voiding dysfunction, urinary incontinence, retention, or urinary tract infection reported
    • Reference – J Urol 2013 Jun;189(6):2125

Application Techniques

• meticulous tissue preparation is required, including removal of antiseptics containing iodine, alcohol, or heavy metals, which may denature fibrin sealants (J Trauma Acute Care Surg 2020 Jan;88(1):e1)
•  premixed and separated component formulations are available, with some products requiring transfer to a dual-syringe applicator device before use (FDA DailyMed 2019 Dec 17 [Evicel], FDA DailyMed 2019 Dec 26 [Tisseel], FDA Label 2015 May [Raplixa])
• dual-syringe applicator devices mix the 2 components together before application, which allows for the components to interact during application to form stable clot made out of fibrin (J Biomed Mater Res B Appl Biomater 2016 Apr;104(3):626)
• application technique of various fibrin sealants
  • application of fibrin sealant typically through either blunt-tip needle or spray
    • dripping method
      • during application, applicator tip should be kept as close as possible to tissue surface without touching the tissue
      • apply individual drops to surface area being treated
      • to prevent uncontrolled clotting, drops should be allowed to separate from each other and applicator tip
    • spraying method
      •  only use specific applicator spray device approved for each product, or similar device cleared by FDA
      • distance between applicator tip head and application bed should be within ranges indicated by device manufacturer (do not spray unless this minimum distance is achieved)
      • to reduce risk of life-threatening gas embolism, only use pressurized gas within pressure range and distance indicated by device
      • spraying in short bursts onto tissue may help to produce even layer
    • References – J Trauma Acute Care Surg 2020 Jan;88(1):e1, FDA DailyMed 2019 Dec 17 (Evicel), FDA DailyMed 2022 Dec 12 (Vistaseal), FDA DailyMed 2019 Dec 26 (Tisseel)
  • application of patches
    • patches have both active and nonactive sides and are tailored to size; they are applied to bleeding tissue, and compressed manually for 3 minutes (⁽³⁾, J Trauma Acute Care Surg 2020 Jan;88(1):e1)
    • patch should be left in place to allow for adherence to wound⁽³⁾

Adverse Effects

• adverse effects may differ based on different products, and include (but are not limited to)
  • wound infection
  • nausea
  • procedural pain
  • hypotension
  • venous thromboembolism (deep vein thrombosis and pulmonary embolism)
  • hemorrhage (such as gastrointestinal, anastomotic)
  • allergic reactions or skin rashes
  • References – FDA DailyMed 2019 Dec 17 (Evicel), FDA DailyMed 2019 Dec 26 (Tisseel), FDA DailyMed 2022 Jun 9 (Artiss), FDA Label 2015 May (Raplixa), FDA DailyMed 2022 Dec 12 (Vistaseal)

Guidelines and Resources

Guidelines

• no relevant guidelines for “Fibrin Sealants” found 2022 Sep 21 on MEDLINE search using guidelines limiter

Review Articles

• reviews can be found in
  • ISRN Surg 2014;2014:203943full-text
  • Expert Opin Biol Ther 2014 Jun;14(6):821
• reviews of topical hemostats can be found in
  • J Trauma Acute Care Surg 2020 Jan;88(1):e1
  • Adv Ther 2020 Oct;37(10):4132
  • Pharmacotherapy 2013 Sep;33(9):935
• reviews of topical hemostatic agents in surgery can be found in
  • Rev Col Bras Cir 2018 Oct 18;45(5):e1900full-text[Portuguese, English]
  • J Am Coll Surg 2014 Sep;219(3):570
• review of topical hemostats for use in neurosurgery can be found in Neurosurg Rev 2022 Apr;45(2):1217
• review of fibrin sealants in cardiac surgery can be found in Adv Clin Exp Med 2018 Jun;27(6):857PDF
• review of hemostatic materials in wound care can be found in Burns Trauma 2021;9:tkab019full-text
• review of cryoprecipitate therapy can be found in Br J Anaesth 2014 Dec;113(6):922full-text

MEDLINE Search

• to search MEDLINE for (Fibrin Sealants) with targeted search (Clinical Queries), click therapy or prognosis

Patient Information

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References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

1. Yu P, Zhong W. Hemostatic materials in wound care. Burns Trauma. 2021;9:tkab019full-text.
2. Shander A, Kaplan LJ, Harris MT, et al. Topical hemostatic therapy in surgery: bridging the knowledge and practice gap. J Am Coll Surg. 2014 Sep;219(3):570-9.e4.
3. Spotnitz WD. Fibrin Sealant: The Only Approved Hemostat, Sealant, and Adhesive-a Laboratory and Clinical Perspective. ISRN Surg. 2014;2014:203943full-text.
4. Mandell SP, Gibran NS. Fibrin sealants: surgical hemostat, sealant and adhesive. Expert Opin Biol Ther. 2014 Jun;14(6):821-30.