The American Journal of Surgery 182 (2001) 1S7S

Fibrin sealants in surgical practice: An overview

Mark R. Jackson, M.D.
Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9157, USA

Abstract
The need to effectively manage hemostasis and tissue sealing during surgery has had a strong influence on the development of modern
surgical techniques. A group of agents known as surgical tissue adhesives has been developed to promote hemostasis and tissue sealing
during surgery, and these comprise both natural and synthetic agents. Fibrin sealants are the most effective tissue adhesives currently
available, and they are biocompatible and biodegradable. The fibrin sealants are comprised of purified, virus-inactivated human fibrinogen,
human thrombin, and sometimes added components, such as virus-inactivated human factor XIII and bovine aprotinin. These agents mimic
the final steps of the physiological coagulation cascade to form a fibrin clot. The use of any plasma-derived product in the surgical setting
carries a potential risk of viral transmission. In fact, it was the risk of viral transmission from fibrinogen and thrombin that halted
development work on fibrin sealants in the United States. Since that time, new techniques for isolating and concentrating plasma fractions
have been developed, and national and international guidelines have been introduced to ensure the safety of all plasma products. All plasma
donors are carefully selected and their plasma units screened for viral contamination before processing. All plasma donations and bovine
tissue used in the production of commercial fibrin sealants undergo rigorous viral reduction/elimination steps. As a result of this carefully
controlled and monitored process, there have been no proven cases of viral transmission associated with the use of commercial fibrin sealant.
Fibrin sealants are currently used in a number of surgical specialties, including cardiovascular surgery, thoracic surgery, neurosurgery,
plastic and reconstructive surgery, and dental surgery. The use of fibrin sealants has a positive effect on surgical outcomes, such as improved
time to hemostasis, reduced blood loss, and reduced complications. This review describes the development of fibrin sealants, the
composition of currently available products, and their use in surgical practice. 2001 Excerpta Medica, Inc. All rights reserved.

The surgeons need to manage hemostasis and wound heal-
ing effectively during surgery has played an important role
in the development of modern surgical technologies. Sur-
geons now have available to them a group of agents termed
surgical tissue adhesives, which aid hemostasis and atrau-
matic tissue union. This class of materials comprises a
variety of natural and synthetic hemostatic agents and in-
cludes fibrin sealants, marine adhesives, collagen fleece,
gelatin sponges, and cyanoacrylate derivatives [1 4].
The cyanoacrylates are bacteriostatic for many bacteria
and, as such, are frequently used in periodontics and oral
surgery. However, these compounds are associated with
acute and chronic inflammation and tissue necrosis, and
they are recommended only for superficial application [5,6].
More recently, bovine albumin and glutaraldehyde glue
(BioGlue; CryoLife, Inc., Kennesaw, Georgia) has been
authorized by federal (USA) law for humanitarian use dur-
ing surgical repair of acute thoracic aortic dissection. This
glue polymerizes immediately and establishes a firm adhe-
Tel.: 1-214-857-1896; fax: 1-214-857-1840.
E-mail address: mark.jackson@utsouthwestern.edu
sive bond. Although long-term results have yet to be pub-
lished, BioGlue appears to be a highly effective tissue glue.
Fibrin sealants can be used for hemostasis, wound clo-
sure, and tissue sealing and have been advocated as the
agents that are closest to approaching the ideal operative
sealant [1]. In contrast to synthetic adhesives, fibrin sealants
have the advantage of being biocompatible and biodegrad-
able, and they are not associated with inflammation, foreign
body reactions, tissue necrosis, or extensive fibrosis. Reab-
sorption of the fibrin clot is achieved during normal wound
healing within days to weeks of application, depending on
the type of surgery, the proteolytic activity of the treated
site, and the amount of sealant used [7].
Fibrin sealant, also referred to as fibrin glue or fibrin
tissue adhesive, is a surgical hemostatic agent derived from
plasma coagulation proteins. It has been commercially
available in Europe and Japan for 20 years as an adjunct to
hemostasis, and it is becoming increasingly popular in the
United States in a number of surgical settings.
This review will discuss the history of the development
of fibrin sealants, the composition of the commercially
available products and blood-bank composites, and their use
in current surgical practice.

0002-9610/01/$ see front matter 2001 Excerpta Medica, Inc. All rights reserved.
PII: S 0 0 0 2 - 9 6 1 0 ( 0 1 ) 0 0 9 0 8 - 1
2S M.R. Jackson / The American Journal of Surgery 182 (2001) 1S7S
Historical overview
The clinical use of fibrin emulsion to improve wound
healing was first reported in 1909 by Bergel [8]. Later
studies reported the direct application of fibrin-soaked
gauze and fibrin plaques to control parenchymal bleeding
(reviewed by Matras) [9]. However, it was not until 1938,
when protein separation technology was developing, that
purified thrombin became available. The combination of
thrombin and fibrinogen was first used in 1944 to enhance
the adhesion of skin grafts in soldiers with severe burn
injuries [10]. The use of human fibrinogen was known to be
a potential source for viral hepatitis transmission, and many
of the patients treated with early fibrin sealants became
infected. Additionally, the adhesive quality of these prepa-
rations was poor and, in retrospect, this can be attributed to
a lack of concentrated fibrinogen [9,11]. Before the intro-
duction of effective viral inactivation/elimination tech-
niques, bovine thrombin was used in fibrin sealants reduc-
ing the risk of viral transmission. However, the use of
bovine thrombin, instead of human thrombin, introduced the
risk of coagulopathies resulting from the development of
thrombin and factor V inhibitors [1215]. Overall, the effi-
cacy of the early fibrin sealant composites did not outweigh
the risk associated with their use, and work on fibrin seal-
ants was essentially halted in the United States.
The concept of a fibrin sealant system as we know it
today became a reality in the early 1970s, when techniques
for the isolation and concentration of clotting factors were
improved. In 1972, Matras et al [16] described the success-
ful application of a fibrin glue in peripheral nerve repair in
rabbits, and the procedure was later used in nerve anasto-
mosis in humans [17]. These researchers used cryoprecipi-
tate, a plasma product used in factor VIII deficiency ther-
apy, in conjunction with bovine thrombin solution. The
cryoprecipitate contained elevated concentrations of fibrin-
ogen, factor XIII, fibronectin, and other factors that resulted
in satisfactory adhesion.
After further refinement in the cryoprecipitate constitu-
ents and production methods, the first commercially avail-
able fibrin sealant was launched in Europe in 1982. Since
that time, European surgeons have gained considerable ex-
perience in the use of these fibrin sealants across a variety of
applications. However, the Food and Drug Administration
(FDA) in the United States did not approve the licensing of
the product because of the perceived high associated risk of
hepatitis transmission from the pooled human plasma used
in the production of fibrinogen. The FDA revoked the li-
cense for the clinical use of pooled commercial fibrinogen
concentrates, which stopped further development of com-
mercial fibrin sealants and prevented the importation of
fibrin sealants from Europe [1]. The lack of availability of
these products in the United States, along with the clinical
success reported in Europe, resulted in US surgeons pro-
ducing patient-autologous and blood-bank sourced fibrin
sealants [18].
The first commercially available fibrin sealants in Europe
were Tissucol (also marketed as Tisseel; Immuno AG, Vi-
enna, Austria) and Beriplast HS (identical to Beriplast P;
Behringwerke, Marburg, Germany). The range of currently
available fibrin sealants is summarized in Table 1. Both
Tisseel and Beriplast P are marketed as a two-component
kit: component one contains lyophilized pooled human fi-
brinogen/factor XIII concentrate, which is reconstituted
with antifibrinolytic solution (aprotinin); and component
two is bovine thrombin reconstituted with 40 mM CaCl2.
Tisseel is supplied as a lyophilizate or frozen, whereas
Beriplast P is supplied as a lyophilizate. The two-compo-
nent fibrin sealant is usually applied through a double-
barreled syringe system, which allows simultaneous appli-
cation of equal volumes of the fibrinogen and thrombin
through a blunt-ended needle or spray tip [7]. Both compo-
nent solutions of Tisseel are purified using a two-step vapor
heat method at 60 C and 80 C, whereas Beriplast P
undergoes viral inactivation in aqueous solution at 60 C for
10 hours (pasteurization).
Fibrinogen is an essential component of fibrin sealants,
and it can be obtained as a cryoprecipitate from individual
units of screened-donor blood plasma, greatly reducing the
associated risk of hepatitis and acquired immune deficiency
syndrome (AIDS). However, the final concentration of fi-
brinogen obtained by conventional cryoprecipitation tech-
nology was significantly lower than that found in commer-
cial fibrin sealants. Although a safe and efficient method for
the preparation of concentrated fibrinogen from individual
units of donor plasma was reported in 1987 [19], with the
exception of a few centers of excellence, the use of fibrin
sealants in the United States has remained limited.
Fibrin sealants in current surgical practice
Within the last few years, there have been a number of
reviews that have outlined the uses of fibrin sealants in
current surgical practice [20 23]. The main fields of exper-
tise where a role for fibrin sealants has been established
include cardiovascular surgery, thoracic surgery, neurosur-
gery, plastic and reconstruction surgery, and dental surgery.
There are, as yet, few clinical reports of the application of
fibrin sealants to other surgical areas, such as orthopedics
and urology. Recently, the use of fibrin sealant during total
knee arthroplasty was shown to significantly reduce both the
amount of blood lost during and after surgery, and the
number of blood transfusions required postoperatively was
also reduced [24].
Surgical procedures
Although commercial sealants have been available to
surgeons for many years, there are relatively few random-
ized, controlled clinical trials in the literature. Many of the
 M.R. Jackson / The American Journal of Surgery 182 (2001) 1S7S 3S

Table 1
Composition of fibrin sealants

Human Human Human Bovine aprotinin Virus-inactivated Virus-inactivated

fibrinogen factor XIII thrombin (KIU/mL) fibrinogen thrombin
(mg/mL) (U/mL) (IU/mL)

Tisseel, Tissucol (Duo Frozen 70110 1050 500 3,000 Two-step vapor heat Two-step vapor heat
Baxter-Immuno AG, solution at 60C and 80C at 60C and 80C
Austria)
Tisseel, Tissucol (Kit Lyophilizate 70110 1050 500 and 4 3,000 Two-step vapor heat Two-step vapor heat
Baxter-Immuno AG, at 60C and 80C at 60C and 80C
Austria)
Tisseel (VH Kit Baxter- Lyophilizate 75115 500 3,000 Two-step vapor heat Two-step vapor heat
Immuno AG, USA) at 60C and 80C at 60C and 80C
Beriplast P (Aventis Lyophilizate 90 (65115) 60 (4080) 500 (400600) 1,000 Pasteurization Pasteurization
Behring, Germany) (liquid solution, (liquid solution,
10 h at 60C) 10 h at 60C)
Hemaseel (APR Lyophilizate 75115 500 3,000 Two-step vapor heat Two-step vapor heat
Haemacure, Canada) at 60C and 80C at 60C and 80C
(As Tisseel VH Kit
Baxter-Immuno)
Quixil (Omrix Frozen 60100 None 1,000 None Solventdetergent Solventdetergent
Biopharmaceuticals SA, solution (tranexamic acid treatment, treatment,
Israel) 92 mg/mL) pasteurization nanofiltration
Bolheal (Kaketsuken Lyophilizate 80 75 250 1,000 Dry heat (144 h at Dry heat (96 h at
Pharmaceutical, Japan) 65C) 65C)
Biocol (LFB-Lille, France) Lyophilizate 127 11 558 3,000 Solventdetergent Solventdetergent
treatment treatment
VIGuard F.S. (Vitex: VI Lyophilizate 5095 35 200 None Solventdetergent Solventdetergent
Technologies, USA) treatment, ultraviolet treatment, ultraviolet
C light C light

studies reported are from retrospective case study analyses.
However, a number of prospective randomized, controlled
trials have been carried out in cardiothoracic surgery [21,25]
and in endoscopic hemostasis for bleeding peptic ulcers
[26 28].
Fibrin sealants have been used successfully in a wide
range of procedures in cardiovascular surgery, including
bypass surgery, vascular grafts, valve replacement, repair of
septal defects and vessel/heart chamber rupture, and pros-
thetic implantation [19,29 35].
The single trial that has provided the most significant
data regarding the hemostatic efficacy of fibrin sealants in
surgery was that of Rousou et al in 1989 [25]. In this
multicenter, randomized, clinical trial, 333 patients under-
going either reoperative cardiac surgery or an emergency
resternotomy (return to operating room for bleeding within
24 hours of initial surgery) were randomized to treatment
with fibrin sealant (Tisseel) or other conventional topical
hemostatic agents (collagen, cellulose, or gelatin based).
These investigators found that 92.6% of patients random-
ized to receive fibrin sealant had complete hemostasis at 5
minutes, compared with only 12.4% of patients treated with
conventional topical agents (P 0.001). At 1 year of fol-
low-up there was no evidence of inflammation in response
to fibrin sealant. A post-hoc analysis of the data showed
improved survival, a shorter hospital stay, and less blood
loss at 12 hours in the group treated with fibrin sealant [36].
In summary, this trial provides strong evidence to support
the use of fibrin sealant as a hemostatic agent during reop-
erative cardiac surgery.
A limitation of the hemostatic properties of fibrin sealant
was observed in a single-center randomized clinical trial in
which fibrin sealant was used for suture-hole hemostasis on
polytetrafluoroethylene (ePTFE) patch closures during ca-
rotid endarterectomy [37]. In this study, no differences were
observed in time to hemostasis or volume of blood loss in
groups treated with either fibrin sealant (n 24) or throm-
bin-soaked gelatin sponge (n 23). The reasons for this are
likely to be the more limited adhesive bond to ePTFE
compared with native tissue, and that suture-hole bleeding
from this graft material can be rather brisk, and not the slow,
oozing type of bleeding that is amenable to control with
fibrin sealant.
In thoracic surgery, the sealing properties of fibrin seal-
ants have been particularly useful in reducing complications
arising from air leakage at suture sites or after surgical
dissection in many procedures, such as pleurodesis/decorti-
cation, tumor resection, and lobectomy/pneumonectomy
[30,38 40]. A total of 114 patients undergoing pulmonary
resection (n 63) and pneumonectomies (n 51) were
randomized within the two strata to receive either suturing
alone (n 59) or suturing plus fibrin sealant (n 55) [39].
The number of patients without postoperative air leakages
was significantly higher in the fibrin sealanttreated group
compared with the control group (61% vs 34%; P 0.02,
one-sided chi square test; Fig. 1), with an estimated risk
4S M.R. Jackson / The American Journal of Surgery 182 (2001) 1S7S
Fig. 1. Incidence of nonair leakage in patients undergoing pulmonary resection with or without fibrin sealant treatment [39]. *P 0.02, one-sided chi-square
test; risk reduction, 41% (95% confidence interval, 2% to 65%).
Table 2
Mean blood loss during CotrelDubousset instrumentation for adolescent idiopathic scoliosis [44]
Total blood loss (mL)
Blood loss per level fused (mL)
Blood loss divided per kg body weight (mL/kg)
reduction of 41% (95% confidence interval, 2% to 65%).
When a leakage did occur, the duration of leakage was the
same in both groups. After fibrin sealant treatment, 81% of
patients showed improved airway-tolerance pressure testing
(P 0.01, one-sided test). When the two study strata were
combined, there was a significant reduction in the length of
hospital stay (9 days vs 10 days; P 0.05). Fewer patients
had postoperative complications after fibrin sealant treat-
ment than with suturing alone (14.5% vs 37.3%; P 0.01).
In neurosurgery, fibrin sealants have been used success-
fully for intracranial and spinal surgery, including dura-
plasty, tumor resection, aneurysm repair, and nerve anasto-
mosis [41 43]. Fibrin sealants have been used for a decade
to reduce blood loss during Cotrel-Dubousset instrumenta-
tion for idiopathic scoliosis and are a useful adjunct to help
reduce blood loss during spinal surgery [44]. In one study,
39 consecutive patients undergoing Cotrel-Dubousset in-
strumentation for adolescent idiopathic scoliosis were ran-
domly assigned to receive treatment with or without fibrin
sealant [44]. Fibrin sealant was used to control bleeding
from the bone graft site and in the spine after decortation of
spine fusion. Fibrin sealant treatment significantly reduced
the total volume of blood lost compared with controls (895
mL vs 672 mL; P 0.05; Table 2).
Upper gastrointestinal hemorrhage is a life-threatening
condition, and the optimum strategy for managing recurrent
bleeding is not known. Bleeding in the upper gastrointesti-
nal tract is often managed by local endoscopic injection of
hemostatic agents. The injection of fibrin sealant provides a
highly effective therapy, which can be administered repeat-
Control Fibrin P-value
sealant
895 672 0.05
88.1 66.9 0.1
17.5 13.3 0.05
edly if required [26 28,44 48]. In one large randomized,
comparator-controlled multicenter study, a total of 854 pa-
tients with peptic ulcers were assigned to receive a single
application of polidocanol 1%, a single application of fibrin
sealant, or a repeat application of fibrin sealant. Patients
treated with repeat fibrin sealant were significantly less
likely to have a recurrent bleed compared with those treated
with polidocanol. Treatment failed, making other treatments
necessary (including surgery), in 13.0% of the polidocanol
group and 7.7% of the repeat fibrin sealant group (P 0.05).
Fibrin sealants have also been used in plastic and recon-
structive surgery, including the sealing of skin grafts. Al-
though many of the reports are descriptive, the results of
experimental studies indicate that fibrin sealants can in-
crease graft take at infected sites and reduce wound con-
traction during healing [49,50]. Brown et al [50] showed
that fibrin sealant applied to sutured skin graft significantly
reduced wound contraction in a standardized model. Graft
sites treated with fibrin sealant contracted significantly less
than controls from the ninth postgraft day to the end of the
study (Fig. 2). Fibrin sealants have also been used success-
fully in thermal injury patients (15% or less of total body
surface area) to assist topical hemostasis and reduce blood
loss as a function of graft size [51]. In this study, the
estimated blood loss/graft ratio was 0.50 0.3 mL/cm2 for
patients treated with fibrin sealant compared with 0.98
2.4 mL/cm2 for those who had declined fibrin sealant treat-
ment (P 0.14); for patients over 16 years the difference
between the two groups was significant (P 0.003) [51].
Despite promising early results in the use of fibrin seal-
 M.R. Jackson / The American Journal of Surgery 182 (2001) 1S7S
Fig. 2. Percentage change from initial skin graft wound size after fibrin sealant and saline treatment [50]. *P 0.001, paired Students t test.
ants in osteoinduction, the main role of fibrin sealants in
orthopedic surgery is as a hemostat. In patients with bleed-
ing disorders, the use of fibrin sealants in major procedures,
such as total knee arthroplasty and hip replacement, signif-
icantly reduces blood loss [22,23]. In a recently published
randomized clinical trial, fibrin sealant was found to be
effective in obtaining surgical hemostasis during total knee
replacement arthroplasty [24]. Fifty-eight patients were ran-
domized to either fibrin sealant or control. All patients
received perioperative thromboprophylaxis with low-mo-
lecular-weight heparin. Intraoperative blood loss, postoper-
ative drain blood loss, and need for postoperative blood
transfusion were all significantly reduced with fibrin seal-
ant.
Fibrin sealants are a useful addition to sutures facilitating
wound healing and providing optimal wound integrity in
situations where sutures cannot control, or may aggravate,
bleeding [52]. Their effectiveness as a suture support may
also lead to fewer sutures being required during surgery
with the associated benefits of reduced operative trauma
and, in general, better cosmetic results than sutures alone.
Other uses
Fibrin sealants have also been used as tissue-adherent
carriers for the local delivery and slow release of drugs,
including antibiotics, growth factors, and for agents used in
chemotherapy [11,20]. These uses are reviewed in more
detail in the final article in this supplement.
Viral transmission
The risk of virus transmission by fibrin sealants is still a
subject of much debate. Theoretically, viruses remaining in
commercial preparations after viral reduction steps could be
5S
absorbed and retained by the patient. This could result in the
transmission of such viruses as hepatitis B, hepatitis C,
human T-cell leukemia virus type III/lymphadenopathy-
associated virus (HTLV-III/LAV), human immunodefi-
ciency virus type 1 (HIV-1), and possibly other blood-borne
viruses, such as HIV-2, Epstein-Barr, herpes simplex, cyto-
megalovirus, and varicella-zoster virus [53]. Recently, par-
vovirus B19 transmission has also been attributed to the use
of fibrin sealants [54]. Most adults have antibodies to par-
vovirus B19 and, if infection does occur, it is usually mild
in severity in both adults and children. However, infection
can be more serious in pregnant women and neonates and
should be avoided. Since the publication of the report by
Hino et al [54], some commercial manufacturers of fibrin
sealant have introduced polymerase chain reaction testing
for parvovirus B19 to reduce the amount of virus present in
the final product and thus reduce the risk of transmission of
parvovirus B19 to the patient.
Fibrin sealant components (fibrinogen and thrombin) are
subjected to a variety of treatments in order to eliminate or
inactivate a wide range of viruses (Table 1) [7]. Human
plasma products can be solvent detergent treated, two-step
vapor heat treated, or pasteurized. Additional treatments
including dry heat treatment, nanofiltration, and other pro-
duction steps (eg, some chromatography) have a viral re-
duction effect. Not all treatments are as equally effective
against all viruses, and a combination of procedures is
required to ensure a reliable outcome. The established meth-
ods, based on in vitro validation data and clinical experi-
ence, are considered to offer a sufficient margin of safety
against the major human plasma-borne viruses (HIV and
hepatitis B and C viruses). Virus inactivation and elimina-
tion during Beriplast P production is typically from greater
than 9 log10 to greater than 19 log10 for HIV-1, bovine
diarrhea virus and herpes simplex virus type-1 in fibrinogen,
factor XIII, and thrombin (Aventis Behring, data on file).
There are no cases of serious viral transmission after the
6S M.R. Jackson / The American Journal of Surgery 182 (2001) 1S7S
use of commercial fibrin sealants reported in the literature.
This absence appears to be the result of careful donor
selection, extensive plasma screening, and effective viral
reduction steps during commercial preparation. Single-do-
nor sourced fibrin sealants (blood-bank cryoprecipitate),
introduced in the 1970s when viral contamination was a
problem, are associated with a low risk of viral transmis-
sion, equivalent to that for transfusion of single-donor blood
products [1]. The estimated risk of transfusion-transmitted
infection from a single unit of screened blood was reported
to be 1:63,000 and 1:103,000 for hepatitis B and C, respec-
tively [55], and 1:450,000 to 1:660,000 for HIV [56].
US Regulatory approval
In May 1998, the FDA approved the licensing of the first
commercially manufactured fibrin sealants, Tisseel VH kit
(Baxter-Immuno AG, Vienna, Austria) and Hemaseel APR
(Haemacure, Sarasota, FL). Several other commercial fibrin
sealants are in the process of being licensed, and other fibrin
sealant products are under development in the United States.
For product approval by the FDA, studies must also
address the combination product regulation, which means
that the benefit of each individual component must be dem-
onstrated. The product can have multiple safe and active
components, provided that each makes a significant contri-
bution to the efficacy of the final product. In fibrin sealants,
this means that additives, such as factor XIII and aprotinin,
must be demonstrated to have a significant effect [57]. A
significant benefit of the antifibrinolytic properties of apro-
tinin has not been seen in all studies. Nevertheless, fibrin
sealants containing aprotinin have been launched in the
United States (Table 1) [5759].
Summary
Fibrin sealants are plasma-derived topical hemostatic
agents used increasingly in various surgical settings.
Whereas US surgeons have had to rely on sealants derived
from blood-bank cryoprecipitate and bovine thrombin in the
past, commercially manufactured fibrin sealant kits contain-
ing highly purified and virally inactivated human fibrinogen
and human thrombin are now available. The appropriate use
of fibrin sealants can improve blood conservation and re-
duce intraoperative bleeding in certain procedures. Issues
that remain unresolved relate to the design of optimal de-
livery systems for unique surgical applications, the devel-
opment of different formulations of fibrin sealant (such as a
fibrin sealant dressing), and cost-effectiveness. Nonetheless,
fibrin sealant can be a useful adjunct to surgical hemostasis,
and all surgeons should be familiar with its uses and limi-
tations.
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