Hemostati c Agents

Orrett E. Ogle, DDS*, Jason Swantek, DDS, Amandip Kamoh, DDS

Bleeding during surgery is a serious clinical problem that can be very disconcerting to
the patient and could have serious consequences. During the course of nearly all types
of surgery, blood vessels will be disrupted, causing some bleeding, but in the dental
setting, this is usually easily controlled. In oral surgery, pressure is commonly used to
control bleeding, and this is successful in most cases. In major oral and maxillofacial
surgical procedures electrocautery and suture ligatures are most commonly used to
control bleeding from small and major vessels. At times, however, where generalized
oozing is present and the use of pressure is not effective, and the use of electrosurgical
instruments couldendanger teethor nerves, topical hemostatic agents may beneeded.
During the recent military conflicts, particularly Iraq, there have been significant
advances in hemostatic materials that have proved to be very effective in hemorrhage
control on the battlefield. Several of these products are now being adapted for civilian
use, and now there is a multibillion dollar hemostasis market with new products and
solutions rapidly emerging. This article presents some of these products that are
useful for oral surgery or that may become useful. Although the emphasis will be on
agents that may be used within the oral cavity, the article will also describe agents
that could be useful to oral and maxillofacial surgeons.
The authors hope that the reader will not be lulled into believing that hemostatic
agents will become the panacea to the control of surgical hemorrhage. The most
important step to always remember in bleeding control is direct pressure, and hemo-
static agents should always be considered secondarily. The dentist should be familiar
with the general techniques of hemorrhage control for different types of bleeding
episodessmall vessels, large vessels, oozing, drug-induced, or when an underlying
coagulation defect is present.
Having a general knowledge of the coagulation process will allow the clinician to
better understand how the hemostatic agents work and when they should be applied.
Hemostatic agents provide control of external bleeding by enhancing or accelerating
the natural clotting process through various physical reactions between the agent and
blood.
The authors have nothing to disclose.
Oral and Maxillofacial Surgery, Woodhull Medical & Mental Health Center, 760 Broadway,
Brooklyn, NY 11206, USA
* Corresponding author.
E-mail address: Orrett.Ogle@WoodhullHC.NYCHHC.org
KEYWORDS

Hemostasis

Hemostatic agents

Dental surgery
Dent Clin N Am 55 (2011) 433439
doi:10.1016/j.cden.2011.02.005 dental.theclinics.com
0011-8532/11/$ see front matter 2011 Elsevier Inc. All rights reserved.
HEMOSTASIS
The process of hemostasis is a very complex one that involves 3 major steps: (1)
vasoconstriction, (2) formation of a platelet plug, and (3) coagulation (secondary
hemostasis).
The first step is an immediate constriction of damaged blood vessels caused by
vasoconstrictive paracrine released by the endothelium. This results in a temporary
decrease in blood flow within the injured vessel. The second step is a mechanical
blockage of the defect by a plug that forms as platelets stick to the exposed collagen
(platelet adhesion) and become activated, releasing cytokines (serotonin, throm-
boxane A2, and endothelin1) into the area around the injury. Released platelet factors
(ADP, fibronectin, thrombospondin, fibrinogen and PDGF) reinforce the vasoconstric-
tion and activate more platelets that stick to one another (platelet aggregation) to form
the platelet plug. At the same time, exposed collagen and tissue factor initiate the third
step, a series of reactions known as the coagulation cascade that ends in the forma-
tion of fibrin polymer. The fibrin protein fiber mesh reinforces and stabilizes the platelet
plug to become a clot.
The clotting cascade (secondary hemostasis) is traditionally broken up into 2 basic
pathways, the intrinsic pathway and the extrinsic pathway. The intrinsic pathway is
primarily activated by collagen, which is exposed and binds factor 12 to initiate this
cascade. The extrinsic pathway is stimulated by tissue factor, which is exposed by
the tissue injury and through factor 7 activation initiates this pathway. These 2 path-
ways then converge in a common pathway where thrombin converts fibrinogen to
fibrin and then the final clot.
Intrinsic Pathway (Contact Activation Pathway)
The intrinsic cascade is initiated when contact is made between blood and exposed
negatively charged surfaces. Upon exposure of a negatively charged surface, prekal-
likrein, high molecular weight kininogen, and factors 12 and 11 initiate the intrinsic
pathway. Upon contact activation, prekallikrein is converted to kallikrein, which acti-
vates factor 12 to 12a, which in turn activates factor 11 to 11a. With Ca1 present,
factor 11a activates factor 9 to 9a, which cleaves factor 10 to 10a, the beginning of
the common pathway. Contact activation of the intrinsic pathway can also occur on
the surface of bacteria, and through the interaction with urate crystals, fatty acids,
protoporphyrin, amyloid b, and homocysteine.
Extrinsic Pathway (Tissue Factor Pathway)
Factor 3 (tissue factor) is released from the tissue immediately after injury and initiates
the extrinsic pathway. Factor 3 forms a complex with factor 7a, which catalyzes the
activation of factor 10, which cleaves to become factor 10a.
Common Pathway
The intrinsic and extrinsic coagulation cascades converge at activated factor 10a,
resulting in the conversion of prothrombin (factor 2) to thrombin (2a). Thrombin activa-
tion occurs on activated platelets. Thrombin then converts fibrinogen to fibrin mono-
mers, activates factor 13 to 13a (transglutaminase), which then cross-link the
monomerswith the aid of calciumto form fibrin polymer and thus the clot Fig. 1.
HEMOSTATIC AGENTS
A hemostatic agent (antihemorrhagic) is a substance that promotes hemostasis (ie,
stops bleeding). These agents act to stop bleeding either mechanically or by
Ogle et al 434
augmenting the coagulation cascade. The ideal hemostatic agent should be effective,
and the agent itself, along with its metabolic breakdown products, should be safe to
use within the body. The locally acting hemostatic agents generally work by increasing
the rate of vasoconstriction, sealing vessels/vascular channels, or by promoting
platelet aggregation. Gelfoam (Pfizer Incorporated, NY, USA) and Surgicel (Ethicon
Incorporated, Somerville, NJ, USA), which work proximally in the intrinsic coagulation
pathway via contact activation, have been used in dentistry for many decades and
remain the major hemostatic agents in oral surgery. Bone wax controls bleeding by
mechanically sealing bleeding channels in cancellous bone. All three agents have
been proven to be effective and safe. The authors will present other hemostatic agents
that have recently been introduced.
CHITOSAN PRODUCTS
Chitosan-based products are a new generation of hemostatic medical products that
have been shown to achieve early hemostasis and improve postoperative healing. Chi-
tosan is a naturally occurring, biocompatible, electro positively charged polysaccha-
ride that is derived from shrimp shell chitin. This charge attracts the negatively
charged red blood cells, forming an extremely viscous coagulum that seals the wound
Coagulation Cascade
Extrinsic Pathway
Tissue Damage
Contact With Damaged Vessel
Tissue Factor
Factor VII Factor VIIa
Factor XIIa Factor XII
Factor XI
Factor XIII Factor XIIIa
Fibrin clot
(tight)
Factor X
Factor Va
Factor VIIIa
Factor X
Fibrinogen (Factor I)
Prothrombin (Factor II) Thrombin
Fibrin
(loose)
Factor Xa
Factor IXa Factor IX
Factor Xia
Ca++
Ca++
Ca++
Ca++, Phospholipid
Ca++, Factor VIII,
Platelet Phospholipid
Ca++, Factor V
Platelet Phospholipid
Intrinsic Pathway
Fig 1. Coagulation cascade: intrinsic and extrinsic pathways.
Hemostatic Agents 435
and causes hemostasis. It is thought that chitosan may enhance hemostasis by inter-
acting with cellular components forming a cellular lattice that entraps cells to form an
artificial clot. Chitosan may have advantages over other therapies due to its ability to
inhibit bleeding independent of normal coagulation factors. The rapidly formed coag-
ulumis extremely advantageous in patients with coagulopathies or those on anticoag-
ulant medications. Although these products are derived from shellfish, no reactions
have been found in skin testing using chitosan on shellfish-sensitive patients.
HemCon Medical Technologies, Incorporated (Portland, OR, USA) currently manu-
factures many chitosan-based products including dental dressings, nasal packings,
and bandage wound dressings. A recent study showed that hemostasis was achieved
in less than 1 minute in patients where HemCon dental dressing (HemCon Medical
Technologies, Incorporated) was used, which was significantly faster than the control
average hemostasis time, 9.5 minutes. Approximately 32% of HemCon dental
dressing-treated sites had significantly better healing compared with the control sites.
1
Celo (Medtrade Products Limited, Cheshire, UK) is a granular formchitosan-derived
product that was approved by the US Food and Drug Administration (FDA) in 2007.
There are currently no available studies investigating the use of Celo for oral
procedures.
FIBRIN SEALANTS
Fibrin sealant is a natural or synthetic combination hemostatic agent and tissue adhe-
sive. Not only does fibrin sealant have hemostatic properties, but it also has adhesive
properties and an impact on angiogenesis and wound healing. Fibrin sealants are usu-
ally comprised of fibrinogen (factor 1a), fibrin-stabilizing factor, thrombin (factor 2a),
and aprotinin.
2
When these agents are combined, the common pathway of the coag-
ulation cascade is mimicked, and fibrin strands are cross-linked, forming a stable fibrin
clot. When all four components are applied to the surgical site, a fibrin gel is formed.
Tisseel (Baxter Healthcare, Deerfield, IL, USA) and Hemaseel (Angiotech Incorpo-
rated, Vancouver, British Columbia, Canada) are the 2 products on the market. Both
of these products are identical with no difference in clinical use.
2
Davis and
colleagues
3
conducted a study that included 71 patients who underwent various
oral and maxillofacial procedures (dentoalveolar, cosmetic, and reconstructive) in
which Tiseel was used. Seventy patients had successful outcomes 6 months postop-
eratively with 1 recurrent oroantral fistula. Some clinicians have suggested that fibrin
glue could be used in bone grafting procedures, particularly sinus lift surgery. There
are currently few studies evaluating the use of fibrin sealant as a bone grafting adjunc-
tive material,
4
and the available data have been inconsistent, indicating more research
is needed before concrete conclusions can be made about using fibrin sealants as an
adjunctive agent in bone grafting.
The only contraindication to using synthetic fibrin sealant is in patients with sensi-
tivity to bovine proteins. There have been reports of tissue necrosis when fibrin sealant
is used improperly. An excessively thick sealant layer may prevent revascularization at
the surgical site, causing tissue necrosis.
OSTENE
For many years, bone wax was the only option to control bone bleeding. Bone wax is
mainly composed of water-insoluble beeswax and is widely used for bone hemostasis
in a variety of situations. It has no hemostasis quality but rather tamponades the
vascular spaces within cancellous bone. There are negative issues regarding the
use of bone wax in the jaws, however. Bone wax is water-insoluble and will remain
Ogle et al 436
at the site indefinitely, forming a physical barrier that inhibits bone healing. In defects
where bone wax was applied and removed after 10 minutes, there was complete inhi-
bition of bone regeneration.
5
Bone wax also increases infection rates by decreasing
the bacterial clearance of cancellous bone and providing a nidus for infection. In
a recent study evaluating the infection rates following spinal surgery, surgical site
infections occurred in 6 of 42 cases (14%) when bone wax was used and 1 of 72 cases
(1.4%) when it was not used.
6
Bone wax has also been shown to increase
inflammation,
7
causing a foreign body giant cell reaction at the site of application
due to its water insolubility and longevity.
Ostene (Ceremed, Incorporated, Los Angeles, CA, USA) is a synthetic bone hemo-
static material that was first approved by the FDA in 2004 for use in cranial and spinal
procedures as a bone hemostatic agent. It is a sterile mixture of water-soluble alkylene
oxide copolymers that produces minimal postoperative inflammation, making it ideal
for cranial and spinal surgery, where inflammation may be harmful to neural tissues.
Because Ostene is water-soluble, it does not remain at the site of application and
addresses all of the known negative events associated with bone wax. It dissolves
in 48 hours, does not swell, and is not metabolized. The materials main polymer
component inherently reduces bacterial adhesion and the incidence of infection.
Wellisz and colleagues
8
showed that Ostene-treated rabbit tibial cortical defects
had a significantly lower rate of osteomyelitis and positive bone cultures compared
with the bone-wax treated defects.
Ostene is applied in a similar fashion as bone wax. It requires no mixing and is used
straight from its sterile foil packet; it should be applied to a thickness of 1 to 2 mm. It
has a putty-like consistency when warmed to body temperature by kneading it with
gloved fingers. Ostene is supplied in 2.5 gram- or 3.5 gram-sized bars within sterile
peel pouches with either 10 or 12 bars in a box. Although Ostene is more expensive
than bone wax, its benefit compensates for the increase cost.
ACTCEL AND GELITACEL
ActCel (Coreva Health Science, LLC, Westlake Village, CA, USA) is a new topical
hemostatic agent that is made from treated and sterilized cellulose and available in
similar fabric meshwork as Surgicel. Once the meshwork comes into contact with
blood, it expands to 3 to 4 times its original size and is almost immediately converted
to a gel. Complete dissolution of the product takes place within 1 to 2 weeks. Because
of its purity and the fact that it degrades rapidly into biocompatible end products
(glucose, water), it does not adversely affect wound healing. It is known that when Sur-
gicel is placed in the mandibular canal with the inferior alveolar nerve exposed there
have been reports of neurotoxic effects. ActCels mechanisms of action are multiple,
enhancing the coagulation process biochemically by enhancing platelet aggregation
and physically by 3-dimensional clot stabilization. ActCel has been used in third molar
sites and is advertised to help prevent dry sockets. It has also been used in periodontal
and orthognathic surgery.
Gelitacel (Gelita Medical B.V. Amsterdam, The Netherlands) is a fast-working,
oxidized resorbable cellulose haemostatic gauze of natural origin made from highest
alpha-grade selectedcotton. It is not based on viscose andhas state-of-the-art knitting
technology for easy passage in endoscopic procedures. The special biochemical char-
acteristics of its resorbable cellulose allows resorption as quick as 96 hours, therefore
giving it decreased risk for encapsulation. Gelitacel is approved for dental surgery in
Europe, is available at half the cost of Surgicel, and has better absorbing properties.
The authors were unable to find FDA approval for this product.
Hemostatic Agents 437
FLOSEAL
FloSeal Matrix Hemostatic Sealant (Fusion Medical Technologies, Mountain View,
CA, USA) is a proprietary combination of 2 independent hemostasis-promoting
agents. It consists of bovine-derived gelatin granules coated in human-derived
thrombin that work in combination to form a stable clot at the bleeding site. When
applied to a bleeding site, the gelatin granules swell by about 10% to 20% as it
contacts blood, causing a seal at the bleeding site. The thrombin portion of the
product activates the common pathway of the coagulation cascade and converts
fibrinogen to a fibrin polymer, forming a clot around the stable matrix. It is resorbed
by the body within 6 to 8 weeks, consistent with the time frame of normal wound heal-
ing. Because of the products flowability, it can adapt to irregular wounds. FloSeal can
be used in all surgical procedures (other than ophthalmic) as an adjunct to hemostasis
when control of bleeding by ligature or conventional procedures is ineffective or
impractical. It is effective on hard and soft tissue. FloSeal matrix hemostatic sealant
has been used as a first-line hemostatic agent in major oral surgical cases.
Because FloSeal is made from human plasma, it may carry a risk of transmitting
infectious agents (eg, viruses) and theoretically, the Creutzfeldt-Jakob disease
(CJD) agent. It should also not be used in patients with known allergies to materials
of bovine origin.
QUIKCLOT
QuikClot (Z-Medica, Wallingford, CT, USA) brand products derive their primary hemo-
static properties from kaolinite, a naturally occurring mineral material. When kaolin is
exposed to human plasma, factors 12 and 11 are activated, thereby activating the
intrinsic coagulation pathway. QuikClot is a granular hemostatic agent that effectively
controls external hemorrhage by pouring it into a wound followed by a pressure
dressing to achieve hemostasis. The proposed mechanism of action is that the Quick-
Clot adsorbs water, concentrating clotting factors. This exothermic reaction produces
significant heat that may create secondary injury.
In order to be effective, QuikClot must be applied to the source of the bleeding, the
torn blood vessel itself. There is currently no dental use for this product, but the
authors believe that it could eventually be modified to be used in oral surgery.
SUMMARY
Hemostasis is an integral and very important aspect of surgical practice. As a rule,
most bleeding from dental surgery can be controlled by pressure. When the applica-
tion of pressure does not yield satisfactory results, or where more effective hemostasis
is required, hemostatic agents should be used. These agents act to stop bleeding
either mechanically or by augmenting the coagulation cascade. Some of the newer
agents that are available to the dental profession have been presented.
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