hemostab,blknktic agents

5/21/2018 Hemostab,blknktic Agents

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H e m o s t a t i c A g e n t s

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 tocontrol 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 could endanger teeth or nerves, topical hemostatic agents may be needed.

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: [email protected]

KEYWORDS

Hemostasis Hemostatic agents Dental surgery

Dent Clin N Am 55 (2011) 433439doi:10.1016/j.cden.2011.02.005 dental.theclinics.com0011-8532/11/$ see front matter 2011 Elsevier Inc. All rights reserved.
mailto:[email protected]://dx.doi.org/10.1016/j.cden.2011.02.005http://dental.theclinics.com/http://dental.theclinics.com/http://dx.doi.org/10.1016/j.cden.2011.02.005mailto:[email protected]


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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

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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 DamageContact 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++, PhospholipidCa++, Factor VIII,

Platelet Phospholipid

Ca++, Factor VPlatelet Phospholipid

Intrinsic Pathway

Fig 1. Coagulation cascade: intrinsic and extrinsic pathways.

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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-

ulum is 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 form chitosan-derivedproduct 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

colleagues3 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 currentlyfew 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

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at the site indefinitely, forming a physical barrier that inhibits bone healing. In defects

where bone wax was appliedand 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 andaddresses 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 colleagues8 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 sterilepeel 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. Becauseof 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 selected cotton. It is not based on viscose and has 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.



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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. Whenapplied 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 theintrinsic 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.

REFERENCES

1. Malmquist JP, Clemens SC, Oien HJ, et al. Hemostasis of oral surgery wounds with

the hemcon dental dressing. J Oral Maxillofac Surg 2008;66:117783.

2. Fattahi T, Mohan M, Caldwell GT. Clinical applications of fibrin sealants. J Oral

Maxillofac Surg 2004;62:21824.

3. Davis BR, Sandor GK. Use of fibrin glue in maxillofacial surgery. J Otolaryngol

1998;27:10712.

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4. Kim WB, Kim SG, Lim SC, et al. Effect of Tisseel on bone healing with particulate

dentin and plaster of Paris mixture. Oral Surg Oral Med Oral Pathol Oral Radiol

Endod 2010;109(2):e3440.

5. Ibarrola JL, Bjorenson JE, Austin BP, et al. Osseous reactions to three hemostatic

agents. J Endod 1985;11(2):7583.

6. Gibbs L, Kakis A, Weinstein P, et al. Bone wax as a risk factor for surgical-site

infection following neurospinal surgery. Infect Control Hosp Epidemiol 2004;25:

3468.

7. Allison RT. Foreign body reactions and an associated histological artifact due to

bone wax. Br J Biomed Sci 1994;51:147.

8. Wellisz T, Yuehuei H, Wen X, et al. Infection rates and healing using bone wax and

a soluble polymer material. Clin Orthop Relat Res 2008;466:4816.


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