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R E V I E WAustralian Dental Journal 2003;48:(2):89-96

Current concepts of the management of dental extractionsfor patients taking warfarin

G Carter," AN Goss,t J Lloyd,t R TocchettiS

A b s t r a c t

Background: Controversy has surrounded thecorrect management of patients therapeuticallyanticoagulated with warfarin who require dental

extractions. The risk of bleeding must be w eighed upagainst the risk of thromb oemb olism w hen decidingwhether to interfere with a patient's warfarinregimen. An improved understanding of theimpo rtance of fibrinolytic mechanism s in the oralcavity has resulted in the developm ent of variouslocal measures to enab le these patients to be treatedon an outpatient basis.Methods : A review of the literature was und ertaken.This w as supplem ented by the authors' clinical trialsand extensive clinical experience withanticoagulated p atients.Results: Various protocols for treating patientstaking warfarin have been reviewed and sum marizedand an overview of the ha emo static and fibrinolyticsystems is presented. A protocol for manag ement ofwa rfarinized p atients requiring den tal extractions inthe outpatient setting is proposed.C o n c l u s i o n s : Patients therapeutically anticoagulatedwith warfarin can be treated on an ambulatorybasis, without interruption of their w arfarin regimenprovided app ropriate local measures are used.

Key words: Warfarin, anticoagulation, extractions, oral

surgery.

(Accepted for publication 23 December 2002.)

IN T R OD U C T ION

Warfarin is the most commonly prescribed oral

anticoagulant used to prevent and treat

thromboembolism. Because this is a long-term

*Senior Registrar, Oral and Maxillofacial Surgery Unit, RoyalAdelaide Hosp ital, Adelaide Dental Hospital and T he Universi ty ofAdelaide, South Australia.tProfessor and D irector, Oral and Max il lofacial Surgery Unit , RoyalAdelaide Hosp ital , Adelaide D ental Hospital and Professor of Oraland M axillofacial Surgery, School of De ntistry, The University of

Adelaide.$Director, Haemostasis and Thrombosis Unit, Division ofHaematology, Royal Ad elaide Hospital.S Senior Medical Scientist, Biotherapeutic Services, Division ofHaematology, Royal Ad elaide Hospital.

treatment, the numb er of such patients requiring dentalextractions is on the rise. Patients receiving warfarin

who undergo dental extractions may have prolonged

and excessive haemorrhage: 4 The clinician who is

faced with a warfarinized patient requiring extractionshas to balance the risk of reducing or stopping the

anticoagulant therapy w ith that of excessive bleeding.Traditionally emphasis has been given to stopping

bleeding by altering the warfarin dosage. However,

cessation or decrease in the anticoagulant therapy

exposes the patients, especially those with artificial

heart valves , to the r isk of throm boem bolism. 9 - 1 4 Most

patients and health professionals, when given thechoice of som e oral bruising or oozing versus potentialstroke or similar catastrophic event, cho ose not to riskstopping their anticoagulant. Various protocols have

been sug gested for d enta l extrac t ion in ant icoagulatedpatients. 1 5 There is no standard therapeutic approach tothese patients and it appears that each patient'streatment plan is tailored by their cardiologist, local

medical officer, and dentist. In support of thehypothesis that impaired haemostasis is the result of

either deficient coagulation (imp aired fibrin deposition)or increased fibrinolysis (fibrin resolution), local

measures to inhibit fibrinolysis have evolved andenabled dental extractions to now be performed in

therapeutically warfarinized patients on an outpatientbasis.

Ove rview o f the haem ostat ic and f ib r ino lyt ic system s

In connection with vascular injury, the integrity of

the vascular system is maintained by the haemostatic

mechanism. Through this physiologic mechanism,

haemorrhage is arrested at the site of injury between

four biological systems: the vessel wall, the platelets,and the c oagulation and fibrinolytic systems (Fig 1).

Th e v es s e l wa l l

Wh en a vessel is injured, vasoconstriction occ urs asan early event, in order to reduce the blood flow and

extravasation of blood components. Thevasoconstriction of arteries and arterioles is under

neural control, whereas the constriction of smaller

vessels (including cap illaries) is controlled by hum oral

Australian Dental Journal 2003;48:2.9



V L S I

Vila Ca'

Vascular injury

Neural mechanismslf Humoral+local factors

Vasoconstriction

Platelet response(adhesion, activation, aggregation, secretion)

Primary haem ostasis

(`platelet plug')

Secondary haem ostasis(coagulation system)

Intrinsic ascadextrinsic ascade

Contac t ac t i va t ion

X IIXIIa

i s sue th romboplas t in (w ound)

X TXa

IX 11 , X a

IIaIIX0 , X a

C aVa —>.-I XIII

v

Prothrombin —0.- Thrombin Ca'

Fibrinogen

Fibrin. m onomer

Fibrin polymer I – unstable

Ca'

,1 1 p,Plasminogen activators

Fibrin ploymer II – crosslinked -41C— Plasmin<— Plasminogen

Fibrinolysis

Fig 1. Interaction between the haemostatic and fibrinolytic systems.

and local factors. Compounds such as adenosine

diphosphate (ADP), serotonin and Thromboxane A2,released from platelets, po tentiate vasoconstriction."

The p la te le tsWhe n platelets are exposed to an injured vessel wall ,they will adhere to the thrombogenic subendothelial

structures and in particular to perivascular collagen.

Von Willebrand factor, fibronectin and fibrinogen

present in plasma, as well as in c granules in platelets,bind to the platelet membrane, and are important for

platelet adhesion. Platelets are initially activated by

substances such as ADP, adrenaline, serotonin,thrombin, platelet activating factor, and collagen,which bind to the platelet membrane and change its

surface morphology. This is followed by granular

secretion and activation. The activated plateletsparticipate in the coagulation process and provide a

surface for assembly, activation and binding ofcoagulation proteins subsequently activated in a

sequential mann er." Platelet adhesion is followed b y acontinuous aggregation mediated by ADP,thromboxanes and prostaglandins. The aggregated

platelets form the platelet plug, which is responsible forimmediate (primary) haemostasis. This platelet plug

appears to serve as a surface for the form ation of a clotw here the blood coagu lation factors are active. The clotand the platelet plug are necessary for effective

haem ostasis . The bleeding t ime is used to tes t pr imaryhaemostasis.

The coagula t ion sys tem

The coagulation system converts the plasma proteinfibrinogen into fibrin by the enzyme thrombin. The

process includes several reactions occurring in a

cascading-like manner, and can be initiated by two

different pathways, the intrinsic pathway (factor XII-dependent) and the extrinsic pathway (thromboplastin-depend ent) . While the two systems differ in methods ofactivating the coagulation system, they share a

common pathway for production of fibrin. In theintrinsic system , a circulating surface-sensitive protein,the Hagem an factor (factor XII) , is activated on contactwith a foreign surface. This contact (and subsequent

reac t ion) in i t ia tes the coag ulat ion cascad e. Fac tor X IIcan be activated by contact with collagen, vascular

basement membrane, activated platelets, orphospholipids from platelets. The process ultimately

results in the polymerization of fibrin, which is then

stabilized by factor XIII. The intrinsic pathway is

assessed by the activated partial thromboplastin time

(APT T). In the ex tr insic system t issue thromb oplast in

elaborated a t the s i te of t issue injury forms com plexeswith factors V, VII, and X in the presence of calciumions to convert prothrombin to thrombin. This systemalso facilitates aggregation of platelets and enhances

the activity of the intrinsic system. 1 8 The extrinsic

system is assessed by the International Normalized

Ratio ( INR) or p rothrombin t ime (PT ).

The f ibr ino ly t ic sys tem

Physiological fibrinolysis has been defined as the

degradation of fibrin by the enzyme plasmin. The

conversion of the zymogen plasminogen to the activeenzyme plasmin is a fundamental phase in the

activation proce ss. Plasminogen is a circulating plasmaprotein produced in the liver that is activated by two

different pathways of which the extrinsic fibrinolytic

system is dependent on ac t ivators bound in the t issues(tissue plasminogen activator-t-PA), and the intrinsicf ibrinolytic system on hum oral precursors circulating inthe blood. Activation of the pathways results in the

conversion of plasminogen to plasmin.

The possible pathogenic role of local fibrinolysis inthe oral cavity on bleeding after oral surgery in healthyindividuals, as well as patients with defects of the

coagulation system has been suggested by several

authors: 9 - 2 ° Fibrin deposited in the oral cavity can be

resolved both b y the activation of blood fibrinolysis as

XIIIa

Fibrinolytic system

9 0ustra lian De ntal Journal 2003 ;48:2.



Table 1. Commonly accepted indications for oral

anticoagulant treatment, and aims of treatment

1. Venous thrombosis and pulmonary embolism:Primary preventionTreatment of established thrombosisSecondary prevention

2. Myocardial infarction:Prevention of venous thromboem bolismPrevention of systemic embolism

Prevention of re-infarction3. Valvular heart disease, prosthetic heart valves, cardiacarrhythmia and cardiomyopathy:Prevention of systemic embolism

4. Systemic embolism:Secondary prevention

5. Transient cerebral ischaemia:Prevention of recurrent transient ischaemiaPrevention of stroke

6 Reconstructive artery surgery and athe rosclerotic periphe ralvascular disease:Prevention of thrombotic occlusion

well as by the plasminogen activators in the oral

environment. An increased fibrinolytic activity in thef luid from gingival crevices in patients with periodontaldisease, as compared to subjects with healthy gingiva,has previously been reported. 2 1 The presence ofactivators of fibrinolysis associated w ith oral epithelialcells and in the saliva has also been demonstrated,19'22-27as has the absence of inhibitors of fibrinolysis in the

s a l i v a . 2 8 - 2 9

Warfarin

Warfarin is a vitamin K antagonist that impairs the

liver synthesis of coagulation factors II, VII, IX and X ,and endogenous proteins C and S affecting both the

intrinsic and extrinsic coagulation pathways, resultingin impaired fibrin formation.

I n d ic a t i o n s f o r u s e

Oral anticoagulants such as warfarin are consideredeffective in the prophylaxis and treatment of venous

thromboembolism, 3 0 -" and for the prevention ofsystemic emboli from a cardiac source. 3 2 The aim of

anticoagulant therapy is to reduce the coagulability ofblood into an optimal therapeutic range within which

the patient is protected against thrombosis at the costof being exposed to a small risk of spontaneousbleeding. Commonly accepted indications for warfarintreatment and the aims of treatment are summ arized inTable 1.

P h a r m a c o k i n e t i c s

Warfarin is rapidly absorbed from the uppergastrointestinal tract, and is highly p rotein bound but itis the free fraction only that is pharmacologicallyactive. The half-life is independent of the dose but

usually falls within the rang e of 35-45 hours. Wa rfarin

is distributed to approximately 8 to 27 per cent of thebody weight, which is similar to that of albumin (to

w hich it is bound). W arfarin is com pletely metabolizedby the l iver and sub sequently eliminated by the kidneys.

Table 2. Therapeutic levels of anticoagulation and

treatment duration

Clinical state IN R

Therapeutic rangeusing rabbit brain

thromboplast in(ISI value.3 )

Duration

Prophylaxis — venousthromboembolism(high-risk surgery) 2.0-3.0 1.35-1.6 x PT ' Variable

Prophylaxis — venousthromboembolism(hip surgery) 2.0-3.0 1.35-1.6 x PT Variable

Treatment of deepvenous thrombosis,or pulmonaryembolism

2.0-3.0 1.35-1.6 x PT

Threemonths

Sixmonths

To prevent systemicembolism in patientswith atrialfibrillation, valvularheart disease, tissueheart valves, oracute m yocardialinfarction 2.0-3.0 1.35-1.6 x PT Lifelong

Mechanical prostheticheart valves,recurrent systemicembolism 2.5-3.5 1.5-1.7 x PT Lifelong

Adapted f rom Hirsch e t a l . 1992."

M o n i t o r in g — P ro t h ro m b i n t im e t e s t /I N R

Since the early 1940s the PT method developed byQuick has been the primary means of monitoring

the level of anticoagulant contro1. 3 3 The test isperformed by adding thromboplastin to citratedpatient blood. By the late 1970s there were many

commercial thromboplastins available, with differinglevels of sensitivity. Subsequently, in 197 8, the W orldHealth Organization (WHO) recommended that the

PT be standardized. In 1983, the WHO published the

recommendations for reporting the level ofanticoagulation using an INR. The IN R w as developedto normalize the PT test based on the sensitivity of

different thromboplastins. As a result, an INR isessentially the same rega rdless of which thrombop lastina par t icular laboratory uses . An INR of 1 correspondswith a normal haemostatic capacity. Therapeutic levels ofanticoagulation are reached w ith INR values betw een 2and 3.5. When th e INR is 5 or higher, there is a seriousr isk of spontaneous bleeding episodes . In 1986, an AdHoc com m ittee sponsored by the Am erican College ofCh est Physicians (AAC P) and the National Heart, Lungand Blood Institute formulated new guidelines for

anticoagulation. 3 4 The committee reviewed theliterature and clinical findings and determined that

patients could be t reated w ith lower doses of w arfar inthan used previously to prevent thrombosis and at thesame time minimize complications associated with

anticoagulation (Table 2). Some investigators still

recomm end h igher levels of anticoagulation.35

C o m p l ic a t io n s o f w a r f a r in th e r a p y

Complications include bleeding, drug interactions,

overdose and rare non-haem orrhagic side effects . By far

Austra l ian D ental Journal 2003;48:2.1



Table 3. Drugs commonly used in dentistry thatable 4. Local measures to control bleeding in

interact with warfarinarfarinized patients undergoing dental extractions

Drugffect on INR

Carbamazepine (Tegretol)Metronidazole

T

Sulphonamides ( tr imethoprim, sulfamethoxazole)

TErythromycinMiconazole (oral gel)

'

Tetracycline

Note: Prolonged use of any oral antibiotic is not recom men ded dueto potential for gut flora suppression and risk of elevated INR due tovitamin K deficiency.Aspirin, NSAID s: increased risk of bleeding due to antiplatelet effect;avoid concurrent use (except patients at high risk forthromboembolism).Local anaesthetic agents, paracetam ol, and codeine do not interactwith w arfarin.

the most common complication is bleeding, mostcom m only sim ple bruising or haem aturia, but bleedingcan also be gastrointestinal, intracranial,

retroperitoneal and in other sites. Spontaneous bleeding

is likely to occur when the INR is excessivelyprolonged. An excessive INR can be returned to the

therapeutic range by either withholding warfarin for

one to two days, administering low doses of vitamin K(0.5-5m g slow iv injection), or infusing a concentratedfactor replacement or fresh frozen plasma.

Warfarin is subject to many drug interactions, whichmay increase or decrease its anticoagulant effect.

Important drugs commonly encountered in dentistry

and their effects on the IN R in patients taking warfarinare summ arized in Table 3.

Dental extractions and warfarinThe controversy surrounding patients taking

warfar in w ho require denta l extrac t ions centres on thedecision whether to continue or withdraw them edication prior to surgery. Four different philosophiescan be distinguished.

1) No change in the warfarin therapy

It is clear that continuity and consistency of aregimen of anticoagulation are beneficial to all patientswho require such therapy. Several authors in the past

have published reports recommending leaving the

anticoagulant dose unaltered for simple oral surgicalprocedures such as denta l extrac t ions . 2 ' 7 ' 3 6 - 4 ° Accordingto these authors, the small but potentially hazardous

effect of discontinuing anticoagulant therapy is not

justified in patients' anticoagulated within thetherapeutic range. However , a c loser look a t the s tudypopulations on which these conclusions were based

discloses that in the majority of cases with few or no

problems post-operatively, PT values (INR not yet in

use) were either on the low side of the therapeutic rangeor we re virtually normal. The m ost recent l i terature hasrecommended that dental extractions can be safely

performed in patients therapeutically anticoagulatedwith w arfar in , without the need for topical or regionalm edication to enhance or stabilize clot form ation at thesurgical site. 4 1 - 4 3 Further controlled studies using large

• Local anaesthetic• Controlled, minimally traumatic surgical technique• Local pressure with gauze pack s• Sutures• Absorbable packs (e.g., Surgicel®, Gelfoam®)• Tranexamic acid m outhrinse, or• Fibrin Sealant — autologous or donor based

patient groups are required before this technique ca n besafely advocated.

2) No change in the warfarin therapy plus local

measures

A varie ty of procedures to secure local haem ostasishave been suggested in the literature. The largevariation in these procedures indicates a lack inconsensus of t reatment m ethods, probably because thesuggested methods led to an insufficient reduction in

the bleeding complications following dentalextractions. A sound surgical technique takes prioritywhen extracting teeth in all patients whether they are

taking warfarin or not. Steps to encourage localclotting include: c onstant application of pressure to th einvolved tissues even when, for example, a tooth is

being luxated; +/- placement of an absorbable pack

(e.g., Gelfoam®, Pharmacia and Upjohn, Michigan,

USA, Surgicel®, Ethicon Inc, New Jersey, USA) in

each sock et to help serve as a matrix for clot formation;+/- placem ent of sutures under tension; applicat ion ofheavy biting pressure in immediate post-operative

period and clear verbal + written instructions withregard to mouth care and diet in the post-operative

period (Table 4).

The comp licat ion of t issue haematom a as a resul t ofa local anaesthetic injection has not been discusse d inrelation to the dental patient receiving warfarin. Thatthis may be an unrecognized potential problem isevident from the fact that several authors have reportedecchymosis, haematomas, or facial swellings as post-operative com plications following d ental extractions inpatients receiving oral anticoagulants.''''' However, inthe papers reviewed non e of them con jectured as to the

cause of these complications, and none gave specificinformation regarding the local anaestheticm ethodology of their protocols . Guidel ines developedfor the dental treatm ent of the haem ophiliac patient areappropriate in making recommendations for treating

the anticoagulated patient. Short 27-gauge needles

should be used to allow aspiration and minim ize tissuedamage." In addition, the duration of the infusion of

the local anaesthetic into the tissue should be for a

minim um of lm w ith 2m b eing preferable.45Periodontalligament injections may be used where appropriate.

Besides injections over b one, intraseptal injections are

also considered safe. Injections into highly vascularizedareas such as the sites for the posterior superioralveolar nerve block, the long buc cal nerve and greaterpalatine area should be avoided. ' The inferior alveolar

92ustra lian Dental Journal 20 03;48:2.



nerve block has the greatest potential for a major

complication, as it is possible for a dissectinghaematom a to develop w hich could occlude the airway.The Gow-Gates mandibular block technique is

preferable to the conventional inferior alveolarinjection or the Akinosi injection because whenperformed correctly, it has the lowest positive

aspiration rate and supplemental injections are not

necessary to anaesthetize the buccal and lingualgingivae." In this case a long needle w ould be nece ssaryto place the anaesthetic in the proper location.

2a) Tranexamic acid

I t seems that one of the m ost s ignif icant pathogenicfactors for the developm ent of bleeding after oral surgeryis the ac tivation of fibrinolysis in the oral cavity. In 1989a study by Sindet-Pederson et al. demonstrated thatmaintenance of oral anticoagulant therapy inconjunction w ith oral surgery does not result in severebleeding com plications in patients receiving a tranexamicacid m outhwa sh post-operatively. ' Several other studieshave confirm ed that anticoagulation treatmen t does notneed to be withdraw n before oral surgery provided thatlocal antifibrinolytic therapy is instituted.48-51

Tranexamic acid is the active trans-stereoisomer ofamino-methyl cyclohexane carboxylic acid and has

been shown to have powerful antifibrinolyticproperties. First described by Okamoto and Okamotoin 1962, 5 2 the molecule is a competitive inhibitor of

plasminog en activation and a non -com petitive inhibitorof plasmin. Tranexamic acid can be administeredsystemically or topically. In patients on oralanticoagulants, systemic treatment is not

recom m ended, since these patients run a greater risk ofdeveloping thromboembolism. Administration of

10mL of a 4.8 per cent tranexamic acid mouthwash

results in an average concentration of 7pg oftranexamic acid/mL saliva after two hours, and the

drug rem ains at detectable levels in the saliva for eighthours. Since the concentration of tranexamic acid in

plasma is barely detectable after use of themouthwash," there is insignificant inhibition ofsystemic fibrinolysis and side effects following this

treatment are not to be expected, provided the patientsfollow the directions for using the drug (i.e., do not

swallow it). Tranexamic acid has also been shown to

accelerate normal wound healing."-' A 4.8 per cent

mouthwash is available in Australia through the

pharmacy department of major hospitals. Patients areadvised to rinse with 10m L for 2m four times a day fortwo to seven days.' Dentists are able to contact the

Hospital pharmacy departments by phone and obtain

the prepared mouthwash at a cost of approximately

$15 to the patient.

2b) Fibrin sealant

Fibrin sealant has been used for enhancement of

local haem ostasis after dental extractions for over tw odecades. 5 5 - 6 ° Fibrin sealing mimics the last phase of

Austra l ian De ntal Journal 2003;48:2.

blood clotting, i.e., the conversion of fibrinogen tofibrin.' The preparation may be homologous from a

pooled donor source or autologous, derived from the

patient 's own blood. Several hom ologous fibrin sealantpreparations exist but concern over possible virustransmission has excluded their availability in Australia.The autologous system, w hich can b e prepared throughmajor hospitals, has two components. The first

component consists of autologous fibrinogen, FactorXIII, and fibronectin dissolved in a sterile calciumchloride solution (which had b een s tored in the f rozenstate at —70°C). Bovine thrombin, and anantifibrinolytic drug (to imped e clot degradation by thefibrinolytic system) make up the second component.

The two components are mixed as they are applied tothe surgical site with specialized fibrin glue applicatorkit (Fibrijet® Micromedics, Minnesota, USA)com pris ing a tw in syringe assembly (Fig 1) . Thrombinconverts fibrinogen to fibrin so that clotting is initiatedand the mixture solidifies. At the same time thrombin

activates factor X III ( in the presence of ionized calcium)which then catalyses the cross-linkage of fibrin, thus

increasing the strength of the clot. During woundhealing the clot m aterial undergoes g radual lysis and iscomp lete ly absorbed w ithin two w eeks. Aside from i tsadhesive and haemostatic properties, the sealant has

been found to enhance wound healing. Studiescom paring the effec tiveness of f ibrin sealant in patientsundergoing d ental extrac t ions w ho are therapeuticallyanticoagulated with warfarin have shown equallysuccessful outcomes with respect to haemostasis.6t-62The disadvantages of fibrin sealant include; necessityfor blood donation by the patient (approximately

80m L tw o to three days prior to the proposed surgery),lack of ready availability, exclusion of p atients allergicto bovine products (bovine thrombin used); and cost-currently approximately $300. Current

recommendations for its use in therapeuticallywarfarinized patients include non-availability oft ranexam ic ac id m outhwash, pat ients likely to be non-compliant with a mouthwash, and more extensivedentoalveolar procedures such as cystic enucleations.63

We p ropose the fol lowing c har t when presented w itha patient requiring dental extractions who is takingwarfarin (Fig 2):

IN R

<2.0.0-4.0

No modifications required No modifications required

Use local measures (Table 4) Use local measures (Table 4)

Notify LMO or cardiologist

Re: sub therapeutic atnicoagulation

Fig 2. Protocol relating INR to management.

3) Decrea sing the level of anticoagulation ortemporarily discontinuing the anticoagulant

In pat ients in wh om the r isk of thromb oem bolism isless of a problem, it has been suggested by some that

9 3

>4.0

No surgical treatment

Until INR reduced

Notify LMO or cardiologist

Re: over anticoagulation



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A ddre s s f o r c orr e sponden c e / repr in t s :

Professor AN Goss

Oral and M axillofacial Surgery UnitThe University of AdelaideAdelaide, South A ustralia 5005

Em ail: [email protected]

96ustra l ian D ental Journal 2003 ;48:2.

warfarin tg reference

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