This document discusses topical hemostatic agents used in surgical practice. It describes how fibrin sealants work by participating in the coagulation cascade to form a fibrin clot. Fibrin sealants are prepared either commercially from pooled plasma through fractionation and viral reduction processes, or in hospital blood banks from single donor plasma through cryoprecipitation to obtain fibrinogen and automated thrombin generation. Fibrin sealants are effective in controlling surgical bleeding in a variety of settings such as parenchymal organs and gastrointestinal bleeding. They promote hemostasis, reduce blood loss, and induce wound healing.

1. Transfusion and Apheresis Science 45 (2011) 305–311
Contents lists available at SciVerse ScienceDirect
Transfusion and Apheresis Science
journal homepage: www.elsevier.com/ locate/ transci
Topical hemostatic agents in surgical practice
Masci Emilia b,⇑, Santoleri Luca c, Belloni Francesca b, Bottero Luca a, Stefanini Paolo a,
Faillace Giuseppe a, Bertani Gianbattista c, Montinaro Carmela c, Mancini Luigi c,
Longoni Mauro a
a 1st Unit of General Surgery ‘‘Città di Sesto S.G. Hospital’’, Istituti Clinici di Perfezionamento, Milan, Italy
b Post-Graduated School of General Surgery, University School of Medicine, Milan, Italy
c Blood Transfusion Service ‘‘Niguarda Ca’ Granda Hospital’’, Milan, Italy
a r t i c l e i n f o
Article history:
a b s t r a c t
Hemostasis is of critical importance in achieving a positive outcome in any surgical inter-vention.
Different hemostatic methods can be employed and topical hemostatic agents are
used in a wide variety of surgical settings. Procoagulation agents have different hemostatic
properties and the choice of a specific one is determined by the type of surgical procedure
and bleeding. Hemostatic treatments include fibrin sealants, microfibrillar collagen, gelatin
hemostatic agents, oxidized regenerated cellulose and cyanoacrylates adhesives. Surgeons
should be familiar with topical hemostatics to ensure an appropriate use. Our purpose is to
illustrate the currently available agents, their mechanism of action and their effective
applications, in order to ensure an optimal use in operating room.
2011 Elsevier Ltd. All rights reserved.
1. Introduction
Management of hemostasis has always been an issue of
fundamental importance in any surgical procedure.
Despite the priority of the topic, for a long time no signif-icant
progress was made. Until the 17th century, surgeons
achieved hemostasis mainly by applying hot oil and cau-teries
to wounds. It was only in 1600 that Ambroise Parè,
a French surgeon, introduced vascular ligation as the pref-erable
method to provide bleeding control; since then,
hemostasis has been achieved largely by mechanical
means (ligatures, stitches and clips). New technologies
for the prevention and control of bleeding were gradually
introduced in surgical practice over the past century: elec-trical
scalpel (1924), bipolar forceps (1940s) and recently
the radio frequency and ultrasonic scalpel (2000s). A criti-cal
problem for the surgeon in the operating room always
was oozing bleeding, where cautery and suture ligation are
not feasible. For this reason, over the past decades, means
such as lasers (CO2, Argon, and Nd-YAG) and spray-electrocoagulation
have been introduced. Topical agents
have also been developed to promote hemostasis in a wide
variety of surgical procedures where the control of bleed-ing
may result particularly difficult or impossible (coagul-opathies
and platelet dysfunction, parenchymal tissues,
bony surfaces, etc.). Most of these topical agents were orig-inally
developed to improve wound healing in soldiers
with severe burn injuries during WWI, WWII, Vietnam
War, etc. Topical hemostatic agents can be divided in ac-tive
and passive agents [1]. Active agents participate at
the end of the coagulation cascade to form a fibrin clot.
This group includes products containing fibrinogen and
thrombin (fibrin sealants). These agents are known as
adhesive hemostatics because of their hemostatic and tis-sue
sealing action. Sealants with purified thrombin and
fibrinogen were first successfully used in the 1970s, when
techniques of plasmatic protein separation had just been
improved. The first fibrin sealants to be commercially
available in Europe were, in the early 1980s, Tissucol and
Beriplast, whereas in the United States the FDA (Food
⇑ Corresponding author. Tel.: +39 3406099189; fax: +39 0226257601.
E-mail address: emymasci@tiscali.it (M. Emilia).
1473-0502/$ - see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.transci.2011.10.013

2. 306 M. Emilia et al. / Transfusion and Apheresis Science 45 (2011) 305–311
and Drug Administration) approved the licensing of fibrin
sealants only in 1998 because of the presumed risk of viral
hepatitis transmission. The lack of availability of these
products in the US until 1998 resulted in the production
of fibrin glue from blood-bank cryoprecipitate (home
made) but the final concentration of fibrinogen was signif-icantly
lower than the one found in commercial fibrin seal-ants
[2,3]. At the moment fibrin sealants are still the most
effective hemostatic adhesive agents available for surgical
practice.
Passive hemostatics, including collagen, gelatines and
regenerated oxidized cellulose, are not biologically active;
their mechanism of action is to provide platelet activation
and aggregation. They are of bovine, equine, swine or veg-etable
origin and are available as sponges, sheets, powder,
etc.
The last category of topical agents is represented by syn-thetic
(cyanoacrylates) and semi-synthetic (glutaraldeide-albumina)
sealants. They does not have any intrinsic
hemostatic activity but, through a rapid polymerization
process, have adhesive and sealing properties (wound
closure, vascular anastomosis protection, and prevention
of leakages) (Table 1).
2. Fibrin glue
Fibrin sealants are involved at the end of the coagula-tion
cascade to induce a clot at the site of bleeding. They
are constituted by two component: component one con-tains
human purified fibrinogen and component two con-tains
thrombin. The two components usually contain
added plasmatic proteins such as factor XIII [4], fibronectin
and antifibrinolitic agents like aprotinin and tranexamic
acid. Fibrin sealants can be prepared on industrial scale
by plasma fractionators or from single plasma donations
by blood establishments or hospital blood banks (home
made sealants).
The industrial fibrin sealants are obtained by fraction-ation
of many liters of plasma. Fibrinogen is usually pre-pared
by precipitation from the cryoprecipitate or from
Cohn fraction I. The procedure may include a co-purification
of other plasma proteins such as fibronectin, factor XIII and
von Willebrand factor and an ultrafiltration step to concen-trate
fibrinogen to more than 80 g/l. The manufacturing
pools have to be processed with one or two viral reduction
and inactivation steps: solvent/detergent, vapor-heat
treatment or pasteurization. Viral reduction can be com-pleted
by a nanofiltration step. Viral inactivation is more
effective versus lipid-enveloped viruses such as human
immunodeficiency virus (HIV), hepatitis B virus (HBV), hep-atitis
C virus (HCV) and West Nile virus than against non-enveloped
viruses, such as parvovirus B19 and hepatitis A
virus (HAV): this is the reason why manufacturing pools
are also screened by nucleic acid testing for parvovirus
B19 and HAV. Industrial thrombin is generated by an activa-tion
process of pre-purified human or bovine prothrombin
fractions using calcium salts. An immunization risk related
to the use of bovine derived thrombin [5–7] is present. The
production of thrombin includes chromatographic steps
and ultrafiltration. The viral inactivation has been achieved
combining of two of these following procedures: solvent/
detergent treatment, pasteurization and nanofiltration.
Thrombin solutions, after careful antithrombin removal,
have a high stability level and thrombin concentration after
ultrafiltration is typically over 500 IU/ml.
Non-commercial fibrin sealants can be obtained from
single plasma units by blood establishments or hospital
blood bank setting. Plasma units, collected in hospital
blood-banks, can be used in autologous or homologous set-tings.
Autologous clinical use eliminates the risk of transfu-sion-
transmitted disease to the recipient but are not feasible
when blood collection is not possible, such as patients with
coagulation disorders or people undergoing emergency pro-cedures.
Fibrinogen is usually produced by a process of cry-oprecipitation
from whole plasma units. Human
cryoprecipitate is the most practical source of fibrinogen
for single-donation manufacture. Freezing and thawing of
the plasma results in the precipitation of fibrinogen to gen-erate
the cryoprecipitate; most of the cryo-poor superna-tant
is discarded after centrifugation at 3000–4000 g. The
volume of cryoprecipitate solution obtained from 200 ml
of plasma is about 10 ml. The cryoprecipitate is collected
into a sterilized syringe and used fresh, or it may be frozen
until use. Fibrinogen can be also prepared by precipitation
with ethanol, ammonium sulfate and polyethylene glycol.
Cryoprecipitation method has been reported to have the
highest fibrinogen yield, whereas ammonium sulfate pre-cipitation
has been reported to allow preparation of a fibrin
sealant with higher tensile strength. The fibrinogen concen-tration
in these fibrin sealant is typically close to 20 g/l, and
the formation of the fibrin clot, upon mixing with thrombin,
takes 2–10 s. The strength of the fibrin clot appears to be
Table 1
Classification of topical hemostatic agents and sealants.
Categories Product Origin Active ingredients
Adhesive hemostats EVICEL Human Human fibrinogen + human thrombin
Tissucol Human/animal Human fibrinogen + human thrombin
Beriplast Human/animal Human fibrinogen + human thrombin
TachoSil Human/animal Equine collagen + fibrinogen and thrombin
Topical hemostats Surgicel Vegetable Oxidized regenerated cellulose
FloSeal Animal Bovine collagen + bovine thrombin
Spongostan Animal Porcine gelatin
Surgiflo Animal/Human Porcine gelatine + human thrombin
Adhesives Omnex Synthetic Cyanoacrylate
Bioglue Semisynthetic Bovine albumin glutaraldeide
Coseal Synthetic Polyethylene glycol
Glubran Synthetic Cyanoacrylate

3. M. Emilia et al. / Transfusion and Apheresis Science 45 (2011) 305–311 307
strong enough to fit many clinical applications but a poten-tial
disadvantage of some of these preparations, because of
their relatively low fibrinogen concentration, is the weak-ness
of the fibrin clot obtained upon mixing with thrombin.
Until recently, the thrombin component was generally de-rived
from commercial bovine sources. Bovine thrombin
carries immunological risk and patients exposed to topical
bovine thrombin may develop antibodies to thrombin and
factor V and immune-mediated coagulopathies. In addition,
the risk of transmitting infections due to viral or prion
agents (such as bovine spongiform encephalopathy, the hu-man
variant of Creutzfeldt–Jakob disease) have been raised.
For this reason automated devices for the production of
thrombin from single donor plasma have been developed;
thrombin generation is achieved typically in 10–30 min by
plasma activation in the presence of negatively charged
beads providing the formation of thrombin from
prothrombin. Calcium salts are added to counterbalance cit-rate
anticoagulant solutions. One such system can provide a
mean thrombin concentration close to 50–60 IU/ml, stable
for over 4–6 h at room temperature on condition of 10–
15% ethanol (final concentration) is added prior to plasma
activation. Recently, thrombin could also be prepared from
whole blood using a similar medical device; thrombin
concentration was in the same range and could coagulate
fibrinogen in less than 5 s. The viral safety of allogenic single-donor
fibrin sealant is currently based on careful donors
selection and viral screening. Viral risks are statistically very
low in developed countries but surveillance should always
be predominant due to emerging infections agents like West
Nile virus or Dengue virus. We expect that methods to pre-pare
fibrin sealant from virally inactivated plasma or cryo-precipitate
will be developed provided these treatments
do not alter the functional activity of fibrinogen and the
capacity to generate thrombin [8].
Fibrin sealants are applied by means of a double syringe
system, which allows simultaneous application of equal
volumes of fibrinogen and thrombin through a blunt nee-dle
or spray tip. The spay technique may be particularly
useful when the surgical setting requires a large and uni-form
deposition of sealant. Thrombin, a plasmatic protein
activated by both intrinsic and extrinsic coagulation path-ways,
is a critical component of the clotting cascade: acti-vated
thrombin converts fibrinogen to fibrin which, along
with factor XIII and platelets, induce the formation of a fi-brin
clot. The direct application of fibrin sealant on the site
of bleeding promotes hemostasis, reducing blood loss.
Also, unlike synthetic adhesives, fibrin sealants are bio-compatible
and biodegradable and induce neither inflam-matory
response nor tissue necrosis. Till 2007, the only
topical thrombins commercially available were derived
from bovine plasma; cases of antibody formation to bovine
thrombin have been described. In 2007 and 2008, two new
topical thrombins received approval for use from the US
Food and Drug Administration: human plasma derived
thrombin and human recombinant thrombin [9–11]; at
the moment in the United States three stand-alone topical
human recombinant thrombin products are available [12–
14]. Fibrin sealants, when conventional hemostatic meth-ods
are ineffective or impractical, can be used to achieve
hemostasis in a wide range of surgical procedures,
reducing blood loss and the need for transfusions. Fibrin
sealants are particularly effective in controlling surgical
bleeding in congenital or acquired bleeding disorders
(e.g., patients receiving antiplatelet or anticoagulant thera-pies
undergoing urgent surgical procedure), parenchyma-tous
organs hemostasis, damage control surgery,
gastrointestinal bleeding, difficult to reach anatomic sites,
such as nasal and oropharyngeal cavities. Another impor-tant
application of fibrin glue lies in its ability to seal tissue
surfaces as a consequence of the polymerization of fibrin
monomers. Fibrin glue effectiveness as a sealant is still
controversial but consistent data seem to support its use.
Fibrin glue also has s bio-stimulating action that starts a
few hours after application with the proliferation of fibro-blasts
and the beginning of the granulation process. In fact,
the fibrin plug is able to promote collagen production and
consequent wound healing. These products also have a po-tential
as biodegradable carriers for the topic release of
drugs [15]: they have been used for the delivery of antibi-otics,
growth factors and antineoplastic drugs into tumor
sites. Finally, fibrin glues might have a role in reducing
the incidence of intraabdominal adhesions after surgery
[16] by forming a protective barrier but there is no strong
evidence to support this theory.
2.1. Surgical settings
Commercially available fibrin sealants have specific
indications related to their different chemical composition.
Intravascular administration is contraindicated because of
the potential for thromboembolic complications or hyper-sensitivity
reactions to human blood products, animal
derived protein or any of the excipients. Adhesives contain-ing
tranexamic acid, an antifibrinolytic agent, are contrain-dicated
in neurosurgery because epilepsy or cerebral
edema may occur in case of contact with the liquor. Fibrin
glues have been successfully used in many general surgery
procedures and the recent diffusion of laparoscopy, with its
limited possibilities as to direct hemostasis, has led to
further development of chemical–pharmacological
hemostatic methods. Fibrin sealants are useful in achieving
hemostasis on the surface of parenchymatous organs, in
spleen-conservative surgery, nephron sparing resections
and liver surgery (liver resection, partial liver grafts in liver
transplantation). Fibrin glue has been used for its adhesive
properties for pancreatic and biliary leakages prevention,
tension free mesh fixation in laparoscopic transabdominal
inguinal hernia repair [17], digestive anastomoses protec-tion,
complex perianal fistulas management. Biological
seals have been used in plastic and reconstructive surgery
in achieving hemostasis in burn patients and in graft adher-ence
to wound surfaces.
The clinical effectiveness in patients undergoing to liver
resection is debated. In a randomized clinical trial Noun et
al. studied 77 patients submitted elective liver resection
for benign lesions (n = 35) and malignant lesions (n = 42).
Patients were randomly allocated to 1 of 2 groups: fibrin
sealant group (n = 38) and control group (n = 44). Fibrin
Sealant group received at peritoneal closure a single dose
of 5 ml of fibrin sealant applied to the liver cut surface,
control group received no sealant treatment. The mean

4. 308 M. Emilia et al. / Transfusion and Apheresis Science 45 (2011) 305–311
total fluid drainage during the three postoperative days
and bilirubin concentration were significantly lower in
the group with fibrin glue; respectively 242 ± 249 ml vs.
505 ± 666 ml and 24 ± 21 mmoles/l vs. 65 ± 47 mmoles/l.
The Authors concluded that fibrin glue application to the
hepatic stump after hepatic resection provides effective
sealing with good systemic and local compatibility [18].
Different results were reported in a prospective random-ized
study designed by Figueras et al. a total of 300 pa-tients
undergoing hepatic resection were randomly
assigned to FG application or control groups. Postopera-tively,
no differences were observed in the amount of
transfusion (0.15 ± 0.66 vs. 0.17 ± 0.63 PRCU; P = 0.7234)
or in the patients that required transfusion (18% vs. 12%;
P = 0.2), respectively, for the FG or control group. There
were no differences in overall drainage volumes
(1180 ± 2528 vs. 960 ± 1253 mL) or in days of postopera-tive
drainage (7.9 ± 5 vs. 7.1 ± 4.7). Incidence of biliary fis-tula
was similar in the FG and control groups, (10% vs.
11%). There were no differences regarding postoperative
morbidity between groups (23% vs. 23%; P = 1). The
Authors concluded that the application of FS in the raw
surface of the liver does not seem justified [19].
Fibrin sealants are successfully used in cardiovascular
surgery, including coronary artery bypass grafting sur-gery,
valve operations, surgical repair of congenital heart
defects, ventricular rupture after myocardial infarction
and prosthetic implantation. Codispoti et al. investigated
the effectiveness of fibrin sealant (Beriplast P) in post-car-diopulmonary
bypass coagulopathy in pediatric cardiac
surgery. After confirming the presence of significant coag-ulopathy
following cardiopulmonary bypass, patients
were randomised to the use of BP (group BP) or no inter-vention
(group C). Fibrin glue was applied over suture
lines and microvascular bleeding sites. Fifty-two patients
(n = 26 in each group) were recruited. Patients receiving
BP spent less time in theatre to achieve hemostasis
(P 6 0.05), had a lesser amount of bleeding intraopera-tively
(P 6 0.01), at 4 h (P 6 0.05) and at 24 h (P 6 0.05),
required a lower amount of transfusions of red cells
(P 6 0.01), FPP (P 6 0.05) and platelets (P 6 0.05) [20].
In vascular surgery the sealing properties of fibrin glue
have been useful in prevention of suture hole bleeding of
arterial sutures involving ePTFE or woven Dacron, i.e. caro-tid
endoarterectony with ePTFE patch reconstruction and
aortic aneurysm repair. In a prospective randomized con-trolled
trial the hemostatic effectiveness of EVICEL Fibrin
Sealant, a second-generation fibrin sealant that contains
only human components, no aprotinin or tranexamic acid
(75 patients) or manual compression (72) in polytetrafluo-roethylene
(PTFE) arterial anastomoses were compared.
The primary endpoint was the absence of bleeding at the
anastomosis at 4 min after randomization. Secondary end-points
included hemostasis at 7 and 10 min, treatment fail-ures
and the incidence of complications potentially related
to bleeding. Adverse events were recorded. A higher per-centage
of patients who received FS versus manual com-pression
achieved hemostasis at 4 min (85 versus 39 per
cent respectively; P 0001). Similarly, a higher percentage
of patients who received FS achieved hemostasis at 7 and
10 min (both P 0.001). The incidence of treatment failure
was lower in the FS group (P 0001). The rate of complica-tions
potentially related to bleeding was similar (P = 0.426).
The Authors concluded that the FS is safe and significantly
shortens the time to hemostasis in vascular procedures
using PTFE [21] In thoracic surgery fibrin glue is effective
in prevention of postoperative alveolar air leak by its appli-cation
on suture site after lung resections; sealants can also
be administrated into pleural cavity to achieve pleurodesis
in patients with intractable pneumothorax [22] In a pro-spective
randomised blinded study the role of autologous fi-brin
sealant (Vivostat) to reduce post-surgical air leakage
and drainage volumes following lobectomy in pulmonary
surgery was investigated. Fourty patients undergoing elec-tive
lobectomy were randomly allocated to two groups: FS
group (n = 20) and control group (n = 20); fibrin sealant
group donated 120 ml of whole blood which was processed
by the Vivostat system. Fibrin sealant was applied over all
areas at risk of air leaks and bleeding, in control group no fi-brin
sealant was used. Compared with the control group,
mean bleeding/exudate volumes were significantly reduced
in the Vivostat group (day 1, 370 vs. 525 ml; total, 424 vs.
782 ml; both P 0.001), and drains were inserted for a
shorter time (medians, 1 vs. 2 days, P = 0.07). Significantly
fewer patients had air leakage at any time in the Vivostat
group (40 vs. 80%, P = 0.02), and air leakage volumes were
significantly lower compared with the control group (med-ian
differences: day of surgery: 0.6 l/min, P = 0.01; total
0.8 l/min, P = 0.03) [23].
Fibrin sealants have also been used in orthopedic sur-gery:
they are effective in bleeding control in patients with
coagulation disorders (es. hemophilia patients) and reduce
intraoperative blood loss and postoperative blood transfu-sion
requirements in patients who underwent major proce-dures
such as total knee and total hip replacement surgery.A
prospective, randomised controlled trial of the use of FS in
150 consecutive patients undergoing total knee replace-ment
has been conducted. Patient were randomly allocated
to three groups: fibrin sealant group (n = 50) received 10 ml
of reconstituted fibrin sealant (Quixil) intraoperative, tran-examic
acid group (n = 50) received intravenous TXA, con-trol
group (n = 50) received no pharmacological
intervention. There was a significant reduction in the total
calculated blood loss for those in the topical fibrin spray
group (p = 0.016) and tranexamic acid group (p = 0.041)
compared with the control group. The reduction in blood
loss in the topical fibrin spray group was not significantly
different from that achieved in the tranexamic acid group
(p = 0.72) [24].
Fibrin sealants are widely used in a variety of neurosur-gical
procedures including aneurism repair, tumor resec-tion,
dural closure to prevent cerebrospinal fluid (CSF)
leakage, nerve anastomosis, and bleeding control during
spinal surgery for scoliosis. A prospective randomized
study was undertaken to test the hypothesis that applica-tion
of a fibrin sealant to exposed cancellous bone can
significantly reduce blood loss during Cotrel–Dubousset
instrumentation for idiopathic scoliosis. Thirty-three
patients were randomly assigned to the fibrin sealant or
nonsealant groups; another 10 patients operated on before
planning the study were included as historical controls.
Blood loss in the sealant group averaged 672 ml compared

5. M. Emilia et al. / Transfusion and Apheresis Science 45 (2011) 305–311 309
with 894 ml in the sealant control group. No patient in the
sealant group required homologous blood. The authors
conclude that fibrin sealant is a useful adjunct to spinal
surgical technique [25]. Hemorrhage in the upper digestive
system is an emergency condition. Peptic ulcer bleeding is
usually managed by endoscopic injection of various agents
but most of these are associated with a high rebleeding
rate and can induce tissue necrosis. There are many studies
supporting the hypothesis that fibrin glue injection is
effective for arrest of peptic ulcer bleeding and safer than
the use of other agents but randomized clinical trials to
compare the efficacy of FG and other agents are rare and
no statistically significant differences are reported. A ran-domized
trial compared the hemostatic effect of endo-scopic
injection with fibrin glue and epinephrine for
peptic ulcer bleeding. 51 patients entered this trial: initial
hemostasis was obtained in all enrolled patients, reblee-ding
was more in the epinephrine group than in the fibrin
sealant group (4 [15%] of 26 vs. 14 [56%] of 25 = 0.003), vol-ume
of blood transfusion, number of surgeries, hospital
stay, and number of deaths were similar between both
groups. The authors concluded that fibrin sealant injection
is more effective in preventing rebleeding than epineph-rine
after endoscopic therapy, but no difference in out-comes
with either therapy were noticed [26].
2.2. TachoSil
TachoSil consists of an equine collagen sponge coated
on one side with fibrinogen and thrombin and, unlike its
precursors, does not contain aprotinin nor any product of
bovine origin. The coated side appears yellow because it
is colored with riboflavin. This is the side which is applied
to the surgical site, participating in the coagulation cascade
to form a fibrin clot that resembles the final steps of the
natural process of blood clotting; the collagen patch pro-motes
activation and aggregation of platelets, serves as
anchoring and sealing material, absorbs fluid from the
wound site. TachoSil has been used in a wide variety of
surgical settings. In general surgery it has been tested in li-ver
resection to prevent bile leaks and reduce blood loss
[27], to manage conservative treatment of splenic trauma,
to promote colonic and small intestine anastomotic heal-ing,
to reduce alveolar air leaks following pulmonary resec-tions
[28].This product may also be used during minimally
invasive procedures, even though introducing and manip-ulating
it with laparoscopic instruments can sometimes
be difficult. However, for most of its applications,
TachoSil’s efficacy has yet to be proved by randomized
controlled trials.
3. Topical hemostatics
Topical hemostatics are absorbable agents that can be
used alone or in combination with fibrin sealants. These
products include collagen, gelatine and oxidized cellulose
and they are commercially available in many forms: gauze,
sheet, sponge, and fleece. Their mechanism of action is to
promote platelet activation and aggregation when directly
applied to the bleeding tissue and they can absorb body
fluids several times their own weight. They can be used
to control suture hole bleeding and to achieve hemostasis
on the surface of parenchymatous organs, but should not
be used to stop arterial bleeding (fibrin sealants are more
appropriate). Local hemostatics agents differ in biodegrad-ability
and their dissolution and absorption depends on the
material, the site of implantation and other local factors;
when hemostasis is achieved, it is preferable to remove
from the surgical site the material in excess to limit the
inflammatory response, the risk of bacterial contamination
and, because of its volume expanding potential, to prevent
nerves constriction against bony surface postoperatively.
3.1. Collagen based products
Collagen based agents, bovine or equine derived, in
addition to promoting hemostasis are useful as a scaffold
upon which cells proliferate and migrate accelerating
wound healing. Many agents are combined with thrombin
in order to enhance the effectiveness. There are many for-mulations
commercially available: sponge, powder, fiber
and sheet. These products may be useful in several proce-dures
in general, hepatic, orthopedic and cardiovascular
surgery: sponges and sheets are especially indicated to ob-tain
hemostasis in parenchymal tissues. Collagens of ani-mal
origin, especially bovine derived, have the potential
to promote immunological events but occurrence of aller-gic
reactions is low.
3.2. Gelatin hemostatic agents
Gelatin-based hemostatic agents are prepared from
purified pork skin gelatin or bovine derived gelatine. They
provide a mechanical matrix that promotes clotting and
can be combined with topical thrombin. Gelatin-based
agents are available in sponge, powder or granular forms.
Gelatin sponges in particular can absorb a large amount
of blood and other fluids and can be useful in anorectal sur-gery,
nasal bleeding, neurosurgery, urology. Gelatin matri-ces
are able to adjust to irregular wounds and surgical
cavities and are practical to use in minimally invasive pro-cedures.
Rare cases of abscess or granuloma formation
have been reported with the use of gelatin-based hemo-statics.
FloSeal is a bovine-derived granular matrix com-bined
with human-derived thrombin: the gelatin
formulation ensures conformation to tissue surfaces and
confined spaces and provides a matrix that promotes the
formation of a stable clot. FloSeal matrix has been success-fully
used in neurosurgery, thyroidectomy [29], orthopedic
and cardiovascular surgery. A multicenter, prospective
study evaluated the hemostatic effectiveness of an absorb-able
porcine gelatin in combination with human thrombin,
Surgiflo, in patients undergoing endoscopic sinus surgery.
The authors concluded that Surgiflo was clinically effective
in controlling bleeding in irregular wounds, such as those
on mucosal surfaces after sinus surgery, in 96.7% of pa-tients
[30].
3.3. Cellulose-based products
Cellulose-based hemostatics are vegetable-derived
products, biodegradable and biocompatible; they are

6. 310 M. Emilia et al. / Transfusion and Apheresis Science 45 (2011) 305–311
completely reabsorbed by hydrolysis with a low rate of for-eign-
body reactions and no immunologic risk. They also
have antimicrobical activity and can be used for the preven-tion
and treatment of surgical site infection [31]. There are
two formulations commercially available: oxidized regen-erated
cellulose obtained from wood pulp cellulose and oxi-dized
cellulose obtained from cotton fiber. The first
experiments in animal models date back to the 40s [32]. Cel-lulose-
derived hemostatics have been successfully used in
general surgery, neurosurgery, otorhinolaryngoiatry and
cardiovascular surgery and their application is especially
useful in capillary and venous oozing control. However
more studies concerning their appropriate use, advantages
and limitation are needed.
3.4. Adhesives
Adhesives are low viscosity liquids that polymerize in
few seconds forming a solid film that connects atraumati-cally
the tissues surfaces. This property makes adhesives
effective tissue sealants and effective hemostatic agents.
They can be divided in synthetic (cyanoacrylates and PEG
– polyethylene glycol sealants) and semisynthetic (glutar-aldeide-
albumina) sealants. Cyanoacrylate monomers
polymerize in the presence of local hydroxyl groups
through an exotermic reaction. Cyanoacrylates have
numerous surgical and medical applications such as skin
closure and wound repair (especially in pediatrics) with
formation of an antimicrobial barrier, esophageal and gas-tric
varices management, air leaks prevention in lung
resection [33], suture hole bleeding prevention in arterial
anastomoses, reparation of peripheral nerves. Some formu-lations
are approved only for topical use and not for inter-nal
use because of potential toxicity. Albumin cross-linked
with glutaraldeide adhesives produces a strong film that is
effective in achieving hemostasis in large vascular anasto-moses
[34], aortic dissection treatment, pulmonary paren-chyma
and bronchial anastomosis sealing, neurosurgical
procedures.
4. Conclusions
Good hemostasis during surgical procedures plays a key
role in achieving successful patient’s outcome. Therefore,
in addition to traditional hemostatic methods, several top-ical
hemostatic agents have been developed to reduce time
in theatre and complications by decreasing intraoperative
bleeding and need for blood transfusions and by facilitat-ing
modern surgical technologies such as minimally inva-sive
surgery, endoscopy and robotic procedures. A wide
variety of commercial products is now available and an
extensive knowledge of these agents is of critical impor-tance
to ensure positive results and to reduce overall costs
in surgery. The ideal hemostatic should be safe, effective,
practical and cost-effective. Nonetheless, up to date no
strong evidence about the proper use of topical hemostat-ics
in different surgical specialties has been provided and
rigorous controlled trials are still to be performed. In fact,
randomised controlled trials conducted so far involve
mostly fibrin sealants, whose effectiveness in reducing
blood loss, especially in orthopedic surgery, has been dem-onstrated.
A large number of commercial and blood bank
prepared (‘home made’) fibrin sealants are commonly used
in a variety of surgical settings: these products are some-how
similar in composition but actually vary widely as to
components and preparation methods. Adjunctive local
hemostatic treatments include collagen, gelatins, oxidized
celluloses, synthetic and glutaraldeide-albumina adhe-sives;
more data about their feasibility, clinical effective-ness
and limitations are required. In conclusion, topical
hemostatic agents are increasingly becoming a key ele-ment
to achieve optimal hemostasis in specific surgical
procedures, particularly when standard techniques are
insufficient, but several concerns about their appropriate
use and overall cost still have to be solved.
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