Overview of Topical Hemostatic Agents and Tissue Adhesives - UpToDate

Overview of topical hemostatic agents and tissue adhesives - UpToDate 07/01/22 11'48
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Overview of topical hemostatic agents and tissue

adhesives
Author: Elizabeth Peralta, MD
Section Editor: Amalia Cochran, MD, FACS, FCCM
Deputy Editor: Kathryn A Collins, MD, PhD, FACS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2021. | This topic last updated: Jan 03, 2022.
INTRODUCTION
Intraoperative bleeding is controlled using standard surgical techniques (eg, electrocautery,

vessel ligation, suturing). Using these techniques, blood loss is minimal, with most routine,
elective operations in patients with normal hemostasis. Topical hemostatic agents (physical
agents, biologically active agents) and tissue adhesives are used as an adjunct or alternative
to standard surgical techniques to manage bleeding from surgical surfaces, and are
particularly useful for diffuse nonanatomic bleeding, bleeding associated with sensitive
structures, and bleeding in patients with hemostatic abnormalities.
The mechanism of action, indications, and clinical application of the most common topical
hemostatic agents and tissue adhesives used in surgery are reviewed here. Devices used to
achieve surgical hemostasis through vascular control during dissection are discussed
elsewhere. (See "Overview of electrosurgery" and "Instruments and devices used in
laparoscopic surgery".)
HEMOSTATIC AGENTS
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Topical hemostatic agents are used when surgical hemostasis is inadequate or impractical.
The two main categories of topical hemostatic agents are physical agents, which promote
hemostasis using a passive substrate, and biologically active agents, which enhance
coagulation at the bleeding site ( table 1). (See 'Physical agents' below and 'Biologically
active agents' below.)
Indications for use — Topical hemostatic agents are primarily used for diffuse bleeding
from:
● Peritoneal or pleural surfaces

● Cut surfaces of solid organs [1-3]
● Cut edges of bone
● Bleeding near nerves
● Bleeding near vital structures at risk for cautery-induced injury
● Bleeding from vascular structures or grafts due to suture holes (see 'Surgical scenarios'
below)
● Nasal structures as nasal packing [4,5]
● Dental extraction sites [6]
Topical hemostatic agents can also be used for other purposes, including the management
of:
● Air leak following lung resection [7]

● Eardrum perforation [8]
● Endoscopic control of gastrointestinal bleeding [9-11]
● Leakage prevention from colonic anastomoses [12]
Contraindications — Topical hemostatic agents should not be used intravascularly,

because they will cause thrombosis. Also, they should not be used in confined spaces where
expansion of the product could lead to compression. (See 'Adverse effects and complications'
below.)
Physical agents
Dry matrix — Dry matrix agents promote hemostasis through several effects. The matrix
material provides a stimulus that activates platelets and the extrinsic pathway and provides a
scaffold for thrombus deposition. The dry matrix also absorbs water, concentrates
hemostatic factors at the site of bleeding, and tamponades bleeding vessels by exerting
pressure. These agents are easy to use; however, they are less effective if bleeding is brisk.
The agent is applied to the site of bleeding, followed by gentle pressure with a surgical
sponge. Care must be taken in removing the sponge because these agents generally adhere
to the underlying tissue and will remove the clot that has formed if removed quickly. A useful
technique for removal is wetting the sponge thoroughly and lifting the sponge from one
edge, slowly rolling the sponge off the clotted area.
Oxidized regenerated cellulose — Oxidized regenerated cellulose (ORC) is a dry,

absorbable sterile mesh (eg, Surgicel) that can be applied directly to an area of bleeding. A
single-layer sheet is fully absorbed in approximately 14 days [13]. Results are optimal if
bleeding is minimal (ie, oozing).
ORC is commonly used to control bleeding at vascular anastomotic sites, the cut surfaces of
solid organs, and retroperitoneal or pelvic surfaces after lymphadenectomy. Because ORC is
pliable, it can be rolled and passed easily through laparoscopic trocars [14,15].
In vitro studies have found that ORC has bactericidal activity against a wide range of gram-
positive and gram-negative organisms because of its acidic pH [16,17]. The low pH also
inhibits proteases and elastase, which may be beneficial in chronic wounds; however, this
same property may inhibit its resorption [18]. Residual ORC is associated with infection and
adhesion formation. In one study of 360 patients with postoperative pelvic abscess,
unabsorbed ORC was identified as a risk factor, and in some cases un-resorbed ORC was
found at laparotomy more than 12 months after it was placed [19].
Gelatin matrix — Gelatin (eg, Gelfoam, Surgifoam) is a hydrocolloid made from acid
partial hydrolysis of porcine-derived collagen that is whipped into foam and then dried. It is
available in sponge or powder form [20,21]. Gelatin sponge absorbs blood or fluid up to 40
times its weight, and it expands up to 200 percent in its dimensions [22].
The dry sponge form can be tailored to any shape, and although rigid when dry, the sponge
is pliable after moistening and passes easily through laparoscopic ports. Once in place,
pressure is applied for several minutes to achieve hemostasis. The sponge can be left in
place and is completely absorbed after four to six weeks.
Because gelatin foam has a neutral pH, it does not inactivate thrombin, and thus, it is
common practice to moisten it with topical thrombin to synergize the effects of these agents.
The relative effectiveness of gelatin foam with or without thrombin has not been the subject
of clinical trials. In a pig model of splenic laceration, gelatin foam without thrombin required
two 20 second periods of finger pressure to stop breakthrough bleeding, while gelatin foam
with thrombin needed only one 20 second period [23].
The disadvantages of gelatin include an increased incidence of infection, granuloma, and

fibrosis formation and, similar to dry matrix product, the potential for disruption of the clot if
the sponge is removed [13,20]. Although all brands of gelatin matrix are derived from
porcine connective tissue, it is not considered to be antigenic.
Microporous polysaccharide spheres — Microporous polysaccharide spheres (MPS;

eg, Arista) are derived from potato starch, which accelerates clot formation by acting as a
molecular sieve to absorb water and concentrate platelets and blood proteins. MPS is
available in powder form.
MPS is used by first applying pressure to the bleeding site with a dry surgical sponge for two
minutes to achieve a relatively dry surface, then liberally applying the powder with the
bellows applicator. Gentle pressure is reapplied with a fresh surgical sponge for one to two
minutes until hemostasis is achieved.
The advantages of MPS include low cost, rapid absorption within 48 hours, and freedom
from transmissible viruses or alloantigens. In addition, MPS does not act as a nidus for
infection or cause foreign body reactions [24,25]. It is used in cosmetically sensitive areas
such as face lifts and been approved for use in neurosurgery [26].
Microfibrillar collagen — Microfibrillar collagen (MC) is an absorbable acid salt

obtained from bovine collagen (eg, Avitene). MC acts as a scaffold for clot formation and
activates platelets. MC can be applied directly to the bleeding site as a powder [27,28], but
foam sheet formulations (Avitene Ultrafoam) are available. MC is fully absorbed within three
months. MC remains effective with heparinization but is less effective when platelet counts
3
are below 20,000/mm3.
MC is indicated for use in neurosurgery and urology, and also for providing hemostasis in
vascular surgery. A manufacturer-sponsored single-center trial (64 polytetrafluoroethylene
[PTFE] arterial bypass graft anastomoses in 32 patients) found a significantly shorter time to
hemostasis using microfibrillar collagen compared with oxidized, regenerated cellulose (125
versus 416 seconds) [29].
MC is contraindicated in blood scavenging systems because the fibers can pass through the
filters, causing embolization and, potentially, disseminated intravascular coagulation.
Bone wax and putty — Blood oozing from the cut surface of medullary bone is a common
feature of median sternotomy, orthopedic, and neurosurgery procedures. Agents placed into
the cut surface to minimize bleeding are made of natural or synthetic substances.
● Bone wax – Bone wax, which is composed of beeswax, paraffin, and wax-softening
agents, physically occludes bleeding vessels within bone to stop bleeding. When using
bone wax, a minimal amount should be used, and it is rubbed across the surface of the
bone surface without leaving a raised plug. Bone wax is inexpensive and effective but
can lead to infection or granuloma formation, which can interfere with bone healing
[30,31]. In one retrospective study in neurosurgical patients, the incidence of surgical
site infection significantly decreased when bone wax was no longer used (14.2 versus
1.3 percent) [31].
● Ostene – Ostene is a wax-like compound of a water-soluble alkaline oxide copolymer

that occludes bleeding vessels in bone like bone wax, but it does not persist in the
wound as a foreign body. In animal studies comparing Ostene with bone wax, Ostene
did not remain in the wound beyond three weeks, and bone healing was more
pronounced in the Ostene group [32,33].
● Bone putty – A resorbable hemostatic bone putty (Hemasorb Plus) is comprised of

granular hydroxyapatite/beta-tricalcium phosphate and water-soluble components that
are fully synthetic and resorbable. It is available in moldable strips and in an applicator
that does not require kneading.
External agents — In rescue or battlefield situations, external hemorrhage is generally

controlled with direct pressure and standard dressings; however, when these are ineffective,
external topical agents can be used as specialized dressings to temporize hemorrhage until
definitive management is possible. A number of products have been used by the United
States military to control external bleeding in the combat setting, and some have been
extended for civilian use ( table 1) [34-37]. In the operating room, externally applied agents
should be removed under anesthesia just prior to prepping and draping unless there is a risk
of severe, life-threatening hemorrhage upon removal of the dressing. In this situation,
proximal vascular control should be obtained prior to removing the material.
Some of these agents have been tried for controlling bleeding during surgery, but their
indications and effectiveness are not fully known at this time.
HemCon bandage — The HemCon bandage is a dressing composed of lyophilized

chitosan, a biodegradable complex carbohydrate derived from chitin. Its hemostatic function
is attributed to the strong adhesive properties of chitosan, which attaches firmly to wet
tissues and seals bleeding vessels [34]. Successful use of this bandage as a hemostatic agent
for prehospital combat casualties has been reported when standard methods were
unsuccessful [36].
HemCon bandage has also been used in a civilian emergency medical services system when
conventional treatment (ie, pressure and gauze dressings) failed to control external bleeding
wounds, or for obvious arterial bleeding. Results included [38]:
● HemCon bandage controlled hemorrhage in 27 of 34 cases (79 percent), most often

within three minutes of application.
● The bandage effectively controlled bleeding in 19 of the 25 cases in which direct

pressure had initially failed.
● No adverse events or complications were reported. Proper training in the use of this
bandage was considered essential as user error was a contributing factor in most of the
documented failures.
ChitoFlex — ChitoFlex is a rolled version of chitosan in a different formulation than the
HemCon bandage. It is very pliable and is designed to be packed into a wound tract [35].
QuikClot — QuikClot is a kaolin-based dressing. Kaolin is an inorganic product that

activates factor XII of the coagulation cascade. Kaolin-based QuikClot products are available
for a variety of applications for control of external as well as internal bleeding during surgery
[39-41].
The prior formulation of QuikClot was a zeolite-based granule with low (1%) moisture that,
when placed on a bleeding wound, absorbed water and concentrated red cells, platelets, and
clotting proteins at the injury site, thereby promoting rapid coagulation and arresting
hemorrhage [34]. The reaction released significant amounts of heat, with the potential of
causing thermal injury in some tissues, depending on the formulation used (granules, gauze,
pad).
QuikClot in the form of a gauze or pad has been used in combat situations to control
external bleeding [42]. (See "Prehospital care of the adult trauma patient", section on
'Hemorrhage control'.)
The safety of using kaolin-based QuikClot intracorporeally compared with standard

laparotomy pads was evaluated among 68 patients undergoing damage control laparotomy
[43]. No difference in complications rates was detected. Compared with standard sponges,
the use of the kaolin-impregnated sponges in 31 infants undergoing the Norwood procedure
had a significantly lower intraoperative use of blood products and lower incidence of
perioperative bleeding requiring return to operating room for hemostasis (0 versus 41
percent) [44].
Nustat — Nustat consists of hemostatic fibers composed of cellulose and silica. It is

approved for use in the United States for external use in rescue and combat situations. The
same pad with the addition of a radio-opaque thread, supplied under the name NuStat
Trauma Pad, is approved for use inside the surgical field for temporary control of arterial or
other brisk bleeding [45].
Biologically active agents — Biologically active agents augment hemostasis. Hemostasis is

a dynamic process occurring in four general phases (initiation and formation of the platelet
plug, propagation of the clotting through the coagulation cascade, termination of clotting by
antithrombotic control mechanisms, and removal of the clot by fibrinolysis). These are
discussed in detail elsewhere. (See "Overview of hemostasis".)
Topical thrombin — Topical thrombin is reconstituted from a lyophilized powder. It can be

applied using a sprayer, which is useful for managing diffuse bleeding from oozing
peritoneal and pleural surfaces or applied with a syringe to direct its application to a specific
area of bleeding. Topical thrombin can also be used in conjunction with a gelatin matrix
agent (sponge or granules) that provides the thrombin with an immediate scaffold for clot
formation [46-48]. (See 'Gelatin matrix' above.)
Topical thrombin in combination with gelatin foam or granules is useful for promoting
hemostasis at vascular graft suture hole sites. Due to its liquid nature, thrombin applied in
combination with gelatin granules (eg, FloSeal, Surgiflo) may control bleeding more quickly
than thrombin-soaked pieces of gelatin foam. (See 'Effectiveness' below.)
Urine does not significantly inhibit the activity of thrombin or thrombin-fibrin combination
products at their application site. The urologic literature describes the use of FloSeal gelatin
matrix thrombin solution to the partial nephrectomy bed [49]. This may have an advantage
over dry matrix agents (and suture material), which can act as a nidus for stone formation
[50].
Human thrombin and a recombinant thrombin are available for use, largely replacing bovine
thrombin [51]. (See "Fibrin sealants", section on 'Components'.)
Fibrin sealant — Fibrin sealants are typically a two-component system that includes a
solution of concentrated fibrinogen and factor XII and a solution of thrombin and calcium.
When mixed together just prior to use, a fibrin clot forms. Fibrin sealant can be used to
control bleeding at vascular anastomotic sites. They are also used to control bleeding from
cut surfaces. Fibrin sealants and their application are reviewed in more detail separately. (See
"Fibrin sealants".)
Tranexamic acid — Tranexamic acid is a synthetic derivative of the amino acid lysine that
exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on
plasminogen molecules [52]. Systemic tranexamic acid administered at the outset for surgery
reduces intraoperative blood loss as well as blood loss from drained spaces such as the knee
or mediastinum, but may be contraindicated in patients with intravascular stents or

thrombophilia [53]. (See "Initial management of moderate to severe hemorrhage in the adult
trauma patient", section on 'Developing treatments for hemorrhage'.)
Topical application of tranexamic acid to the bleeding surface has the potential to inhibit
local fibrinolysis at the site of bleeding, reducing bleeding with minimal systemic effects. The
effects of topical tranexamic acid have been evaluated primarily during orthopedic surgery
[54] but also with head and neck surgery [55], cardiac surgery [56,57], and breast surgery
[58]. A systematic review identified 28 trials that compared topical tranexamic acid in surgical
patients (cardiac, thoracic, spinal, knee, or head and neck surgery) compared with no
tranexamic acid or placebo [59]. Blood loss was significantly reduced in those who received
tranexamic acid (pooled ratio 0.71, 95% CI 0.69-0.72), which decreased the need for blood
transfusion. The authors noted that there was significant statistical heterogeneity between
trials for the blood loss and blood transfusion outcomes. Additional high-quality trials are
needed to better identify the effects of topical tranexamic acid on thromboembolism and
mortality before topical tranexamic acid can be recommended.
Light-activated hemostatic agent — A novel, hydrophobic light-activated adhesive (HLAA),

which is a fluid/blood-resistant tissue glue, is in the investigational stages for use in surgical
and minimally invasive therapeutic cardiovascular procedures [60]. It consists of a
prepolymer, poly(glycerol sebacate acrylate) that is biocompatible, biodegradable, and
hydrophobic, which, when mixed with a photoinitiator and exposed to ultraviolet light, cross-
links in situ. HLAA can be applied as a liquid and activated when needed to cure and bond.
HLAA does not dissolve in an aqueous or intravascular blood environment, even when
subjected to pressure and flow.
Effectiveness — High-quality data establishing the effectiveness of topical hemostatic

agents in surgery are lacking. The package insert and US Food and Drug Administration
(FDA) medical device application for each hemostatic agent contain data from animal studies
and unpublished trials that compare its effectiveness usually with gelatin foam or oxidized
regenerated cellulose. Published randomized trials in which topical agents were used for
minor intraoperative bleeding sites include the following:
● In three trials involving patients undergoing vascular, spinal, or cardiac surgery,
hemostatic sealants (Floseal, Proceed) were found to have significantly higher rates of
hemostasis (88 to 99 versus 57 to 93 percent) at 10 minutes after application compared
with thrombin-gelatin combination [21,61,62].
● In a trial of 69 patients undergoing obstetric, gynecologic, general, vascular, and

cardiothoracic surgery, an autologous fibrin sealant resulted in a significantly higher
rate of hemostasis (94 versus 65 percent) at five minutes after application compared
with oxidized regenerated cellulose [63].
● In a multicenter trial, 333 patients were randomly assigned to receive the fibrin sealant
or a conventional topical hemostatic agent [64]. Fibrin sealant controlled bleeding
successfully within five minutes of application in significantly more patients (93 versus
12 percent) compared with conventional topical agents. There were no differences in
volume of blood products used or mortality between the two groups.
TISSUE ADHESIVES AND SEALANTS
Tissue adhesives can be used to promote hemostasis but are predominantly used as an
alternative to sutures for tissue approximation. Most commonly, cyanoacrylates are used to
close minor wounds and skin incisions under low tension in patients who do not have serious
medical comorbidities that could impair wound healing. Other agents, such as albumin-
based tissue adhesives and polyethylene glycol hydrogels, and surgical applications other
than skin closure, have also been investigated.
Fibrin sealant — Fibrin sealants are typically a two-component system that includes a
solution of concentrated fibrinogen and factor XII, and a solution of thrombin and calcium. In
addition to their hemostatic properties (see 'Fibrin sealant' above), fibrin sealants have
properties that make them useful for promoting graft adhesion or to seal leakage. Fibrin
sealants are reviewed in more detail separately. (See "Fibrin sealants".)
As an example, in a review of 65 patients who underwent abdominoplasty, fibrin sealant

reduced the rate of seroma formation, and when drains were used in combination with fibrin
sealant, drain output volume was also reduced [65].
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Cyanoacrylate — Cyanoacrylate tissue adhesives octyl-2-cyanoacrylate (eg, Dermabond) and

butyl-2-cyanoacrylate (eg, Histoacryl) are liquid monomers that change to strong polymers
with exposure to moisture. The properties of tissue adhesives are discussed elsewhere. (See
"Minor wound repair with tissue adhesives (cyanoacrylates)", section on 'Properties of tissue
adhesives'.)
Cyanoacrylates are used primarily for skin incision closure during surgery. However,
cyanoacrylates have also been used to repair the cornea [66-68]; fixate skin grafts [69]; repair
vessels [70,71]; fixate mesh during hernia surgery [72]; during circumcision [73-78]; to seal
dural leaks [79], air leaks (ie, bronchopleural fistula), and lymphatic leaks; and endoscopically
to seal bleeding esophageal varices or peptic ulcer [9-11]. The use of cyanoacrylates for
closure of minor wounds and methods of application are discussed in detail separately. (See
"Minor wound repair with tissue adhesives (cyanoacrylates)".)
As a substitute for typical sutured skin closure (eg, subcuticular sutures), tissue adhesives
have been used for a variety of open and laparoscopic procedures, including inguinal and
femoral hernia repair, testicular surgery, lymph node biopsy, thyroid surgery, hand surgery,
excision of skin lesions, blepharoplasty, vein excision, and intraoral surgery [80-96]. The most
common elective use of cyanoacrylate tissue adhesive in the operating room is as a final,
waterproof seal over subcutaneous absorbable sutures in lieu of a taped-on dressing.
Compared with traditional, sutured techniques, two separate meta-analyses found that the
risk of infection, cosmetic outcomes, surgeon and patient satisfaction, and cost were
equivocal between sutured closure and adhesive closure [86,97]. However, suture repair was
associated with a lower risk of wound dehiscence. Notably absent from studies evaluating
tissue adhesives are procedures involving incisions in areas of high tension (eg, elbow, knee,
shoulder). In addition, patients whose medical comorbidities increase the risk for impaired
wound healing have also been excluded from such studies.
The larger of these meta-analyses included 26 trials evaluating the use of tissue adhesives
for closure of surgical incisions [86]. An earlier updated Cochrane review that included 14
trials (n = 14) had similar conclusions [97]. The updated review identified an additional six
studies.
● Among 29 trials that evaluated wound infection rates, no significant differences were
found.
● Among 20 trials, wound dehiscence occurred in significantly more incisions closed with
tissue adhesives compared with standard wound closure (5 percent [38/762] versus 1.2
percent [9/779]). Adhesives may take more time to apply, and if higher tension is
needed upon an incision, sutures may minimize dehiscence
● Among 16 trials comparing the speed of closure using tissue adhesives versus skin
sutures, 14 found tissue adhesives to be faster than skin sutures, one found sutures to
be faster than adhesives, and one found no difference. Comparing tissue adhesives
with staples, three of four studies found staples to be faster; the remaining study found
no difference. Compared with adhesive tape, one study found no significant difference.
Albumin based — Albumin-based tissue adhesives combine albumin and an organic

compound immediately prior to use. The mixture forms a matrix with adhesive properties.
One such compound consists of a combination of bovine albumin and glutaraldehyde
(Bioglue, ArterX) [49,98-104]. Another example is the combination of human albumin and
polyethylene glycol (FocalSeal-L, Progel), which has been used to treat pulmonary air leak
[105,106]. A trial that compared autologous fibrin tissue adhesive to a commercial
preparation and controls that did not receive tissue adhesive application during spinal cord
surgery found no difference between autologous and commercial preparations, but,
compared with the control group, the volume of cerebrospinal fluid drainage was
significantly reduced (586 versus 1026 mL) [107].
Polyethylene glycol hydrogel — A completely synthetic tissue adhesive (CoSeal) combines

two forms of polyethylene glycol (PEG) to form a hydrogel. This compound has been used to
treat bleeding vascular graft suture holes and has also been used during vitrectomy surgery
[108,109]. In a multicenter trial that randomly assigned 148 patients undergoing
polytetrafluoroethylene (PTFE) vascular graft placement to PEG hydrogel or thrombin/gelatin
sponge, the median time to achieve vascular control was significantly less for those treated
with PEG hydrogel (16.5 versus 189 seconds) [108]. However, no differences were seen at the
primary endpoint of 10 minutes (86 versus 84 percent). A drawback of PEG hydrogel is its
tendency to swell up to four times its initial volume over a 24-hour period, with some
continued swelling thereafter, thus limiting its application in confined spaces.
Urethane-based — A synthetic polyurethane tissue adhesive (TissuGlu) has been approved

for internal use in the United States based upon studies demonstrating reduced fluid
accumulation beneath abdominoplasty flaps without the need for external drains [110-113].
ADVERSE EFFECTS AND COMPLICATIONS
Adverse effects of topical hemostatic agents and tissue adhesives and sealants are related to
the composition and characteristics of the preparation, location of placement, and
absorption time. Excessive amounts of a slowly degrading product can serve as a nidus for
infection, and agents placed into a confined place can cause compression of surrounding
structures, particularly if the product has a tendency to expand. As examples, gelatin foam
matrix in combination with thrombin has complicated eye and spine surgery, causing
blindness and paralysis, respectively [114].
● Air/gas embolism – Air or gas embolism, which has caused death, has been reported
with the use of injectable agents such as spray thrombin and fibrin sealant [115-118].
This risk increases when the products are sprayed too close to the tissue or when the
maximum pressure recommended in the fibrin sealant kit is exceeded.
● Surgical infection – There are many clinical reports of wound infections associated
with the use of hemostatic agents. Adverse factors such as emergency procedure,
transfusion, and prolonged operative time are associated with an increased risk of
surgical wound infection and frequently coexist with the need for hemostatic agents,
and thus, any analysis of the risk of infection due to hemostatic agent is confounded.
The risk of infection may be minimized by removing excess topical hemostatic agents
from the wound after hemostasis is achieved, when possible.
● Impaired wound healing – Excess application of topical hemostatic agents can impede
wound healing. Granuloma formation has been reported with the use of microfibrillar
collagen, gelatin foam, and cyanoacrylate [13,119-121]. In addition, the metabolites of
cyanoacrylates (ie, cyanoacetate and formaldehyde) can cause an inflammatory
response in the surrounding tissues.
● Hypotension – The development of profound hypotension in some individuals after

direct parenchymal injection of bovine-derived fibrin sealant is believed to be related to
highly concentrated bovine thrombin [122]. The hypotension, which lasts approximately
30 seconds, responds to epinephrine; in addition, this complication can be avoided by
reducing the use of bovine thrombin and by compressing the injection sites.
● Anaphylaxis – Allergic reactions (including anaphylaxis) are associated primarily with

bovine-derived products (eg, bovine thrombin) [123]. These products should not be
used in patients with a history of prior anaphylactic reactions to plasma products or IgA
deficiency [46]. A history of prior anaphylactic reactions to plasma products or of IgA
deficiency contraindicates the use of fibrin sealants prepared from plasma or
cryoprecipitate. (See "Fibrin sealants", section on 'Contraindications'.)
A single case report of a systemic allergic reaction during a laparoscopic

cholecystectomy was associated with the use of microfibrillar collagen [124].
● Bloodborne disease – A complication common to all blood components is the potential

transmission of an infectious disease, even from screened and tested blood [125]. In
addition to the patient, health care workers in the operating room may theoretically be
exposed to an infectious disease risk when sealants are applied in an aerosolized form.
The use of recombinant human thrombin should reduce the risk.
Nevertheless, although viral transmission is theoretically possible, no cases have been

documented with the use of fibrin sealant over the past 20 years, particularly with
respect to transmission of hepatitis or HIV. This may be more attributed to extensive
viral protection methods, including viral screening (serology and nucleic acid testing
[NAT]), complemented by viral reduction methods, including filtration, heat treatment,
solvent-detergent cleansing, precipitation, pH treatment, and chromatography.
Autologous preparations of fibrin sealant virtually eliminate any infectious disease risk
[126-128].
● Vascular thrombosis – No increased rate of vascular or graft thrombosis has been

reported with the topical use of hemostatic agents. Although there were concerns in
the past that polyester grafts (eg, Dacron) could allow thrombin to leak into the lumen
and lead to thrombosis and embolism, this is not an issue with currently available
grafts. Topical hemostatic agents should not be injected into a blood vessel or within an
opened vessel.
Embolization of gelatin matrix into the bloodstream from spraying it onto the cut
surface of bone has been reported [129].
Blood salvage (eg, CellSaver) should not be used when blood has been in contact with
gelatin or collagen, because fibers can pass through the filters and cause intravascular
coagulation.
● Immune-mediated coagulopathy – A bleeding diathesis can occur in patients who

develop factor V deficiency because they make an antibovine factor V antibody (bovine
factor V is a contaminant of bovine thrombin preparations) that cross-reacts with
endogenous factor V. As discussed above, the use of human thrombin should prevent
this complication. (See "Fibrin sealants", section on 'Thrombin'.)
As an example of this issue, in one prospective study of 151 patients undergoing

cardiac surgery, 95 and 51 percent of those with prior exposure to bovine thrombin
demonstrated a seropositive response to bovine and human coagulant proteins,
respectively [130]. The adjusted odds ratio for development of an adverse postoperative
outcome was 5.4 when multiple antibodies to bovine coagulant proteins were present
preoperatively. Such antibodies may persist for years following the initial exposure to
bovine thrombin [131].
CHOICE OF AGENT
The choice of topical hemostatic agents to use depends upon amount and location of
bleeding, availability of a given agent, cost considerations, and surgeon preference [132].
Biologically active agents (eg, topical thrombin, fibrin seal) are more useful for brisk bleeding
compared with dry matrix agents (eg, gelatin matrix) and are more effective in the setting of
coagulopathy or in defibrinated fluid such as pooled serum or cerebrospinal fluid.
Although more expensive, fibrin sealants have significantly higher rates of hemostatic
control compared with thrombin-gelatin combinations. Fibrin sealant and bovine albumin-
glutaraldehyde tissue adhesive (eg, Bioglue) are appropriate choices when moderate
bleeding does not respond to other measures. (See 'Effectiveness' above.)
Surgical scenarios — Options for using topical hemostatic agents for various surgical
scenarios are given below, including a cost for each agent. Cost key: ¢ = less than 50 United
States dollars (USD), $ = 50 to 100 USD, $$ = 101 to 300 USD, $$$ = 301 to 500 USD, $$$$ =
501 to 750 USD.
Large artery bleeding/repair (aorta, femoral, carotid):
● Bioglue ($$$$) is approved in the United States for large vessel repair in cardiovascular
surgery.
● NuStat Trauma Pad applied to the bleeding artery will stop bleeding temporarily to
allow visibility for control and repair of the vessel and organ.
● Other topical hemostats are not generally approved for arterial bleeding, except
microporous polysaccharide spheres (Arista; $), which have been evaluated in a femoral
artery porcine model (to a systolic blood pressure of 155 mmHg) [133].
Pulsatile needle hole bleeding in vessel adventitia or in vascular graft material:
● Apply microporous polysaccharide spheres (Arista; $).
● Apply thrombin-soaked gelatin foam (Gelfoam, Surgifoam; $) or oxidized regenerated

cellulose (eg, Surgicel; $).
● Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).
● Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).
Pulsatile external exsanguinating hemorrhage, preoperative setting (arterial rupture, arterial

injury):
● Apply compression with external agents (eg, kaolin based [$], chitosan based [$$]).
● Pack with dry fibrin sealant dressing ($$$$+).
Spleen, liver, kidney parenchymal surface post-trauma or partial resection:
● Wrap with oxidized regenerated cellulose (eg, Surgicel; $) or microfibrillar collagen

(Avitene Ultrawrap; $$$) with or without suture fixation.
● Apply microporous polysaccharide spheres (eg, Arista) and hold sponge pressure for
several minutes ($).
● Spray with thrombin ($).
● Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).
● Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).
● Apply fibrin glue-oxidized regenerated cellulose "sandwich." This technique has been
described for sutureless hemostasis of laparoscopic wedge excisions of the kidney
[134].
Venous or capillary oozing from area of dissection or deserosalization:
● Apply oxidized regenerated cellulose (eg, Surgicel Nu-Knit, Surgicel Fibrillar) with
sponges and hand pressure ($ to $$).
several minutes ($ to $$).
● Spray with thrombin ($ to $$).
● Spray with fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).
Cavity or potential space, nerve or other tissue not amenable to cautery, need to avoid
compression of nerve:
several minutes. Irrigate away remaining powder ($).
● Avitene Flour, EndoAvitene (OK to leave in place; $$).
● Spray with fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).
Cost considerations — Topical hemostatic agents are usually prepackaged for one-time use
in quantities that are generally sufficient to manage bleeding from a single site. Although
these preparations should not be used unnecessarily, they are cost effective if they save
operative time, reduce transfusions, and prevent a return to the operating room. The cost of
these agents falls in the range between an electrosurgery pen and the handset of various
tissue-sealing energy sources (eg, ultrasonic desiccator).
Less expensive agents are frequently used in a routine or preventive setting to minimize
blood loss. The more expensive agents (fibrin sealants and microfibrillar collagen) are often
more effective in the setting of coagulopathy or anticoagulation and are frequently the
preferred choice when bleeding is not easily controlled. (See 'Effectiveness' above.)
Although it is easy to compare the direct cost of the various topical hemostatic agents, it is
difficult to assess the associated costs of surgery related to hemostatic agents, such as
operating room time and blood transfusion products. Using length of stay (LOS) as a rough
estimate of cost, a study of 36,950 patients correlated length of stay after cardiothoracic
surgery with the choice of hemostatic agent and found significantly less likelihood of
exceeding expected LOS for fibrin sealant (FloSeal) compared with other hemostatic agents
(Surgicel plus thrombin, Gelfoam plus thrombin) [135].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Acquired bleeding
disorders" and "Society guideline links: von Willebrand disease".)
SUMMARY AND RECOMMENDATIONS
● A major goal during any surgery is minimization of blood loss, which reduces the need
for blood transfusion. Bleeding during surgery is controlled using standard surgical
techniques such as electrocautery, vessel ligation, and suturing. Topical hemostatic
agents and tissue adhesives are useful adjuncts to manage bleeding from surgical
surfaces and are particularly useful for diffuse nonanatomic bleeding, bleeding
associated with sensitive structures, and bleeding in patients with hemostatic
abnormalities. (See 'Introduction' above.)
● Hemostatic agents work primarily by exerting physical effects or by enhancing existing

hemostatic mechanisms ( table 1). Physical agents include dry matrix agents, bone
waxes, and external agents. Biologically active agents that enhance normal hemostatic
mechanisms include thrombin-based products, fibrin sealant, tranexamic acid, and
others. (See 'Hemostatic agents' above.)
● Tissue adhesives can be used to promote hemostasis and are also used as an
alternative to traditional closure of surgical incisions. Agents include cyanoacrylates,
albumin-based adhesives, polyethylene glycol hydrogels, and urethane-based agents.
Agents with adhesive qualities are most commonly used to close surgical skin incisions
or minor wounds, but other applications in surgery have been investigated. For skin
closure using cyanoacrylates, the risk of infection, cosmetic outcomes, and cost are
similar between sutured closure and adhesive closure. However, sutured closure is
associated with a lower risk of wound dehiscence and is quicker to accomplish. (See
'Tissue adhesives and sealants' above.)
● Adverse effects and complications from topical hemostatic agents and tissue adhesives
are generally uncommon. Most problems can be avoided by limiting the amount of
agent remaining within the wound once hemostasis has been achieved. Thrombin-
based agents, which are blood products, have the potential for transmission of
bloodborne disease, and anaphylaxis and immune-mediated coagulopathy are rare
complications associated with bovine-derived agents. Other complications include
embolism, infection, impaired wound healing, and thrombosis. (See 'Adverse effects
and complications' above.)
● The choice of which topical agent to use depends upon the character, amount, and
location of bleeding; the availability of a given agent; surgeon preference; and cost
considerations. Dry matrix agents are less useful when bleeding is brisk. Fibrin sealant
and bovine albumin-glutaraldehyde tissue adhesive (eg, Bioglue) are appropriate
choices when moderate bleeding does not respond to other measures. (See 'Choice of
agent' above and 'Effectiveness' above.)
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123. Milde LN. An anaphylactic reaction to fibrin glue. Anesth Analg 1989; 69:684.
124. Kitamura K, Yasuoka R, Ohara M, et al. How safe are the xenogeneic hemostats?--Report
of a case of severe systemic allergic reaction. Surg Today 1995; 25:433.
125. Kawamura M, Sawafuji M, Watanabe M, et al. Frequency of transmission of human

parvovirus B19 infection by fibrin sealant used during thoracic surgery. Ann Thorac Surg
2002; 73:1098.
126. Reiss RF, Oz MC. Autologous fibrin glue: production and clinical use. Transfus Med Rev
1996; 10:85.
127. Oz MC, Jeevanandam V, Smith CR, et al. Autologous fibrin glue from intraoperatively
collected platelet-rich plasma. Ann Thorac Surg 1992; 53:530.
128. Quigley RL, Perkins JA, Gottner RJ, et al. Intraoperative procurement of autologous fibrin
glue. Ann Thorac Surg 1993; 56:387.
129. Ferschl MB, Rollins MD. Thromboemboli, acute right heart failure and disseminated
intravascular coagulation after intraoperative application of a topical hemostatic matrix.
Anesth Analg 2009; 108:434.
130. Ortel TL, Mercer MC, Thames EH, et al. Immunologic impact and clinical outcomes after
surgical exposure to bovine thrombin. Ann Surg 2001; 233:88.
131. Randleman CD Jr, Singla NK, Renkens KL, et al. Persistence of antibodies to the topical
hemostat bovine thrombin. J Am Coll Surg 2010; 211:798.
132. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical
hemostatic agents: efficacy and recommendations for use. Ann Surg 2010; 251:217.
133. Burgert JM, Gegel BT, Austin R 3rd, et al. Effects of arterial blood pressure on rebleeding
using Celox and TraumaDEX in a porcine model of lethal femoral injury. AANA J 2010;
78:230.
134. Finley DS, Lee DI, Eichel L, et al. Fibrin glue-oxidized cellulose sandwich for laparoscopic
wedge resection of small renal lesions. J Urol 2005; 173:1477.
135. Krishnan S, Conner TM, Leslie R, et al. Choice of hemostatic agent and hospital length of
stay in cardiovascular surgery. Semin Cardiothorac Vasc Anesth 2009; 13:225.

Topic 15069 Version 29.0
GRAPHICS
Topical hemostatic agents for managing bleeding
Trade
How names in Absorption Adverse
Agent Source
supplied United time [1] effect* [2] expen
States
Physical agents
Wax-based
Bone wax Beeswax Stick form Not Indefinite Impaired ¢

applicable bone
healing
Ostene (soluble Synthetic Stick form Ostene 48 hours ¢

copolymer alkaline oxide
implant copolymers
material)
Dry matrix
Absorbable Porcine Sponge, Gelfilm, 4 to 6 weeks Infection, $

gelatin (gelatin powder Gelfoam, abscess or
matrix) Surgifoam, granuloma
Gelfoam formation,
hemostasis fibrosis, clot
kit (also disruption if
contains sponge is
human removed [1]
thrombin)
Oxidized Plant Mesh Surgicel 1 to 2 weeks Δ Foreign $

regenerated (Nu-Knit, body
cellulose Fibrillar, reaction,
SNoW) infection,
adhesions [1]
Microfibrillar Bovine Sheets Actifoam, >8 weeks Granuloma $$

collagen Avitene formation,
(collagen (Ultrafoam), allergenic
hemostat) Endo
Avitene,
Instat MCH,
Helistat
Helitene,
Syringe
Avitene
Powder Avitene
Flour
Microporous Synthetic Powder Arista AH 24 to 48 Use of >50 g $

polysaccharide hours can alter
spheres (MPH) glucose load
in patients
with
diabetes
External agents
Chitosan Biodegradable Adhesive HemCon Not Training ¢

complex dressing bandage applicable needed to
carbohydrate (Chitoflex) ensure
derived from proper
chitin application
Kaolin- Aluminosilicate Gauze Quikclot Not Possible clot ¢

impregnated mineral sponge applicable disruption
sponge when
sponge
removed
Hemafiber Cellulose and Dressing, NuStat Not Possible clot $

silica surgical OTC, applicable disruption
pad, elastic NuStat when pad
wrap Trauma Pad removed
XR, NuStat
Flex
Biologically active agents
Topical thrombin Bovine Liquid Thrombin- Not Intravascular $$

JMI applicable application
leads to
Human Evithrom
thrombosis
Recombinant Recothrom Antibody

human formation
(rHuman) against
bovine
thrombin
can inhibit
coagulation
and prolong
prothrombin
time/INR
Fibrin sealant Human Liquid Artiss, Immediate Potential $$$

(human fibrinogen Tisseel (also exposure to
and human contains blood-borne
thrombin) ◊ synthetic viruses
aprotinin),
Evicel,
TachoSil,
Evarrest,
Vistaseal
Human CryoSeal Not av

autologous Fibrin
Sealant
System
Vitagel
(autologous
fibrinogen
and bovine
thrombin)
Human Powder Raplixa (Refer to Not av

(spray and Absorbable
direct gelatin
application; sponge,
for use above)
with
absorbable
gelatin
sponge)
Dry Fibrin Sealant Freeze-dried Dressing Not Not $$$$

Dressing (DFSD) § fibrinogen and applicable applicable
thrombin
applied to
gauze
substrate
Bovine albumin- Bovine Liquid Bioglue Antibody $$$$

glutaraldehyde formation
tissue adhesive against
bovine
thrombin
can inhibit
coagulation
and prolong
prothrombin
time/INR
Combination preparations
Thrombin/gelatin Bovine or Liquid Floseal 6 to 8 weeks Antibody $$$

porcine (bovine), formation
Surgiflo against
(porcine) bovine
thrombin
can inhibit
coagulation
and prolong
prothrombin
time/INR
Thrombin/collagen Bovine Liquid Costasis 4 weeks Antibody $$$

formation
against
bovine
thrombin
can inhibit
coagulation
and prolong
prothrombin
time/INR
INR: international normalized ratio.
* Although rare, use of protein-containing topical hemostatics and fibrin sealants can be associated
with severe hypersensitivity reactions and formation of antibodies; such reactions may be seen
especially after repeated application.
¶ The cost of topical hemostatics is highly variable in United States and subject to institutional
contracting. Price range (US dollars): ¢: less than 50 dollars; $: 50 to 100 dollars; $$: 101 to 300 dollars;
$$$: 301 to 500 dollars; $$$$: 501 to 750 dollars.
Δ The low pH of the oxidized regenerated cellulose can inhibit proteases and elastase, which can delay
resorption for more than two weeks.
◊ Thrombin and fibrinogen concentrations vary. Fibrinogen concentrations are higher for commercial
preparations. As an example, Tisseel, Evicel, and Vistaseal have fibrinogen concentrations of 70, 55 to
85, and 80 mg/mL, respectively, compared with 2.5 to 25 mg/mL for cryoprecipitate (unmanipulated).
When rapid clot formation (5 to 10 seconds) is desired, thrombin concentrations of 500 to 1000 NIH
units should be used (eg, Tisseel, 500 IU/mL; Evicel, 800 to 1200 IU/mL). [4,5,6]
§ Investigational.
References:
1. Duenas-Garcia OF, Goldberg JM. Topical hemostatic agents in gynecologic surgery. Obstet Gynecol Surv 2008; 63:389.
2. Gabay M, Boucher B. An essential primer for understanding the role of topical hemostats, surgical sealants, and
adhesives for maintaining hemostasis. Pharmacotherapy 2013; 33:935.
3. Hong YM, Loughlin KR. The use of hemostatic agents and sealants in urology. J Urol 2006; 176:2367.
4. TISSEEL VH Kit. Available at:
https://www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/f
ractionatedplasmaproducts/ucm072968.pdf (Accessed on October 27, 2017).
5. EVICEL Fibrin Sealant. Available at:
https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/
FractionatedPlasmaProducts/UCM270787.pdf (Accessed on October 27, 2017).
6. VISTASEAL Fibrin Sealant. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a8708417-2f74-4dfa-
b6f9-ef88f902e0fc (Accessed on December 15, 2021).
Graphic 71852 Version 13.0
Contributor Disclosures
Elizabeth Peralta, MD No relevant financial relationship(s) with ineligible companies to disclose. Amalia
Cochran, MD, FACS, FCCM Other Financial Interest: JAMA Surgery [Web and social media editor]. All of the
relevant financial relationships listed have been mitigated. Kathryn A Collins, MD, PhD, FACS No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Overview of topical hemostatic agents and tissue

Intraoperative bleeding is controlled using standard surgical techniques (eg, electrocautery,

● Peritoneal or pleural surfaces

● Air leak following lung resection [7]

Contraindications — Topical hemostatic agents should not be used intravascularly,

Oxidized regenerated cellulose — Oxidized regenerated cellulose (ORC) is a dry,

The disadvantages of gelatin include an increased incidence of infection, granuloma, and

Microporous polysaccharide spheres — Microporous polysaccharide spheres (MPS;

Microfibrillar collagen — Microfibrillar collagen (MC) is an absorbable acid salt

are below 20,000/mm3.

● Ostene – Ostene is a wax-like compound of a water-soluble alkaline oxide copolymer

● Bone putty – A resorbable hemostatic bone putty (Hemasorb Plus) is comprised of

External agents — In rescue or battlefield situations, external hemorrhage is generally

HemCon bandage — The HemCon bandage is a dressing composed of lyophilized

● HemCon bandage controlled hemorrhage in 27 of 34 cases (79 percent), most often

● The bandage effectively controlled bleeding in 19 of the 25 cases in which direct

ChitoFlex — ChitoFlex is a rolled version of chitosan in a different formulation than the

QuikClot — QuikClot is a kaolin-based dressing. Kaolin is an inorganic product that

The safety of using kaolin-based QuikClot intracorporeally compared with standard

Nustat — Nustat consists of hemostatic fibers composed of cellulose and silica. It is

Biologically active agents — Biologically active agents augment hemostasis. Hemostasis is

Topical thrombin — Topical thrombin is reconstituted from a lyophilized powder. It can be

or mediastinum, but may be contraindicated in patients with intravascular stents or

Light-activated hemostatic agent — A novel, hydrophobic light-activated adhesive (HLAA),

Effectiveness — High-quality data establishing the effectiveness of topical hemostatic

● In three trials involving patients undergoing vascular, spinal, or cardiac surgery,

● In a trial of 69 patients undergoing obstetric, gynecologic, general, vascular, and

TISSUE ADHESIVES AND SEALANTS

As an example, in a review of 65 patients who underwent abdominoplasty, fibrin sealant

Cyanoacrylate — Cyanoacrylate tissue adhesives octyl-2-cyanoacrylate (eg, Dermabond) and

Albumin based — Albumin-based tissue adhesives combine albumin and an organic

Polyethylene glycol hydrogel — A completely synthetic tissue adhesive (CoSeal) combines

continued swelling thereafter, thus limiting its application in confined spaces.

Urethane-based — A synthetic polyurethane tissue adhesive (TissuGlu) has been approved

ADVERSE EFFECTS AND COMPLICATIONS

● Hypotension – The development of profound hypotension in some individuals after

● Anaphylaxis – Allergic reactions (including anaphylaxis) are associated primarily with

A single case report of a systemic allergic reaction during a laparoscopic

● Bloodborne disease – A complication common to all blood components is the potential

Nevertheless, although viral transmission is theoretically possible, no cases have been

● Vascular thrombosis – No increased rate of vascular or graft thrombosis has been

● Immune-mediated coagulopathy – A bleeding diathesis can occur in patients who

As an example of this issue, in one prospective study of 151 patients undergoing

Large artery bleeding/repair (aorta, femoral, carotid):

Pulsatile needle hole bleeding in vessel adventitia or in vascular graft material:

● Apply microporous polysaccharide spheres (Arista; $).

● Apply thrombin-soaked gelatin foam (Gelfoam, Surgifoam; $) or oxidized regenerated

● Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).

● Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

Pulsatile external exsanguinating hemorrhage, preoperative setting (arterial rupture, arterial

● Pack with dry fibrin sealant dressing ($$$$+).

Spleen, liver, kidney parenchymal surface post-trauma or partial resection:

● Wrap with oxidized regenerated cellulose (eg, Surgicel; $) or microfibrillar collagen

● Spray with thrombin ($).

● Apply gelatin matrix-thrombin combination (eg, FloSeal, Surgiflo; $$).

● Spray fibrin sealant (eg, Tisseel, Evicel, Crosseal, Vistaseal; $$$$).

Venous or capillary oozing from area of dissection or deserosalization:

● Spray with thrombin ($ to $$).

● Avitene Flour, EndoAvitene (OK to leave in place; $$).

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SUMMARY AND RECOMMENDATIONS