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Journalof Dental Hygiene

T H E A M E R I C A N D E N T A L H Y G I E N I S T S ’ A S S O C I A T I O N

2007Journal of

Dental Hygiene

Special Supplement to Access magazine

An Examination of the Bleeding ComplicationsAssociated with Herbal Supplements,Antiplatelet and Anticoagulant Medications

• Introduction• Blood Clotting• Parenteral Anticoagulants• Oral Anticoagulants• Oral Antiplatelet Agents• NSAIDS• Herbal Supplements• Practice Considerations for Dental

Professionals

This supplement is sponsored by Philips Sonicare.CEUs available online—see inside front cover.

This special issue of the Journal of Dental Hygiene was funded by aneducational grant sponsored by Philips Sonicare.

This supplement can also be accessed online at www.adha.org/CE_courses/

To obtain one hour of continuing education credit, complete the test atwww.adha.org/CE_courses/course15

Journal of Dental Hygiene

3 From the Editor of the Journal of Dental Hygiene

Rebecca S. Wilder, RDH, BS, MS

An Examination of the Bleeding Complications Associated with Herbal Supplements, Antiplateletand Anticoagulant MedicationsAnn Eshenaur Spolarich, RDH, PhD, and Leslie Andrews, RDH, MBA

4 Introduction

6 Blood Clotting

7 Parenteral Anticoagulants7 Heparin 8 Low Molecular Weight Heparins8 Antithrombotic Agents8 Factor Xa Inhibitor

9 Oral Anticoagulants9 Warfarin

11 Oral Antiplatelet Agents11 Aspirin12 Dipyridamole12 Aspirin with dipyridamole12 Clopidogrel13 Cilostazole13 Ticlopidine

13 NSAIDS

14 Herbal Supplements15 Garlic Allium sativum16 Ginkgo Ginkgo biloba17 Ginseng Panax quinquefolius18 Ginger Zingiber officinale19 St John’s wort Hypericum perforatum L

21 Practice Considerations for Dental Professionals

Inside

Message

Supplement

2 The Journal of Dental Hygiene Special supplement

Journal of DentalHygiene

special supplement

■■ EDITORIAL REVIEW BOARD

Celeste M. Abraham, DDS, MSCynthia C. Amyot, BSDH, EdDJoanna Asadoorian, AAS, BScD, MScCaren M. Barnes, RDH, BS, MSPhyllis L. Beemsterboer, RDH, MS, EdDStephanie Bossenberger, RDH, MSKimberly S. Bray, RDH, MSLorraine Brockmann, RDH, MSPatricia Regener Campbell, RDH, MSDan Caplan, DDS, PhDBarbara H. Connolly, PT, EdD, FAPTAValerie J. Cooke, RDH, MS, EdDMaryAnn Cugini, RDH, MHPSusan J. Daniel, AAS, BS, MSMichele Darby, BSDH, MSCatherine Davis, RDH, PhD. FIDSAConnie Drisko, RDH, BS, DDSJacquelyn M. Dylla, DPT, PTDeborah E. Fleming, RDH, MSJane L. Forrest, BSDH, MS, EdDJacquelyn L. Fried, RDH, BA, MSMary George, RDH, BSDH, MEdEllen Grimes, RDH, MA, MPA, EdDJoAnn R. Gurenlian, RDH, PhDLinda L. Hanlon, RDH, BS, MEd, PhDKitty Harkleroad, RDH, MSHarold A. Henson, RDH, MEdLaura Jansen Howerton, RDH, MSLisa F. Harper Mallonee,BSDH,MPH,RD/LD

Heather L. Jared, RDH, BS, MSWendy Kerschbaum, RDH, MA, MPHSalme Lavigne, RDH, BA, MSDHJessica Y. Lee, DDS, MPH, PhDDeborah S. Manne,RDH,RN,MSN,OCNAnn L. McCann, RDH, BS, MSStacy McCauley, RDH, MSGayle McCombs, RDH, MSShannon Mitchell, RDH, MSTricia Moore, RDH, BSDH, MA, EdDChristine Nathe, RDH, MSKathleen J. Newell, RDH, MA, PhDJohanna Odrich, RDH, MS, DrPhPamela Overman, BSDH, MS, EdDVickie Overman, RDH, BS, MEdFotinos S. Panagakos, DMD, PhD, MEdM. Elaine Parker, RDH, MS, PhDCeib Phillips, MPH, PhDMarjorie Reveal, RDH, MS, MBAKip Rowland, RDH, MSJudith Skeleton, RDH, BS, MEd, PhDAnn Eshenaur Spolarich, RDH, PhDSheryl L. Ernest Syme, RDH, MSTerri Tilliss, RDH, BS, MS, MA, PhDNita Wallace, RDH, PhDKaren B. Williams, RDH, PhDCharlotte J. Wyche, RDH, MSPamela Zarkowski, BSDH, MPH, JD

■■ STATEMENT OF PURPOSE

The Journal of Dental Hygiene is the refereed, scientific publication of the American Dental Hygienists’ Association. It promotes the publication of original research related to the profession, the education, and the practice of dental hygiene. The journal supports the development and dissemination of a dental hygiene body of knowledge through scientific inquiry in basic, applied, and clinical research.

EXECUTIVE DIRECTORAnn Battrell, RDH, BS, [email protected]

DIRECTOR OF COMMUNICATIONSJeff [email protected]

EDITOR EMERITUSMary Alice Gaston, RDH, MS

EDITOR-IN-CHIEFRebecca S. Wilder, RDH, BS, [email protected]

STAFF EDITORKatie [email protected]

LAYOUT/DESIGNJean MajeskiPaul R. Palmer

■■ SUBSCRIPTIONS

The Journal of Dental Hygiene is published quarterly, online-only, by the AmericanDental Hygienists’ Association, 444 N. Michigan Avenue, Chicago, IL 60611. Copy-right 2007 by the American Dental Hygienists’ Association. Reproduction in whole orpart without written permission is prohibited. Subscription rates for nonmembers areone year, $45; two years, $65; three years, $90; prepaid.

■■ SUBMISSIONS

Please submit manuscripts for possible publication in the Journal of Dental Hygieneto Katie Barge at [email protected].

Special supplement The Journal of Dental Hygiene 3

e are very excited to beable to provide this CEsupplement to the Jour-

nal of Dental Hygiene for our mem-bers. The use of “natural” productsand supplements by the general pub-lic is growing at an astounding rate.Current estimates are that over 15million Americans use various vita-mins and herbs in addition to theirprescription medications. Since thesesupplements can be purchased overthe counter (OTC), many patients donot consider them to be medications,and therefore do not report them dur-ing the medical history process. Alloral health care providers need to beaware of the potential benefits anddisadvantages of these supplementsin order to provide a level of care

based on evidence. This timely liter-ature review by 2 internationally rec-ognized authors will provide anoverview of drugs and herbs that alterbleeding and will suggest ways thatoral health care providers can assureproper care and management of theirpatients’ oral and overall health. Thepublication will educate dentalhygienists as they respond to patientquestions and plan treatment strate-gies to improve patient care.

I want to extend huge gratitude toAnn Eshenaur Spolarich, RDH, PhD,and Leslie Andrews, RDH, MBA, fortheir time in writing this supplementand for their extensive knowledge ofa subject that is difficult to decipher.Both of these authors have been ded-icated members of ADHA and have

contributed to the body of knowledgefor our profession in numerous ways.In addition, this supplement wouldnot be possible without the generoussupport from Philips Sonicare.

Rebecca S. Wilder, RDH, MSEditor-in-Chief, Journal of Dental [email protected]

P.S. This is the first print edition ofthe Journal of Dental Hygiene youhave seen since 2004. If you likeseeing the Journal of Dental Hygienein print, please contact us at communications @adha.net and letus know that you enjoyed readingthis special print issue of the Journalas a supplement to Access!

From the Editor-in-Chief of the Journal of Dental Hygiene

W

■■ ANN ESHENAUR SPOLARICH, RDH, PHD, is aphysiologist, practitioner, author, and consultant. Sheteaches pharmacology at the Arizona School of Dentistryand Oral Health and at the USC School of Dentistry.

■■ LESLIE ANDREWS, RDH, MBA, is a former professionaleducator for Philips Oral Healthcare and is currentlyimmediate past president of the Connecticut DentalHygienists’ Association. She is a speaker and author onalternative medicine.

about the authors


Introduction

Cardiovascular disease, includingischemic coronary heart disease,stroke, and peripheral vascular dis-ease, is the leading cause of death inthe United States.1 Stroke is the thirdleading cause of death, and is the pri-mary cause of adult disability.2 Yearly,over 1 million Americans experiencenew or recurrent myocardial infarc-tion (MI) or fatal coronary heart dis-ease. Most of these events occur inthe elderly or in those with known riskfactors for cardiovascular disease.3

The age-adjusted mortality rate dueto coronary heart disease, cerebrovas-cular disease and atherosclerotic dis-ease is 194 per 100 000 cases, whichtranslates to more than 500 000 deathsper year.1 These leading causes ofdeath correspond directly to chronicconditions experienced by manypatients, especially the elderly, whomay live for decades with illnessesthat are typically controlled with med-ication use.2,4

Given these disease trends, dentalprofessionals are seeing more patientstaking anticoagulant and/or anti-platelet medications to prevent arte-rial or venous thrombosis and stroke.5

Controversy and confusion persist asto whether these medications actuallypose a risk for significant postopera-tive bleeding following invasive den-tal procedures. However, excessive orlife-threatening bleeding caused bymedication use in the dental office is

an extremely rare event, even amongpatients at risk.6,7

Determining the proper manage-ment strategy to safely treat patientstaking anticoagulant and antiplateletmedications must take into accountthe risk of thrombus formation in thepatient. The clinician must weigh therisks of potential bleeding complica-

tions against the potential risks asso-ciated with altering the medicationsused to reduce significant cardiovas-cular risk.6 According to Little andassociates (2002), risk of “thrombo-sis is of greater overall clinical impor-tance in terms of morbidity and mor-tality than all of the hemorrhagicdisorders combined.”5

An Examination of the Bleeding ComplicationsAssociated with Herbal Supplements, Antiplatelet andAnticoagulant MedicationsAnn Eshenaur Spolarich, RDH, PhD, and Leslie Andrews, RDH, MBA

SupplementSupplement

AbstractDental professionals routinely treat patients taking prescription, nonpre-scription, and herbal medications that are known or have the potential toalter bleeding. Prescription anticoagulant and antiplatelet medications, aswell as over-the-counter drugs such as aspirin, are typically taken to reducethe risk of thromboembolic events, including stroke. Herbal supplementsare widely used for a variety of indications, and both patients and healthcare practitioners are often unaware of the anticoagulant and antiplateleteffects that occur as either predictable pharmacologic effects or adverseside effects of herbal medicines. In addition, patient use of these herbalsupplements is usually undisclosed to health care providers. The purposeof this literature review is to examine the mechanisms of action of drugsand herbs that alter bleeding, and to educate dental professionals as to theproper care and management of patients using these medications. Deci-sion-making strategies, including interpretation of laboratory tests, andwhen to discontinue the use of these medications are discussed. Patientsundergoing routine dental and dental hygiene procedures do not need todiscontinue the use of anticoagulant and antiplatelet medications. However,alterations in drug use may be required for those patients undergoing inva-sive surgical procedures. It is recommended that herbal supplements mustbe discontinued 2 weeks prior to receiving invasive surgical procedures.Dental practitioners must learn to weigh the risks of discontinuing drug ther-apy against the potential risks to patients, and implement risk reductionstrategies to minimize adverse bleeding complications associated withdental treatment.

Keywords: Anticoagulants, Antiplatelet medications, Aspirin, Bleeding,Clotting, Dental treatment, Garlic, Ginger, Ginkgo biloba, Ginseng, Herbalsupplements, NSAIDS, Platelets, St. John’s wort, Warfarin


The decision to alter the patient’smedication regimen, by either lower-ing the dosage of or discontinuing themedication prior to dental treatment,is not supported by clinical studies inthe literature.6,8,9 Yet, many dental cli-nicians continue to recommend med-ication alteration as a managementstrategy, with the belief that they arepromoting patient safety. Proposedregimens are based on case reports,opinions published in the literature,and habit, and are not supported byclinical data.6,9

The justification for reducing orwithdrawing anticoagulant medica-tion prior to dental treatment can bedated back to a time when less than adozen case reports in the literaturereported excessive bleeding follow-ing dental treatment in patients takingwarfarin. However, it is important tonote that during the timeframe whenthose case studies were published, theprothrombin time test (PTT) wasused to evaluate the effectiveness ofwarfarin; but, testing was not yetstandardized, and variations in clini-cal efficacy were bound to occur.6,10,11

Today, standardized measures, suchas the International Normalized Ratio(INR), are used to assess coagulationtime in patients taking warfarin, andguidelines for therapeutic ranges ofanticoagulation have been estab-lished.12 These guidelines make it eas-ier for the clinician to predict therisks for bleeding in medicated den-tal patients.

A variety of other medications cancontribute to bleeding complicationsin dental patients, including nons-teroidal anti-inflammatory analgesics,hormones, herbs, and dietary supple-ments. It is critical that dental profes-sionals conduct a pharmacologic his-tory review as a component of acomprehensive review of systems forall patients who present for oral healthcare. Assessing the patient’s prescrip-tion and over-the-counter (OTC) med-ication use provides important infor-mation about the patient’s currentmedical status, disease severity, com-pliance with drug and treatment rec-ommendations, and orientation tohealth and wellness.13

Understanding medication usehelps dental professionals anticipateand prevent oral and systemic com-plications associated with adversedrug events.14 Drug-induced adversebleeding events can happen outside ofthe dental office, as well as duringtreatment. Assessing potential bleed-ing complications associated withmedication and supplement use is avital service that dental professionalsprovide to their patients.14 Most dentalpatients taking prescription medica-tions are aware of the bleeding risksassociated with their drugs, and infact, are monitored routinely to detectalterations in coagulation before com-plications arise. However, these same

patients may not fully understand howtheir lifestyle, including diet, alcoholuse, and the use of OTC medications,can alter the bleeding effects of theirprescription medications.

In addition, dental professionalsmust remember to ask their patientsabout the use of herbs, vitamins, anddietary supplements when assessingmedication use. Surveys estimatedietary supplement usage by 12% to24% of the general population.15 Inaddition, usage doubled for individualsaged 65 years and older from 1999 to2002.16 Recent estimates suggest thatover 15 million Americans take herbs,vitamins, or both, along with their pre-scription medications.17 Since these

supplements are available OTC, manypatients do not include these productswhen listing medications on health his-tory forms. For example, over 51% ofpatients scheduled to undergo surgicalprocedures in a Colorado hospital weretaking herbal medications, some ofwhich may alter blood coagulation.18

Further, in a preanesthesia interview ata university medical center, nearly 70%of patients taking herbal medicationsdid not report their usage.19

Several herbs contain substancesthat have coumarin, salicylate, orantiplatelet properties, such as garlic,gingko, and ginseng.20 Although nodefinitive studies have been per-formed to show a direct cause and

effect of herbal use and bleeding com-plications, the literature suggests thatthis is a phenomenon of increasingconcern due to the extreme popularityand increasing use of these products.

During January 2005, the NationalInstitutes of Health (NIH) conducted ajoint conference with the NationalHeart, Lung and Blood Institute(NHLBI), the Office of Dietary Sup-plements (ODS), the NIH ClinicalCenter (CC), the National Center ofComplementary and Alternative Med-icine (NCCAM), the National Instituteof Neurological Disorders (NINDS),the NIH Foundation, and the Office ofRare Diseases (ORD) at the NIH thatspecifically addressed this issue as a

The decision to alter the patient’s medication regimen, by either lowering thedosage of or discontinuing the medication

prior to dental treatment, is not supported byclinical studies in the literature. Yet, manydental clinicians continue to recommendmedication alteration as a management

strategy, with the belief that they arepromoting patient safety.


public health concern. The conferencegoal was to “increase our understand-ing of the potential for dietary supple-ments to interfere with hemostasis andantithrombotic therapies.”15

According to the Natural MedicinesComprehensive Database, approxi-mately 180 dietary supplements havethe potential to interact with warfarin,and more than 120 may interact withaspirin, clopidogrel (Plavix®), ordipyridamole (Aggrenox®). The 2005NIH conference specifically identifiedthe following supplements as havingthis interaction potential:

• Anise • Dong Quai• Omega-3 fatty acids in fish oil• Ajoene in Garlic• Ginger• Ginkgo• Vitamin E• Fucus• Danshen• St. John’s Wort• American Ginseng

In addition, the following herbsmay affect blood clotting, which isdependent on vitamin K:

• High dose vitamin E (specificdosage not indicated), a vitaminK antagonist

• Alfalfa –high vitamin K content• Coenzyme Q10 – dependent on

vitamin K

Several of these listed herbs areconsistently among the top sellers.Data from the Centers for DiseaseControl and Prevention (CDC) in2002 included ginseng, ginkgo biloba,and garlic as the dietary supplementswith the 2nd, 3rd, and 4th highestsales, respectively. St John’s wort was6th and ginger was 9th.21 The popu-larity of herbs with anti-coagulationpotential was further validated byHerbalGram’s report of dietary sup-plement sales in mainstream retailstores in 2004. Garlic was the topseller with ginkgo at 4th, ginseng at7th, St John’s wort at 9th, and gingerat 20th.22 Clearly, the popularity ofthese herbs has not waned.

Of the 11 herbs highlighted duringthe NIH conference, this article will

only focus on garlic, gingko, ginseng,ginger, and St John’s wort for severalreasons. First, as indicated above,these herbs consistently rank high insales, indicating predominant usage.Second, the amount and quality of sci-entific evidence is more prevalent onthese botanicals as compared to otherherbs.

Health care professionals have anincreasing responsibility to under-stand the rationale for use of theseherbal medications and their reportedeffects on the body, given the largepercentage of patients who take them.Unfortunately, it is challenging tolocate accurate, consistent, and com-prehensive information pertaining toherbal medications and their supposedmechanisms of action. While theknowledge base pertaining to herbsand other dietary supplements contin-ues to grow, there are few studies thathave determined conclusively howthese products alter bleeding or inter-act with other herbals and prescrip-tion anti-thrombotic medications.23

Speculation and case reports from theliterature have provided clues as tothe purported mechanisms of action;however, relatively few clinical trialshave been conducted to formallyexamine these issues. Further, casereports in the literature sometimes failto take into account other herbals ordrugs that the patient may have beentaking. Therefore, it is difficult tocredit the results of a case study toone definitive herbal action.

Clinicians encounter this samephenomenon with their own patients.When asked, a patient may know aproduct’s brand name, but cannotidentify the multiple herbs that arecontained within that same product.Further, it is not unusual for a patientto take upwards of 7 individualdietary supplements at the same time,but often on an inconsistent basis.When the CDC last reported ondietary supplement usage (1988-94),14.4% of respondents reported usageof 3 or more supplements.24 The high-est segment of users (22%) wasamong those aged 40 years and older.More recently, the Hartman Group,a research firm, surveyed 43 000 U.S.

households, and found that 31%reported using 7 or more supple-ments.25 These statistics may notreflect, and in fact may underesti-mate, the growing use of combina-tion products, or supplements thatcontain multiple herbs as well asvitamins. Given these trends, it ishighly likely that an individual isunknowingly taking several herbsthat have either anticoagulant orantiplatelet activity. Therefore, useof dietary supplements has the poten-tial to a) cause a bleeding condition,b) exacerbate an existing bleedingcondition, or c) alter the effective-ness of other OTC and prescriptionmedications being taken concur-rently. Obviously, the resulting com-plications may be potentially serious.

The purpose of this article is toassist dental professionals with under-standing the mechanisms of action ofpopular prescription and herbal med-ications that alter bleeding. Drug andherbal interactions will also be dis-cussed. Finally, practice managementconsiderations for medicated patientsand strategies for risk reduction willbe presented to increase the dentalprofessional’s confidence in makingtreatment decisions for patients tak-ing these medications.

Blood Clotting

There are over 50 substances in theblood that affect blood coagulation byacting as either procoagulants or anti-coagulants. Normally, the anticoagu-lant substances predominate, keepingblood clots from forming. However,when a blood vessel is ruptured, pro-coagulant substances in the area of thedamaged vessel become activated andoverride the effects of the anticoagu-lant substances, allowing a blood clotto form.26

When clotting poses risk to apatient, anticoagulant or antiplateletdrug therapy is used to reduce the riskfor thromboembolism. A thrombus isan abnormal clot that forms in a bloodvessel. When the velocity of the bloodflowing past the clot breaks the clotfree from its attachment to the vessel

wall, the free floating clot is referred toas an embolus. Clots that originate onthe left side of the heart on the arterialside of the circulation clog arteries andarterioles that feed organs, resulting inischemia and permanent damage to theorgan tissue. Clots that originate on thevenous side of the circulation or on theright side of the heart flow through thepulmonary arteries to the lungs, result-ing in pulmonary embolism (PE). Riskfor PE is high for patients who areimmobile or bedridden, as intravenousclotting forms in the legs due to bloodpooling in the lower extremities. Thiscondition is known as deep vein throm-bosis (DVT), a problem that can alsooccur in those traveling for long peri-ods of time sitting in a motor vehicle orairplane.

Dental hygienists should be awarethat circulating bacteria and bacterialendotoxins can also activate clottingmechanisms, producing small butnumerous clots that plug blood ves-sels in the periphery, depriving manytissues of oxygen and other essentialnutrients.26 This is why patients whodevelop bacterial endocarditis aretreated with anticoagulants as well asantibiotics: the antibiotics kill thecausative bacteria, while the antico-agulants help to prevent clotting andischemia initiated by bacterial endo-toxins.

ParenteralAnticoagulants

Heparin

Heparin is an endogenous sub-stance produced by many cells in thebody, but is primarily made by mastcells found in the connective tissuesurrounding capillaries in the body.These mast cells continuously pro-duce small quantities of heparin thatdiffuses into the circulation.Basophils in the blood also releaseheparin into the plasma. The concen-tration of heparin in the blood is nor-mally very low, and only producessignificant anticoagulant effectsunder specific circumstances. It isused medically in much higher con-

centrations to prevent intravascularclotting.26

Heparin itself is not an anticoagu-lant; however, by binding to anti-thrombin III, it serves as a catalyst toenhance the inactivation of multiplecoagulation factors, including throm-bin. Heparin also prevents the con-version of fibrinogen to fibrin, thusinhibiting clot formation.5,26 Unfrac-tionated heparin (Hep-Lock®, heparinsodium, heparin calcium) has beenused in medicine since the 1920s, andis used primarily in hospitalizedpatients to treat thromboembolism andPE.27 High-dose therapy is used forDVT and PE, while low-dose therapyis used preventively.5

Both warfarin (Coumadin®) andheparin therapy are started on the firstday of treatment, and the overlapallows for the 4 days to 5 days neededfor warfarin to take effect (see pagexx). Heparin inactivates existing coag-ulation factors relatively quickly,while warfarin therapy blocks the syn-

thesis of new clotting factors by theliver. In older adults undergoing gen-eral surgery, prophylaxis with low-dose unfractionated heparin (LDUH)or an intermittent pneumatic com-pression device, such as compressionelastic stockings, is recommended toprevent DVT and venous throm-boembolism (VTE).28 Heparin is alsoused to prevent clot formation incatheters, shunts, pumps, and infusionmachines (eg. dialysis machines).6

Standard heparin is comprised ofan unfractionated heterogeneous mix-ture of polysaccharide chains withmean molecular weights ranging from12 000 to 16 000 daltons. Heparin isadministered parenterally, usually byintravenous injection, which results inan immediate anticoagulant effect.5,27,29

When administered by intravenousinfusion or as a deep subcutaneousinjection, onset of action occurs any-where from 20 minutes to 30 min-utes.27,29 Response to heparin is variedand unpredictable; therefore, patientsreceiving heparin are monitored withan aPTT (activated partial thrombo-plastin time) test.5,27

Most patients receiving heparin willbe treated in the hospital setting, andinvasive dental procedures should beavoided during active treatment. Den-tal emergencies in these hospitalizedpatients must be treated carefully andconservatively.5 The most commondental patients taking heparin seen out-side of the hospital setting are thosewho are undergoing hemodialysis,who receive heparin on an outpatientbasis. As heparin has a half-life of 1hour to 2 hours, its effects last for onlya few hours after dialysis has beencompleted. It is safe for these patientsto receive invasive dental procedureson the day following dialysis.5

Heparin may induce thrombocy-topenia in up to 30% of users; how-ever, for most affected patients, thisadverse event is not clinically signif-icant. However, heparin may inducean immunologically-mediated throm-bocytopenia in 1% to 2 % of users thatcauses a marked decrease in plateletcount, leading to thromboemboliccomplications, such as PE, skin necro-sis, and gangrene.29 Daily plateletcounts for the first week following theinitiation of drug therapy can help todetect this condition.

Hemorrhage, including gingivalhemorrhage, is another risk associatedwith heparin. This risk is increased bythe use of other anticoagulant med-ications, thrombolytic agents anddrugs that alter platelet function (see

There are over 50 substances in the bloodthat affect blood coagulation by acting aseither procoagulants or anticoagulants.



below). It is important to note thatheparin is often used in conjunctionwith thrombolytics and during the ini-tiation of warfarin therapy to assureadequate anticoagulation. Certaincephalosporins and parenterallyadministered penicillins may alsoincrease risk for hemorrhage inheparinized patients.29

Low Molecular Weight Heparins

Low molecular weight heparins(LMWHs) are the preferred methodfor prophylaxis for elective hipreplacement surgery, started preoper-atively or immediately after surgery,as these drugs have been found to bevery effective in preventing asympto-matic VTE.30 For elective kneereplacement or hip fracture surgery,LMWH or adjusted-dose warfarinmay be used.28 Routine prophylaxisfor VTE with LDUH or LMWH isrecommended for patients withischemic stroke and impaired mobil-ity. These agents are also recom-mended for patients with other riskfactors for VTE including immobil-ity, cancer, heart failure, and severelung disease.28

LMWHs act in a similar manner tostandard heparin, by inhibiting acti-vated factor X and thrombin; however,they produce a lesser effect on theinhibition of thrombin.31,32,33 LMWHsare formed by depolymerization ofunfractionated heparin side chains,producing “smaller” heparin frag-ments, with mean molecular weightsranging from 1000 daltons to 10 000daltons.27

LMWHs are administered subcuta-neously, and exhibit a better bio-availability than standard heparin, asthey are less bound to plasma proteins,endothelial cells and macrophages.They also have a longer half-life (2hours to 4 hours) than heparin, anddosage is based upon body weight.Because LMWHs produce a more pre-dictable anticoagulant response, labo-ratory monitoring during treatment isgenerally not necessary.5,27 Dental pro-fessionals do not need to order labora-tory testing for patients taking thesedrugs for routine dental care.

For patients undergoing orthopedicsurgery to the lower extremities, theoptimal duration of prophylaxis isunknown.28 Risk for DVT followingsurgery is related to the length of timethat the patient remains immobile andother risk factors; risk persists for upto 2 months following total hipreplacement surgery.28,34,35,36,37 Six ran-domized double-blind controlled clin-ical trials demonstrated reduced riskof total and proximal DVT by at least50% for patients with total hipreplacement who received prophy-laxis with either LDUH or LMWH for5 weeks beyond the hospital stay.30

LMWHs can be provided on anoutpatient basis, and patients takingthese drugs have lower risks for hem-orrhage and heparin-induced throm-bocytopenia, as compared to patientstaking heparin. Risks for bleedingincrease when the LMWHs are usedwith thrombolytic agents, oral antico-agulants, and drugs that alter plateletfunction, although they are frequentlyused during initial therapy with oralanticoagulants to ensure proper anti-coagulation. There are 3 FDAapproved LMWHs in the UnitedStates: dalteparin (Fragmin®), enoxa-parin (Lovenox®), and tinzaparin(Innohep• ).27,29 Enoxaparin is the mostwidely used LMWH, and has beenshown to prevent ischemic complica-tions associated with unstable anginaand non-Q wave myocardial infarc-tion (MI).5,29,38

Patients on LMWHs who present tothe dental office can usually receiveinvasive dental treatment without anymodifications necessary to their med-ication regimen. Should excessivebleeding be anticipated, as with oral orperiodontal surgery, a physician con-sultation is warranted to determinewhether the medication should be tem-porarily discontinued prior to per-forming the dental procedure. Giventhe short half-life of these drugs, highdose LMWH can be stopped for oneday on the day before the surgery; then,therapy is resumed following hemo-stasis on the day of surgery. However,the best option is to wait until LMWHtherapy has been completed beforeattempting any elective dental surgery.5

Antithrombotic Agents

There are 3 FDA approvedantithrombotics that are used for theprevention of postoperative deep veinthrombosis (DVT), and for the treat-ment of heparin-induced thrombocy-topenia and related thromboemboliccomplications. These drugs are arga-troban (no brand name), danaparoid(Orgaran®), and lepirudin (Refludan®).

Argatroban is indicated for the pre-vention and treatment of thromboem-bolic complications in patients withheparin-induced thrombocytopenia.This drug is a highly selective throm-bin inhibitor and binds reversibly tothe active thrombin site of free andclot-associated thrombin. Drug admin-istration is by IV, which produces animmediate onset of action. The druginhibits fibrin formation, the activationof numerous clotting factors, andplatelet aggregation.27,29

Danaparoid (Orgaran®) is indicatedfor the postoperative prevention ofDVT following elective hip replace-ment surgery. This drug prevents fibrinformation by inhibiting activated factorX by antithrombin. It is administeredsubcutaneously, with maximum effectoccurring within 2 hours to 5 hours.27,29

Lepirudin (Refludan®) is indicatedfor anticoagulation in patients withheparin-induced thrombocytopeniaand related thromboembolic compli-cations, and has investigational usefor the prevention of ischemic com-plications associated with unstableangina. This drug is a highly specificinhibitor of thrombin, and is adminis-tered by IV. All antithrombotic agentshave a risk for hemorrhage, which isincreased with concurrent use of oralanticoagulants and drugs that alterplatelet function.27,29

Factor Xa Inhibitor

There is 1 antithrombotic agent inthis new class of medications calledfondaparinux (Arixtra®). This drug isindicated for prevention of deep veinthrombosis (DVT) in patients under-going hip or knee replacement or hipfracture surgery. It may also be usedfor the treatment of acute pulmonary

embolism (PE) or for treatment ofacute DVT without PE. Fondaparinuxis a synthetic pentasaccharide thatinhibits activated factor X, whichinhibits thrombin formation. It isadministered subcutaneously, oncedaily. Risk for hemorrhage is increasedwhen this drug is taken concurrentlywith oral anticoagulants, antiplateletdrugs, non-steroidal anti-inflammatorydrugs (NSAIDS), salicylates, andthrombolytics.27,29

Oral Anticoagulants

Warfarin

Warfarin (Coumadin®, Jantoven™)is an oral anticoagulant used for pre-vention and treatment of VTE, PE,atrial fibrillation with risk ofembolism, and to prevent systemicembolism after MI.29 Warfarin is alsoused for anticoagulation therapy inpatients with prosthetic heart valves.Coumarin derivatives work differentlythan the other parenteral anticoagu-lants described above, by inhibitingthe synthesis of vitamin K- depend-ent clotting factors.

Several clotting factors are depend-ent upon vitamin K for their synthesisin the liver. Warfarin binds to the livermicrosomal enzyme vitamin K 2,3-epoxide reductase, and inhibits theproduction of the reduced form ofvitamin K. Reduced vitamin K is anecessary cofactor in the gamma car-boxylation of the 4 vitamin K-depend-ent clotting factors: factors II, VII, IX,X. Precursors to these 4 clotting fac-tors undergo vitamin K-dependentmodification to produce their activeforms. By inhibiting the formation ofreduced vitamin K, coumarins preventthe activation of these clotting factors.Thus, the clotting factors remain asinactive molecules that cannot partic-ipate in the clotting process, therebystopping the formation of thrombinand fibrin.

Warfarin also depresses proteins Cand S, which are endogenous antico-agulants. Levels of these 2 proteinsmay be depressed by warfarin priorto depression of the other clotting fac-

tors, resulting in a dangerous period ofhypercoagulation for a short period oftime. The anticoagulant effects ofwarfarin are not initially evident until8 hours to 12 hours after oral admin-istration, and given its 36 hour half-life, if may take up to 4-7 days of dos-ing to reach the desired targetInternational Normalized Ratio (INR)value.29 For this reason, heparin ther-apy (LDUH or LMWH) usually over-laps warfarin therapy for at least thefirst 2 days of oral anticoagulant ther-apy to allow for the warfarin to takeeffect and to achieve an optimal ther-apeutic range of anticoagulation.28,39

Heparin is discontinued after the INRhas been in the therapeutic range for atleast 2 measurements taken more than24 hours apart.

Despite its widespread use, physi-cians often find it difficult to prescribewarfarin, given its narrow therapeu-tic index. It may take weeks of clini-cal testing (via the INR) to find theexact dose that results in the desiredlevel of anticoagulation. Even smallvariations in dose can result in largeclinical effects, including excessbleeding (over-anticoagulation) orinadequate anticoagulation, whichplaces the patient at risk for develop-ing clots.

Individuals taking warfarin vary intheir response to given doses of thedrug. It is known that a variation inthe gene that encodes the CYP2C9liver enzyme that metabolizes war-farin accounts for about 10% of thedifference in response to the drugobserved in warfarin users. Recently,investigators have identified anothergenetic variation in the VKORC1gene (vitamin K epoxide reductase),which makes a protein that helps con-trol clotting and is the target site ofaction of warfarin. By matching thegenetic variations to the actual dosetaken by study subjects, theresearchers found that individualswith particular variations in theVKORC1 gene generally took similardoses of warfarin. Study results sug-gested that variation in this one geneaccounted for 25% of the overall vari-ance in warfarin dose. In the future,genetic testing could help to predict a

person’s response to warfarin, andcould be used to determine the properinitial dose.40

The major complication of antico-agulation therapy is bleeding. There isa positive relationship between the riskfor hemorrhage and the intensity ofanticoagulation.41 Patients on high-intensity warfarin therapy (INR>3.0)are at higher risk for hemorrhage ascompared to warfarin therapy with anINR that falls between 2.0-3.0. Therisk for intracranial hemorrhaging risesdramatically with an INR>4.0.41,42 Themajor determinants of warfarin-induced bleeding are the intensity ofanticoagulation, unique patient char-acteristics, concurrent use of drugs thatinterfere with hemostasis (eg, aspirin),poorly controlled hypertension, andthe duration of drug therapy.41 Multiplelarge, randomized controlled clinicaltrials support the use of combinationtherapy with aspirin plus warfarin(INR 2.0-2.5) in high- risk patientswith atherosclerotic heart disease.Combination therapy increases the riskof both minor and major bleeding, butnot intracranial bleeding in athero-sclerotic patients. The most commonbleeding complications include epis-taxis (nosebleed), purpura (skin hem-orrhages), gastrointestinal (GI) bleed-ing, hemoptysis (expectorating blood),and hematuria (blood in urine).42,43,44

Unexpected elevations in the INRincrease concerns for adverse bleed-

The majorcomplication ofanticoagulation

therapy is bleeding.There is a positive

relationship betweenthe risk for

hemorrhage and theintensity of

anticoagulation.



ing events. Frequent monitoring oftherapy, including the INR, is espe-cially important in older adults, andadjustments to the treatment regimenare often necessary.45 When the INRis elevated, but no bleeding is present,warfarin therapy can be reduced orstopped, which lowers the INR within24 hours to 48 hours without return-ing it to baseline levels. In patientswith non-life-threatening bleeding, asmall dose of vitamin K1 (1-2.5 mg)is administered orally or subcuta-neously (SC). If urgent correction ofthe INR is needed, a larger dose ofvitamin K1 (2-4 mg) is given initially,with additional 1-2 mg doses givenas needed. When the INR >9.0 and/orbleeding is life-threatening, warfarintherapy is stopped and large doses ofvitamin K1 (3-5 mg orally; 5-10 mgSC) are given. Fresh frozen plasmamay also be given to replace the vita-min K-dependent clotting factors. Vit-amin K1 may also be given by IV inlife-threatening situations, but it mustbe administered slowly and carefullymonitored, given the risk for anaphy-laxis.46,47,48,49,50,51,52

Multiple factors can contribute toalterations in the INR. Poor compli-ance with warfarin therapy is the mostcommon reason for fluctuations inanticoagulation therapy.53 Switchingbetween different brand names ofwarfarin product formulations hasbeen shown to contribute to majormedical complications, and patientsare advised not to switch brands oncethe desired therapeutic effect has beenachieved.29,54 Alterations in vitamin Kintake, interference with intestinalbacterial synthesis of vitamin K, andimpaired vitamin K absorption allcause significant fluctuations inresponse to warfarin.55 Many commonfoods, especially dark green leafy veg-etables and 4 plant oils (soybean,canola, cottonseed, and olive) serveas primary dietary sources for vitaminK.56 Patients should maintain consis-tency in their diet and meet the rec-ommended dietary allowance for vita-min K of 65 to 80 micrograms ofphylloquinone per day.56 Patients whoincrease their intake of “heart-healthy” green vegetables without

informing their physicians may beinadvertently increasing their warfarinrequirements; sudden decreases invitamin K intake then increases therisk for hemorrhagic events.

Other factors that contribute toalterations in anticoagulation effectsinclude illness, fever, thyroid disease,biliary disease, liver disease, malab-sorption syndromes, congestive heartfailure, malignancy, and diarrhea.6,55

Warfarin is also highly affected bymedication use. In fact, more foodand drug interactions have beenreported for warfarin than with anyother prescription medication.57Alco-hol consumption has also beenreported to increase bleeding in war-farin users.55,58

Dental professionals should beaware that many commonly pre-scribed drugs used during dental treat-ment have the potential to alter theeffects of warfarin. The dental drugsthat have been reported to enhance the

anticoagulant effect of warfarininclude antibiotics (cephalosporins,macrolides, metronidazole, quino-lones, penicillins, tetracyclines), anal-gesics (acetaminophen, NSAIDS),prednisone, and the systemic azoleantifungals (fluconazole, ketocona-zole, itraconazole).29,55,59 Single-doseantibiotic prophylaxis for the preven-tion of endocarditis and prostheticjoint infection is not likely to alter theeffect of warfarin, although 3 casereports have been reported in the lit-erature describing elevations in INRfollowing prophylactic antibioticuse.60,61 Salicylates and NSAIDSshould be avoided in warfarin users,given their antiplatelet activity.60 Alldental professionals are encouragedto consult a drug reference guide priorto prescribing any medication to apatient taking warfarin to ensure drugcompatibility and safety. Foods andherbs that alter warfarin activity aresummarized in Table I.

Alcohol Acute binge drinking increases PT/INR

Chronic daily drinking decreases PT/INR

Foods rich in vitamin K Decreases effect of warfarin

Vitamin C Increases effect of warfarin

Cranberry juice Increases effect of warfarin

St. John’s wort Decreases serum levels of warfarin

Alfalfa Decreases effect of warfarin due to largeamount of vitamin K

Coenzyme Q10 Decreases response to warfarin

Bromelain Avoid concurrent use: antiplatelet action

Cat’s claw Avoid concurrent use: antiplatelet action

Dong quai Avoid concurrent use: antiplatelet action

Evening primrose Avoid concurrent use: antiplatelet action

Feverfew Avoid concurrent use: antiplatelet action

Garlic Avoid concurrent use: antiplatelet action

Green tea Avoid concurrent use: antiplatelet action

Ginseng Avoid concurrent use: antiplatelet action

Ginkgo Avoid concurrent use: antiplatelet action

Horse chestnut Avoid concurrent use: antiplatelet action

Red clover Avoid concurrent use: antiplatelet action

Source: Wynn RL, Meiller TF, Crossley HL. Drug Information Handbook for Dentistry. 10th ed.,Hudson:Lexi-Comp, Inc. 2005. 29

Table I. Foods and herbs that alter warfarin activity.


Oral Antiplatelet Agents

Aspirin

Aspirin was first used as an anal-gesic and antipyretic drug in 1899,and has quickly become the mostwidely used drug in the history ofmedicine.62 During the 1960s, theantiplatelet properties of aspirin werediscovered.62 Since then, aspirin hasbecome the most comprehensivelystudied and least expensive of allantiplatelet medications.5 Aspirinblocks the synthesis of thromboxaneA2 from arachidonic acid in plateletsby inhibiting the enzyme cyclooxy-genase 1 (Figure 1). Thromboxane A2is necessary for platelet aggregationand promotes blood clotting. Theinhibitory effect of aspirin on the for-mation of this substance is irreversibleand lasts for the life of the platelet,which is 7 days to 10 days. In fact, asingle dose of aspirin impairs plateletaggregation for up to 4 days, until newplatelets enter the circulation in suffi-cient numbers to exert a thromboticeffect.63

Aspirin reduces mild to moderatepain, inflammation, and fever.29

Aspirin is also used for the primaryprevention of MI in patients atincreased risk, and for the secondaryprevention of ischemic cardiovascularevents, such as stroke.62 Further,aspirin is used as an adjunctive ther-apy during revascularization proce-dures (eg, coronary bypass).29 Aspirinshould be available in the dental officeas a pre-hospitalization drug for use inpatients experiencing MI. It is thoughtthat the fibrinolytic properties ofaspirin, given at an 81-325 mg dose,may help to reperfuse the ischemicmyocardium.64

Despite the cardioprotective bene-fits of this drug, aspirin is still under-used by many at-risk populations.65 It isimportant to note that although aspirinis not approved for primary preventionof ischemic events, it may be possiblefor people who are at an even higherrisk than those who have already expe-rienced an adverse cardiovascularevent to benefit from the effects ofaspirin. The potential number of people

in this highest risk category exceedsthe number of people who are alreadytaking the drug.62 Safety concerns,including risks for hemorrhage andgastrointestinal (GI) ulceration andbleeding, are thought to limit the rec-ommendations of this drug by physi-cians to their patients.62 However, manypatients choose to self-medicate withaspirin, and may be unaware of itspotential adverse effects.

In addition to data that supports thebenefits of aspirin in patients with car-diovascular disease, data from 55 000individuals supports aspirin use forthe prevention of first MI in healthyindividuals, with an overall risk reduc-tion of 32%.66 Both the AmericanHeart Association (AHA) and the U.S.Preventive Services Task Force (USP-STF) have published guidelines forthe use of aspirin for the primary pre-vention of MI.3,67,68

A meta-analysis of all available ran-domized, placebo-controlled clinicaltrials evaluating the effects of low-doseaspirin therapy for secondary preven-tion revealed that aspirin reduces therisk of death by approximately 20%.Further, aspirin also reduces the rela-tive risk for cardiovascular events (eg,MI) and cerebrovascular events(stroke) by 20% to 30%.69

The most common adverse eventassociated with aspirin use is GI ulcer-ation and hemorrhage. These GI com-plications are attributed to aspirin’s

inhibitory effect on prostaglandin syn-thesis, which stops the production ofprotective prostaglandins that coat thewalls of the stomach that normallyform a barrier between the hydrochlo-ric acid and the gastric mucosa. Fur-ther, aspirin inhibits the synthesis ofprostaglandins that protect the kidney.Notably, chronic aspirin use can leadto kidney damage and renal failure.Hemorrhagic stroke is also a risk asso-ciated with long-term aspirin use. Ameta-analysis of 16 clinical trialsdemonstrated an increased absoluterisk of 12 hemorrhagic stroke eventsper 10 000 aspirin users.70 Althoughaspirin increases risk for adversebleeding events, the cardioprotectivebenefits of the drug outweigh theserisks when used appropriately in at-risk patient populations.62

Many adverse events caused byaspirin are dose-related and areextremely rare with low-dose therapy(81 mg per day). Bleeding riskincreases with concurrent use of othermedications that alter hemostasis,including NSAIDS, warfarin, and alco-hol. Drinking more than 3 alcoholicbeverages per day significantlyincreases risk for GI hemorrhage.Aspirin use should be discontinued ifpatients develop tinnitus or hearingloss. Caution should be used whenusing aspirin in patients with bleedingor platelet disorders, peptic ulcer dis-ease, and liver or kidney dysfunction.

Cell membrane phospholipids

↓Arachidonic Acid

↓Cyclooxygenase

↓Prostaglandin G2

↓Prostaglandin H2

______________________________________________↓ ↓ ↓

Prostacyclin Prostaglandins Thromboxane A2vasodilation, PGD2, PGE2, PGF2α vasoconstriction,

inhibits platelet aggregation vasodilation, edema promotes platelet aggregation

Figure 1.The arachidonic acid cascade.

Other serious reactions includehypersensitivity reactions and idio-syncratic reactions.

Patients who are sensitive to tar-trazine dyes, or who have nasal polypsor asthma are more likely to be sensi-tive to aspirin. In patients withbronchial asthma, aspirin and otherNSAIDS may precipitate a conditionknown as aspirin-induced asthma(AIA), a syndrome characterized byaggressive and continuous inflamma-tory disease of the airways. AIA pro-gresses from the upper to lower respi-ratory tract and affects women morethan men, with an average age of onsetat 30 years. Rhinorrhea and nasal con-gestion are the first symptoms, withasthma and aspirin hypersensitivitydeveloping 2 years to 15 years later.Once developed, aspirin intoleranceremains throughout life.71 Further,patients who are allergic to NSAIDSmay not take aspirin or aspirin-con-taining products.29

There is increasing concern aboutthe number of individuals who exhibitaspirin resistance, also known as hypo-responsiveness, to the effects ofaspirin. These individuals experiencefirst MI or suffer a second adverseevent while taking aspirin. For somereason, aspirin therapy is not enoughto stop thrombotic activity. Three pos-sible explanations have been offeredto explain aspirin resistance: plateletsbecome activated by pathways notblocked by aspirin; patients require ahigher dose of aspirin to produce aneffect; or patients generate thrombox-ane A2 despite aspirin therapy.72 Earlydata suggests that aspirin resistance

may be dose related; resistance isfound more often during low-dosetherapy (< 100 mg daily) than athigher doses (> 300 mg daily). Plateletaggregation studies of these individu-als reveal no biochemical activity ofaspirin. Urinary concentrations of athromboxane metabolite (11-dehy-drothromboxane B2), a marker foraspirin resistance, may be used toidentify potential aspirin-resistant indi-viduals. Patients who are aspirin resist-ant should continue to take aspirin forits anti-inflammatory effects, but mayrequire additional antiplatelet thera-pies for risk reduction.72,73

Aspirin has many drug interactions,and dental professionals should con-sult a drug reference text prior to pre-scribing any medications to patientstaking this drug. For example, con-current use of aspirin with NSAIDSmay decrease the serum concentrationof some NSAIDS.29 Dental profes-sionals must remember that the effectsof this drug are irreversible; therefore,additional bleeding will be evidentduring any invasive procedure. Thereis no evidence to support the discon-tinuation of low-dose aspirin therapyprior to dental procedures or dentalsurgery, as the risk for an adverse car-diovascular event outweighs the riskfor intraoperative and postoperativebleeding in dental patients.8,29 Suchbleeding can be managed locally withthe use of hemostatic agents. However,a physician consultation is warrantedto discuss whether patients whorequire major surgery require an alter-ation in aspirin therapy. The decisionto discontinue therapy must take into

account the risks to the patient. If thedecision is to discontinue aspirin, thepatient should stop taking aspirin 10days to 14 days prior to surgery toallow for the synthesis of newplatelets.

Dipyridamole

Dipyridamole (Persantine®) stimu-lates the release of prostacyclin orprostaglandin D2 (PGD2), inhibitingplatelet aggregation and producingcoronary vasodilation. The drug is pri-marily used to prevent angina pectoris,and to maintain the opening of thecoronary arteries following bypass sur-gery. This drug is often used in com-bination with aspirin to prevent coro-nary artery thrombosis, or withwarfarin, to decrease the risk of throm-bosis in patients with mechanical heartvalves. It may also be used prophy-lactically to prevent myocardial rein-farction.27,29 The drug is administeredorally and intravenously.

Aspirin with dipyridamole

Combination aspirin with extended-release dipyridamole is an antiplateletdrug known as Aggrenox®. Aggrenox®

is used to reduce the risk of stroke inpatients who have had either transientbrain ischemia or an ischemic strokedue to thrombosis. The drug contains25 mg of aspirin and 200 mg of dipyri-damole. The aspirin inhibits plateletaggregation by inhibiting plateletcyclooxygenase and the generation ofthromboxane A2. Dipyridamole stim-ulates the release of prostacyclin, theantagonist of thromboxane A2. Theantithrombotic effects of this drug areirreversible, given the aspirin compo-nent of the drug.27,29

Clopidogrel

Clopidogrel (Plavix®) inhibitsplatelet aggregation by a differentmechanism than aspirin. This druginhibits the binding of ADP to itsplatelet receptors, which prevents thebinding of fibrogen between platelets,reducing platelet adhesion and aggre-gation. Clopidogrel also blocks the

A meta-analysis of all available randomized, placebo-controlled clinical trials

evaluating the effects of low-dose aspirintherapy for secondary prevention revealed

that aspirin reduces the risk of death byapproximately 20%.



amplification of platelet activationcaused by released ADP. Plavix® isused as an antithrombotic for the pre-vention of myocardial infarction,stroke and vascular death in patientswith atherosclerosis. It is also pre-scribed for the prevention of throm-boembolic events following the place-ment of coronary stents. 27,29

Plavix® was developed for use forpatients who are unable to tolerate theadverse gastrointestinal effects ofaspirin, and has recently replacedticlopidine (Ticlid®) as the drug ofchoice for patients who are allergic orintolerant to aspirin.27 Evidence sup-ports that both clopidogrel and ticlo-pidine are more effective than aspirinin preventing stroke and other seriousvascular events in high risk patients.74

Like aspirin, this drug produces irre-versible effects that last for the life ofthe platelet. Patients can receive rou-tine dental procedures, including oralprophylaxis, without altering the doseof the drug.5,8 However, patients thatare scheduled to undergo invasive sur-gical procedures, including dental sur-gery, are advised to discontinue thedrug for 7 days prior to surgery.5 Con-sultation with the patient’s physicianprior to discontinuing the drug is war-ranted to ensure patient safety.

Risk for hemorrhage is associatedwith this drug and bleeding may occurat any site, including the oral cavity.Risk for hemorrhage increases withconcurrent use of other drugs that alterhemostasis, including anticoagulantsand antiplatelet drugs. Avoid the useof herbs that demonstrate antiplateletactivity (Table I). Concurrent use ofclopidogrel with naproxen hasresulted in GI blood loss. Cases ofthrombotic thrombocytopenia purpurahave been reported with use of thisdrug, usually occurring within the first2 weeks of therapy.29

At high doses, clopidogrel may alterthe metabolism of some NSAIDS,which can result in toxicity reactions.Finally, CYP3A4 inhibitors, includingthe macrolide antibiotics, maydecrease the effects of clopidogrel.Dental patients who are prescribedthese antibiotics should be closelymonitored.29

Cilostazole

Cilostazole (Pletal®) is an oralantiplatelet drug used to manage thesymptoms of peripheral vascular dis-ease. This drug and its metabolitesinhibit phosphodiesterase III, whichincreases cyclic adenosine monophos-phate (AMP), causing inhibition ofplatelet aggregation and vasodilation.Inhibiting phosphodiesterase IIIincreases cardiac contractility, atri-oventricular (AV) nodal conduction,ventricular automaticity, heart rate,and coronary blood flow.29

The blood levels of cilostazole maybe increased by erythromycin. In-creased blood concentrations of thisdrug are observed with concurrent useof CYP3A4 inhibitors, including themacrolide antibiotics and the systemicazole antifungals. Inhibition ofplatelet aggregation caused by aspirinis potentiated with concurrent use ofcilostazole.29

Ticlopidine

Ticlopidine (Ticlid®) is an irre-versible platelet aggregation inhibitorused to reduce the risk for thromboticstroke. The other primary indicationfor use is to reduce the incidence ofthrombotic complications in patientswith coronary stents. Use of this drugis typically reserved for patients whoare intolerant to aspirin, and for thosewhose aspirin therapy has failed.Ticlopidine has a mechanism of actionthat is unique from other plateletaggregation inhibitors. While the druginhibits adenosine diphosphate (ADP)platelet receptor fibrinogen binding(like Plavix®), this drug also signifi-cantly increases bleeding time. Theincrease in bleeding time can be fur-ther prolonged by the addition ofaspirin.29

Ticlopidine has been associated withlife-threatening hematologic disorders,including neutropenia and thromboticthrombocytopenic purpura.75 Thus, useof clopidogrel has surpassed this drugdue to a better safety profile. Ticlopi-dine use may increase the effect andrisk for toxicity of aspirin, anticoagu-lants, and NSAIDS.29

NSAIDS

Nonselective NSAIDS, such asibuprofen, inhibit both cyclooxyge-nase1 and 2, and thus alter thrombox-ane A2 synthesis and platelet aggre-gation (Figure 1). However, unlikeaspirin, the effects of these drugs arereversible and last for a shorter periodof time, based upon the half-life of theindividual drug.27 When the drug isremoved from the body, platelet func-tion is restored. A recent study demon-strated that platelet function returnedto normal within 24 hours of discon-tinuation of ibuprofen use in healthyindividuals.76 Many professionals con-tinue to recommend discontinuing theuse of NSAIDS at least 7 days prior tosurgery, when in fact, a much shortertimeframe may suffice. Practitionersshould look up the half-life of theNSAID to determine how long it willtake for the drug to clear from thebody.

The degree of platelet inhibitionseems to vary among different nonse-lective NSAIDS, but for most drugs,this effect does not appear to lastthroughout the length of the dosingperiod. For example, taking naproxen500 mg twice daily inhibits plateletaggregation throughout the dosingperiod, versus ibuprofen, whichachieves adequate platelet inhibition

Unlike aspirin, theeffects of NSAIDSare reversible andlast for a shorter

period of time, basedupon the half-life of

the individualdrug.When the drugis removed from the

body, plateletfunction is restored.


at peak levels, but is not sustained,given the short half-life of the drug.Further, data suggests that theantiplatelet effects of naproxen aresignificant and comparable to thoseproduced by aspirin, but are less withibuprofen and diclofenac.77 This sug-gests that naproxen may have greatercardioprotective properties than otherNSAIDS. The variance in effect onplatelet inhibition is among the manyreasons why NSAIDS are not used forcardioprotective therapy.

A large epidemiologic study foundno evidence of cardioprotective effectsof traditional NSAIDS.78 Several stud-ies concluded that current use ofNSAIDS does not substantially reducethe risk of acute myocardial infarction(MI).79,80,81,82 Given the effects ofnaproxen, several investigations exam-ined whether naproxen therapy couldreduce the risk for MI; study resultswere inconclusive.80,81,83,84,85,86,87,88 Thereis also increasing evidence that con-current use of NSAIDS with aspirinmay decrease the cardioprotectiveeffects of aspirin.89,90,91

A recent retrospective case-controlanalysis of 8688 case patients withfirst-time acute MI revealed that cur-rent use of NSAIDS does not alter therisk of acute MI. Further, the risk foracute MI was higher among subjectswho stopped taking NSAIDS within 2months before the MI occurred. Theauthors hypothesize that currentNSAID use does offer some protec-tive effect, such as reducing MI riskrelated to chronic inflammation, butthat this effect only occurs while thedrug is being taken.92

Selective NSAIDS, known as theCOX-2 inhibitors (eg, Celebrex®,Vioxx®, Bextra®), inhibit cyclooxyge-nase 2 without affecting cyclooxyge-nase 1. Thus, their effects predomi-nantly alter prostacyclin versusthromboxane A2 (Figure 1). Studiesin healthy volunteers show that treat-ment with COX-2 inhibitors decreasessystemic production of prostacyclinwith no effects on platelet-derivedthromboxane A2 synthesis.79,93

Expression of cyclooxygenase 2 isincreased during ischemia, which isthought to be a protective mechanism

against vascular injury, causingincreased prostacyclin synthesis, result-ing in vasodilation and decreasedplatelet aggregation to facilitate bloodflow. Inhibition of the COX-2 enzymeblocks these protective effects, andbecause platelet thromboxane A2 isunaffected, the balance of the equilib-rium maintained between these 2prostanoids becomes disrupted. Thisallows the influence of thromboxaneto predominate, increasing vasocon-striction and clotting. This is the mech-anism thought to underlie the adversehypertension and stroke events foundwith long-term use of COX-2 inhibi-tors (eg, Vioxx®)

Herbal Supplements

Physicians closely monitor patientstaking prescription medications thatalter bleeding, because the effects ofthese medications are known. Unfor-tunately, patient use of OTC medica-tions that alter bleeding, including theuse of dietary supplements, is notsupervised as closely, especially sincemany patients do not report taking

these medications. In fact, use of anyform of alternative medicine is notdisclosed to health care providers over60% of the time.17

A study in England documented thata significant number of patients maybe co-ingesting herbal medicines withwarfarin. One thousand three hundredand sixty patients from 35 differentmedical practices were surveyed aboutthe use of garlic, ginseng, ginkgobiloba, feverfew, ginger, and St. John’swort. One hundred and nineteenpatients (8.8% of the respondents)reported taking one or more of theseherbs. When asked if they had dis-cussed their herbal use with any healthcare professional, 92.2% reported thatthey had not. The authors concludedthat all general practitioners prescrib-ing warfarin should always ask aboutthe use of herbal medications. Theyalso added that there are risks involvedwith any herbal preparations, andcharged that physicians, as well as theirpatients, share a joint responsibility todiscuss potential herb-drug interac-tions.94 Dental professionals are alsowell positioned to help patients under-stand the vital nature of this type of

disclosure along with responsible prod-uct use.

Both the desired and adverseeffects caused by prescription medi-cines are predictable, as they are man-ufactured and tested according toexacting standards. The effects ofherbal phytotherapies, includingadverse reactions, are hard to foresee.The FDA does not regulate herbalproduct manufacturing, nor is safetytesting required, so it is challengingto find documented safety and effi-cacy information. However, the pop-ularity of these products has dictatedthe need for further study to gain abetter understanding of how herbsaffect the body, and significantimprovements in both herbal manu-facturing and research have occurredin recent years.

Unlike prescription drugs, individ-ual herbal preparations are often amixture of more than one activeingredient. Thus, it is difficult todetermine which or how many con-stituents of the herbal product arepharmacologically important. In addi-tion, comparable herbal products varyin formulation, and their undefinedcomposition makes analysis of theactive constituents extremely com-plex.95 This further confounds theunderstanding and utility of findingsgleaned from research studies aboutthe effects of herbal drugs.

Ciocon and colleagues have stated“that certain herbals have been asso-ciated with increased risk of bleedingby inhibiting platelet function, plateletaggregation and thromboxane synthe-sis, thrombin and thromboplastinmechanisms, and by those which con-tain coumarin-like effects, and salicy-late-like effects.”96 They propose amnemonic of a “Few G’s” to helphealth professionals remember a listof herbs that are known to alter bleed-ing. The Few G’s include feverfew,plus ginkgo biloba, ginger, garlic andginseng. They add that when the “g”is followed by a vowel (eg, ginkgo),the herb is associated with thisadverse effect. When an herb thatstarts with the letter “g” is followed bya consonant (eg, green tea), there isnot a concern for bleeding.96 This

mnemonic can also be used to remem-ber the herbs that are most likely tointeract with anticoagulant andantiplatelet agents.

It is important to note that otherherbal products have been implicatedin causing adverse bleeding effects aswell (Table II).29 However, this articlewill focus on 5 herbs that are widelyused and have some scientific evidenceto support the effects described here.

Garlic Allium sativum

Recommended Dosage for generaluse: Extract, aged: 4 ml daily;Fresh: 4 g daily; Oil: 10 mg daily

Garlic is a perennial bulb withreported uses as an antilipidemic,antimicrobial, anti-asthmatic and anti-inflammatory. The bulb contains aliinand degradation products such asallicin, polysulfides, ajoenes, mer-captanes, thioglycosides, thiosulfi-nates, adenosine, and selenium.97 Theprimary chemical components thathave been implicated in bleedinginclude volatile oil and ajoene. Theantiplatelet effect of garlic has beendemonstrated by studying some of itspure isolated components on humanplatelet aggregation. Ajoene appar-ently functions as the chemical com-ponent responsible for these effects.98

Ajoene is an unsaturated sulfoxidedisulfide and is a component ofallicin, a sulfinyl compound that givesgarlic its strong odor and flavor. Likeaspirin, the effect of ajoene appearsto be irreversible, which lasts for the

AlfalfaAniseBilberryBladderwrackBromelainCat’s clawCeleryColeusCordycepsDong quaiEvening primroseFenugreekFeverfewGarlic*Ginger*Ginkgo biloba*Ginseng*Grape SeedGreen teaGuaranaGuggulHorse chestnut seedHorseradishHorsetail rushLicoricePrickly ashRed CloverReishiSt. John’s wort*Sweet cloverTurmericWhite willow

*Herbs discussed within this article

Source: Wynn RL, Meiller TF, Crossley HL.Drug Information Handbook for Dentistry. 10thed., Hudson:Lexi-Comp, Inc. 2005.29

Table II. Herbs withanticoagulant/antiplateletproperties.

The antiplatelet effect of garlic has been

demonstrated by studyingsome of its pure isolatedcomponents on humanplatelet aggregation.



life of the platelet, and may potentiatethe effect of other platelet inhibitors.20

Several sulfur-containing compoundsisolated from garlic have also demon-strated significant inhibition of humanplatelet aggregation.99

Garlic oil exerts its effects on thearachidonic acid pathway (Figure 1).Garlic interrupts the synthesis ofthromboxane, and stimulates the syn-thesis of prostacyclin. By reducingthromboxane and increasing prosta-cyclin, garlic decreases plateletaggregation and increases bleeding.Further, garlic inhibits platelet aggre-gation in a dose-dependent fashion.Case reports support that both dietarygarlic and garlic supplements demon-strate these effects.100 Further, theconstituents of garlic, particularlyalliin/allicin, also inhibit the produc-tion and/or release of chemical medi-ators such as platelet-aggregatingfactor and adenosine, which de-creases platelet function.101 Interest-ingly, many herbalists feel that thebest quality, most consistent, andstrongest source of allium sativum isthe natural garlic clove itself.

Harenberg and colleagues (1988)studied the effects of dried garlic intakeon blood coagulation, fibrinolysis,platelet aggregation, serum cholesterollevels and blood pressure in 20 patientswith hyperlipoproteinemia. During a4-week study period, subjects received600 mg (200 mg bid) of dried garlic ina sugar-coated pill. After 4 weeks ofgarlic use, both fibrinogen and fib-rinopeptide A levels significantlydecreased by 10%. Streptokinase-acti-vated plasminogen and fibrinopeptideB beta 15-42 significantly increased by10%. Serum cholesterol levels signifi-cantly decreased by 10%, and both sys-tolic and diastolic blood pressuredecreased.102

In another in vivo study, 6 subjectswere given 5.0 g of crushed garlicbulbs daily for a 3-week study period.Fasting blood samples were taken atbaseline and at weekly intervals toassess the level of serum triglycerides.Results showed that the addition ofgarlic in the diet resulted in signifi-cantly lower levels of serum triglyc-erides and an increase in blood fibri-

nolytic activity by the end of the sec-ond and third weeks.103

Case reports in the literature alsosuggest that ingesting garlic while tak-ing warfarin (Coumadin®) may resultin over-anticoagulation. One case reportdocumented that the INR of a previ-ously stabilized patient on warfarin hadmore than doubled and that hematuriaoccurred 8 weeks after commencementof ingesting 3 garlic tablets a day.97 Izzoand Ernst (2001) cite 2 case reports sug-gesting that the concomitant use of war-farin and garlic resulted in an increasedINR.95 It is evident that this popularherb has the potential to cause adversebleeding effects.

Ginkgo Ginkgo biloba

Recommended Dosage for generaluse: Standardized extract: 40 mg tid

Ginkgo is a tree native to Asia and isnow also found in the United States.The primary use of ginkgo is to pre-vent decreased cerebral functioningand peripheral vascular insufficiencyassociated with Alzheimer’s disease orage-related dementia. Other reporteduses are summarized in Table III.

Components of ginkgo includeflavonoids (ginkgo-flavones) and ter- penoids (ginkgolides and bilobalide).

The ginkgo leaf is processed and oftenstandardized to 24% ginkgo flavong-lycosides and 6% trilactones (terpenelactones). The primary chemical com-ponent that has been implicated inbleeding is the terpene ginkgolides.Ginkgolides, a terpene lactone, arepotent and specific platelet activatingfactor (PAF) antagonists. Their effectsare long lived and are rapidly estab-lished after oral dosing.104 GinkgolideB, one component of ginkgo, inhibitsplatelet activating factor by displac-ing it from its receptor binding site,resulting in reduced platelet aggrega-tion.105 In laboratory tests, ginkgoincreases prothrombin time (PT), andblood salicylate levels, and maydecrease platelet activity.106

Ginkgo holds particular interest tothe baby boomer and geriatric popu-lations as its cerebral and vascularbenefits continue to be researched.

antioxidantperipheral artery diseasecirculatory problemsdepressive mood disorderssexual dysfunction

(“herbal Viagra”)asthmaglaucomamenopausal symptomsmultiple sclerosisheadachestinnitusdizzinessarthritisaltitude sicknessintermittent claudication

Table III. Additionalindications for the use of ginkgo.

Ginkgo holdsparticular interest tothe baby boomer andgeriatric populationsas its cerebral andvascular benefits

continue to beresearched.


Whereas earlier and better knownresearch focused on older and cogni-tively impaired individuals, a recentreview in Herbalgram provided acomprehensive report of its successeswith “healthy and cognitively intactadults.” Both short- and long-termstudies resulted in positive benefits ofginkgo in the improvement ofprocesses such as memory, attention,and speed of processing.107

Case reports document dangerousbleeding episodes following the regu-lar use of ginkgo: intracranial bleed-ing (4 cases), spontaneous hyphema(hemorrhage within the anteriorchamber of the eye) (1 case), andpostoperative bleeding after chole-cystectomy (1 case).96 One of thesereports occurred when a 70-year-oldman presented with bleeding from theiris into the anterior chamber of theeye just 1 week after beginning a self-prescribed regimen of a concentratedginkgo extract twice daily. He wasalso taking 325 mg of aspirin dailyand had done so for 3 years. It is inter-esting to note that when he discontin-ued taking the ginkgo, but not theaspirin, the bleeding resolved. Therewas no recurrence of bleeding 3months later.108

Another case is a 61-year-old manwho developed subarachnoid hemor-rhage after consuming 40 mg ofginkgo 3 or 4 times per day for morethan 6 months. No other medicationwas used. The patient’s bleeding timeincreased to 6 minutes but normalizedto 3 minutes within 4 months after dis-continuing the ginkgo.109

A systematic review by Izzo andErnst discusses 2 case reports docu-menting that patients taking warfarinand aspirin had experienced severespontaneous bleeding after self-pre-scribing ginkgo at recommendeddoses.95 A fatal intracerebral massbleeding was reported in a 71-year-oldman who had taken ginkgo in con-junction with ibuprofen. He was pre-viously in excellent health. He hadbeen taking ginkgo for 21/2 years forself-reported dizziness and had addedibuprofen 600 mg daily for osteoarthri-tis of the hip just 4 weeks prior to hisdeath.110 This is a good example of an

otherwise healthy older patient self-medicating with fatal consequences.

A 40-year-old woman was admit-ted to the hospital with an acute sub-dural hematoma with no history ofhead trauma, falls, alcohol abuse, orbleeding disorders. Her hematomawas evacuated via burr holes, yet herblood results, especially the INR,were difficult to stabilize. After treat-ment and questioning, it was revealedthat she had been taking 40 mg ofginkgo twice daily for the past 2months to “assist her while studying.”Disturbingly, her family continued togive her the herb while in the hospital,stating that they were “just herbs.”Once the herb was discontinued, theblood results returned to normal.97

Clearly, ginkgo has tremendouspotential for causing bleeding com-plications, and with its broad range ofclaimed benefits, the use of this herbis attractive to many. With a growinggeriatric population and baby boomerswishing to preserve cognitive func-tion, it is safe to expect use of thisherb to increase.

Ginseng Panax quinquefoliusPanax ginseng

Recommended dosage for generaluse: Capsules: 200-500 mg extractdaily; Powdered root: 1-4 g daily;standardized extract: 200-500 mgdaily; Tincture: 1-2 ml extract daily(1:1 dilution)

Ginseng is one of the most popular,well-known, and valued herbs world-wide. Panax Ginseng has been usedmedicinally in Asia for more than5000 years and, in China, it is morehighly valued than gold.111 The Chi-nese believe that ginseng can fightcancer, slow aging, protect one againstheart attack and other sudden ill-nesses, strengthen digestion, andreduce high blood pressure, amongnumerous other benefits.112 The Asianpopulation is significant in the UnitedStates. According to the US Census2000, almost 12 million Asians areliving in the United States, and theAsian population increased faster thanthe total population between 1990 and

2000.113 With the increasing interest inboth alternative medicine and tradi-tional Chinese medicine, the use ofginseng will continue to be strong bya large segment of the population.

The word Panax is derived from theGreek word for panacea, as the herb isconsidered a cure-all, ie, good for allparts of the body. In fact, the plant itselfresembles a human figure. Accordingto Chinese sages, ginseng replenishesvital energy, increases production ofvital body fluids, and promotes healthand longevity. This is the concept of atonic or adaptogen, which our culturehas little understanding of.

Standardized ginseng extracts con-tain 5% ginsenosides, an aglyconechemical component believed to actas a stimulant. Ginsenosides act onthe hypothalamus-pituitary-adrenalcortex axis, stimulating the secretionof adrenocorticotropic hormone(ACTH), which increases productionof the adrenal hormones (eg, cortisol,sex hormones, aldosterone). Thus,ginseng produces central nervous sys-tem (CNS) stimulating effects, estro-gen-like effects, and elevates bloodpressure.29 Ginseng is also thought torestore and strengthen the body’simmune response, and promotesgrowth of normal cells.104

The ginsenosides are also believedto have the potential to inhibit platelet-activating factor.106 Ginseng has beenreported to inhibit platelet-activatingfactor (PAF), platelet aggregation,thrombin and thromboplastin, and cancause further bleeding when combinedwith aspirin, heparin, warfarin, and non-steroidal anti-inflammatory drugs.114,115

There are only a few kinds of“true” ginsengs in the botanical genusPanax. There are other plants that arein the ginseng family, but they aremore distantly related to ginsengbotanically, such as eleuthero orSiberian Ginseng. These other gin-sengs affect the body in similar ways.They are not as powerful as “true”ginsengs, but they are less costly. Trueginsengs in the Panax categoryinclude: Oriental, Chinese, Koreanand American ginseng.112

The effects of ginseng are sup-ported by hundreds of laboratory


experiments, but there are very fewcontrolled human studies.112 Two labo-ratory studies assessed the potential forginseng to cause bleeding. Chung andcolleagues (1987) examined the effectof a ginkgolide mixture (BN 52063) inantagonizing skin and plateletresponses to PAF in human subjects.The ginkgolide significantly inhibitedPAF-induced platelet aggregation inplatelet-rich plasma (p< 0.001). Theresearchers concluded that the BN52063 “seems to be an antagonist ofPAF in man.”105

There is some research to suggestthat Oriental ginseng (Ginsana) mayantagonize the anticoagulant effects ofwarfarin. In 1 case report, the INR of a47-year-old man who had been receiv-ing warfarin for 9 months (7.5 mg everyTuesday and 5 mg on all other days) toprevent thrombotic complications asso-ciated with a mechanical heart valvewas stabilized at 3.9 – 4.0. The patientbegan taking Oriental ginseng, andwithin 2 weeks, his INR fell to 1.5. Thepatient denied any other changes in hismedication regimen, including the useof other nonprescription or herbal prod-ucts, diet, alcohol consumption, or otherlifestyle factors that may have affectedhis response to warfarin. The patient’s

INR returned to therapeutic level (3.3) 2weeks after he stopped using ginseng.116

Ginseng possesses a paradoxicaleffect. Despite ginseng’s anticoagu-lant potential, it has been noted todecrease the effectiveness of warfarin.Yuan and colleagues (2004) con-ducted a study with 20 healthy volun-teers to assess this potential drug-herbinteraction. Subjects had no medicalconditions requiring warfarin, nor hadthey taken warfarin or ginseng. Dur-ing the 4-week study period, all of thevolunteers were given warfarin. Dur-ing the second week, the researchersrandomly assigned each volunteereither a placebo or ginseng, taken inaddition to the warfarin. Subjects hadtheir blood clotting times tested usingthe INR. Results of the study revealedthat the subjects taking ginseng hadlower blood levels of warfarin, thuscompromising anticoagulation.117

As previously stated, ginsengincreases the production of adrenalhormones, including the sex hormones,leading to estrogen-like effects. Thereis a case report of postmenopausalbleeding that was attributed to the useof topical ginseng. A 44-year-oldwoman used a ginseng face creamfrom China in the hopes of relieving

some post- menopausal symptoms.After using the cream, she experienced2 episodes of spotting and her follicle-stimulating hormone (FSH) droppedsignificantly. After one month of dis-continuing the product, the bleedingstopped and her FSH returned to pre-vious levels. The authors concludedthat ginseng appeared to have an estro-gen-like effect on genital tissues. 118With its broad range of claimed bene-fits from increased physical enduranceto improved ability to cope with stress,it seems reasonable to expect that allginsengs will continue to be a popularchoice in an increasingly fast-pacedsociety.

Ginger Zingiber officinale

Recommended dosage for generaluse: Dried ginger capsules: 1 g/day;Dried root equivalent: 500mg bid-qid; Fluid extract: 0.7-2ml/day (1:2dilution); Tablets/caps: 500 mg bid-qid; Tincture: 1.7-5 ml/day (1:5dilution)

Ginger is primarily used to relievemotion and morning sickness, andpreliminary research documents itsefficacy in decreasing pain andinflammation associated with arthritisand other joint disorders.106 Tradi-tionally, in herbal folklore, ginger isbest known for settling upset stom-

Ginseng producescentral nervous system (CNS)

stimulating effects,estrogen-like effects,

and elevatesblood pressure.

achs. The major constituents of gin-ger are pungent principles (gingerol,shogaol, zingerone), volatile oils (bis-abolene, zingiberene, zingiberol), andproteolytic enzymes. Many peopleconsider ginger to be a root, but it isactually a rhizome. Zingiber comesfrom the Sanskrit word for ginger,singabera, meaning “shaped like ahorn.”119

The research on ginger is mixedand limited to a few case reports,small scale in vivo studies and somein vitro studies. In one laboratory test,aqueous ginger extract reducedplatelet thromboxane and also inhib-ited platelet aggregation.120 In a smallstudy of 8 healthy male volunteers,subjects ingested either 2 grams ofdried ginger in capsule form or aplacebo. Bleeding time, plateletcount, thromboelastography, andwhole blood platelet aggregometrywere performed before, 3 hours, and24 hours after ingestion. It was con-cluded that the effect of ginger onthromboxane synthetase activity wasdose dependent and only occurs withfresh ginger, and that up to 2 grams ofdried ginger is unlikely to causeplatelet dysfunction when used ther-apeutically. Data obtained from casereports and studies with very smallsample sizes (eg, N=7) suggest thatginger’s antiplatelet effect exists withraw ginger only. For example, in onecase report, an unspecified amount ofmarmalade with 15% raw ginger wasconsumed leading to inhibition ofplatelet aggregation. One week afterdiscontinuing ginger, platelet func-tion was described as spontaneouslyreturning to normal.121 It is importantto note that these are very small sam-ple populations, and additional studyis needed to further define the effectsof ginger on platelet function.

Despite the lack of substantial evi-dence, ginger continues to be includedin published literature reviews thatdetail the ability of herbal therapiesto increase clotting time either aloneor together with another herb or pre-scription drug.96,114,122 Further, as oneof the “few G’s,” health care profes-sionals need to be aware of the poten-tial for adverse bleeding events.

St John’s wort Hypericum perfora-tum LRecommended Dosage for generaluse: 300 mg hypericum extract,standardized to 0.3% hypericin, tid

St John’s wort is a popular herbused to manage mild to moderatedepression. Depression is a silenthealth threat and statistics from theNIH indicate the highest risk is amongmiddle-aged adults, aged 45 years to64 years.123 Depression is consideredto be of epidemic proportion amongadolescents in the United States, andis more common in women. This herbis one of few herbs with a significantbody of research to support its effi-cacy. Given its popularity and numer-ous adverse effects, there are signifi-cant risks associated with undisclosedusage among patients.

St John’s wort has had a colorfulhistory. Ancient Europeans believed ithad magical protective powers againstdisease and evil. Ancient herbalistsfrom Hippocrates to Dioscorides val-ued St John’s wort not only for thetreatment of “melancholia” and otheremotional disorders, but also for burns,wounds (especially those involvingnerve injuries), neuralgia or nervepain, inflammation, ulcers, and more.Today, it is used as an antidepressant.The major constituents of the herbinclude: hypericin, hyperforin, pseudo-hypericin, flavonoids, xanthones, andessential oils.

A meta-analysis of 23 randomizedEuropean clinical investigationsinvolving a total of 1757 patients con-cluded that standardized St. John’swort extract was significantly moreeffective than placebo and just aseffective as standard antidepressantmedications in the treatment of mildor moderate depression.119 Since 1998,7 case reports were received by theMedical Products Agency (MPA) inSweden that demonstrated a reducedanticoagulant effect of warfarin(decreased INR) associated with theconcomitant use of St John’s wort.This is the opposite of the other herbalinteractions previously discussed, andis actually more dangerous, as theeffect would be to potentially increase

clotting. The reduced anticoagulationeffect of warfarin is likely caused byinduction of the liver enzymecytochrome P450 2C9, whichincreases the metabolism of warfarin,thus decreasing its effect.124 None ofthe patients in these studies developedthromboembolic complications, butthe decrease in INR was thought to beclinically significant. The INRreturned to target values either afterthe warfarin dose was increased or theSt John’s wort was withdrawn.

The induction reaction of hepaticcytochrome P450 has been attributedto the hypericum extracts from St.John’s wort, which may double themetabolic activity of the liver, and thusreduce the effects of many drugs.125 Forexample, use of St John’s wort (900 mgper day of hypericum extract LI160)resulted in a significant decrease ofdigoxin when compared to placebo insubject taking 0.25 mg of digoxin perday.126 Digoxin is a drug that is used forthe treatment of congestive heart failureand various types of arrhythmias.29 It iseasy to see that the adverse metaboliceffects of this herb can cause many sig-


National Center for Complementary and Alternative Medicine

Division of National Institutes of Health ClearinghouseP.O. Box 8218Silver Spring, MD 20907-8218Phone: 888-644-6226 FAX: 301-495-4957http://nccam.nih.gov

Food and Drug Administration5800 Fishers LaneRockville, MD 20857Phone: 202-205-5124 Medwatch: 800-332-1088 to report adverse drugeventswww.fda.govwww.cfsan.fda.gov

Websites

American Botanical Council (publishes Herbalgram)www.herbalgram.org

American Holistic Medical Associationwww.holisticmedicine.orgphone: 703-556-9728

Consumer Labs - Independent testing on herbs/supplements

www.consumerlab.com

Food and Nutrition Information Centerwww.nal.usda.gov/fnic

HerbMedwww.herbmed.org

Herb Research Foundationwww.herbs.org

Lexi-Comp, IncorporatedDrug Information Handbook for Dentistry (text)Lexi-Interact (electronic)Dental Lexi-Drugs (electronic)www.lexi.com

Medlinewww.nlm.nih.gov/databases/databases_medline.html

Medline Pluswww.nlm.nih.gov/medlineplus/herbalmedicine.html

MosbyMosby’s 2007 Dental Drug Consult (text)www.elsevierhealth.com

Pubmedwww.pubmed.gov

Pubmed - screened for alternative medicinewww.nlm.nih.gov/nccam/camonpubmed.html

RxList Alternativeswww.rxlist.com

WebMDwww.webmd.com

BROCHURES

American Society of Anesthesiologists Phone: 847-825-5586

“What You Show Know About Herbal Use andAnesthesia”

“What You Should Know About Your Patient’s Use ofHerbal Medicine”

www.asahq.org

JOURNALS AND NEWSLETTERS

Herbalgram - The Journal of the American BotanicalCouncil and the Herb Research Foundation

published quarterly ($50/year = four issues)Phone: 800-373-7105www.herbalgram.org

Self Healing - Andrew Weil, MD newsletterPhone: 1-800-523-3296 www.drweilselfhealing.com

BOOKS

1. LaValle J Krinsky D, Hawkins E, Pelton, R, Willis,N. Natural Therapeutics Pocket Guide. 2nd ed.Hudson: Lexi-Comp, Inc., 2003.

2. Skidmore-Roth L. Mosby’s Handbook of Herbs andNatural Supplements. 3rd ed. Littleton: Mosby,2006.

3. Wynn RL, Meiller T, Crossley HL. Drug InformationHandbook for Dentistry, 11th ed. Hudson: Lexi-Comp Inc., 2006.

4. Brinker F. Herb Contraindications and Drug Inter-actions. 3rd ed. Sandy: Eclectic Medical Publica-tions, 2002.

5. Hobbs C. Herbal Remedies for Dummies. FosterCity: IDG Books Worldwide,1998.

JOURNAL FULL ISSUES AND ARTICLES

• The Journal of the American Medical Association -Volume 280, No. 18 - November 11, 1998. Entireissue devoted to comprehensive alternative medi-cine research and editorials.

• Ang-Lee M Moss J Yuan CS Herbal Medicines andPerioperative Care JAMA July 2001 286;2:208-16.

Resources for Dental Professionals


nificant complications in patients withheart disease.

The National Center for Comple-mentary and Alternative Medicine isstudying the effects of St John’s wortfor a wide spectrum of mood disor-ders. Positive research findings willlikely lead to renewed interest in thisherbal remedy.

Practice Considerationsfor Dental Professionals

The most important risk reductionstrategy implemented by dental profes-sionals is the completion of a compre-hensive health history for every patienton a regular basis. The review of sys-tems allows for the discovery of sys-temic conditions that alter bleeding, orthat require the use of drugs that alterbleeding. Systemic causes of bleedinginclude liver disease, kidney disease,chronic alcoholism, bone marrow sup-pression, blood dyscrasias, Vitamin Kdeficiency, and inherited coagu-lopathies.127,128 As most clotting factorsare formed by the liver, liver diseasecan greatly affect bleeding tendencies.Dental patients may present with liverdisease caused by a variety of conditions,most commonly alcoholism, cirrhosis,and/or infections, such as hepatitis.

Intestinal bacteria continually pro-duce Vitamin K, thus, a deficiency israrely seen in a normal person due toan absence of Vitamin K from the diet.Exceptions are those with gastroin-testinal diseases that result in poor fatabsorption, as Vitamin K is fat-solubleand is absorbed into the blood alongwith dietary fats. One of the mostcommon causes of Vitamin K defi-ciency is failure of the liver to secretebile into the gastrointestinal tract, aslack of bile prevents fat digestion andabsorption, thus reducing Vitamin Kabsorption as well.26

Dental professionals should remem-ber to question patients about recentillnesses, changes in health behaviors,or modifications to their diets. Intesti-nal viruses that cause vomiting or diar-rhea, changes in the intake of greenleafy vegetables, or the use of medica-tions can dramatically alter the

patient’s response to warfarin. Fluctu-ations in the patient’s INR may be seenfor several days, even weeks, followingillness, dietary, or medication changes.It is essential to ask all patients takingwarfarin about the results of their mostrecent INR. A follow-up with thepatient’s physician may be warranted.

At every appointment, patientsshould provide a list of all of the med-ications and herbs that they take,including dosing schedules. This med-ication list should be documented inthe treatment record at every appoint-ment. Follow-up questioning of thepatient is conducted as a component ofthe comprehensive health history toensure that this list is accurate andcomplete. It is important to note thatmany patients think of some herbs asmerely popular cooking ingredients(eg, garlic and ginger) and/or that theseplant-derived substances are all natural,and must therefore be “safe” healthproducts for ingestion. For this reason,patients must often be prompted to dis-close the use of herbal medications.Remember that many herbal prepara-tions contain multiple herbs within onesupplement and that patients may notalways know what herbs they are con-suming in these products. While clearlyherbs provide substantive and benefi-cial health properties, consuming herbson a regular basis from either supple-ment use or cooking can potentiallyalter bleeding.

It is imperative that dental profes-sionals have access to a good drug ref-erence guide, either as a chairside ref-erence text or in the form of anelectronic database, to assist with com-pleting an accurate medication list.Many popular dental drug resourcesalso contain information on herbalmedications, although dental profes-sionals may find it helpful to also havea resource that is strictly devoted toherbal supplements. Resources providevaluable information about drug dos-ing, common side effects, drug inter-actions, and precautions for treatingpatients using these medications. Den-tal professionals should look up allmedications that a patient is takingprior to prescribing other medicationsto ensure safety and compatibility. Text

versions of reference guides should bereplaced on an annual basis, as the fieldcontinuously evolves and changes. Theadvantages to electronic databasesinclude speed of access to and theimmediate availability of a vast quan-tity of information, and access to themost current drug data. Suggested re-sources for dental professionals are listedat the end of this paper. (Please seeResources for Dental Professionals.)

Dental professionals should alsoobserve their patients for physicalmanifestations of bleeding complica-tions. Signs of altered bleeding mayinclude excessive or diffuse bruising,petechial hemorrhaging, prolongedbleeding following dental procedures,and spontaneous gingival bleeding.Patients may report bruising easily ornoticing an increase in bleeding withtoothbrushing and flossing. Bruisingis frequently observed in elderlypatients taking antiplatelet and anti-coagulant medications, who alsodemonstrate epithelial thinning as anormal part of aging. Clinical signsfrom observation and symptomsdescribed by the patient should bedocumented in the treatment record.

Whenever there is doubt as to thepatient’s safety and/or the stability ofhis current medical status, the patient’sphysician should be contacted. Thedental professional must be preparedto discuss the nature of the concern andproposed dental treatment with asso-ciated or potential risks, then requestany information needed to safely pro-ceed with treatment. Results fromrecent, relevant laboratory tests shouldbe obtained for the treatment record.Copies of any test results ordered bythe dentist that are required prior to ini-tiating dental treatment should be for-warded to the patient’s physician asneeded. Conversations with thepatient’s physician must be docu-mented in the treatment record.

As previously discussed, few anti-coagulant and antiplatelet medicationsrequire discontinuation prior to routinedental treatment. Exceptions have beenpreviously noted elsewhere in thispaper. However, discontinuation maybe required prior to invasive dental sur-gery. Herbal supplements should


always be discontinued prior to anytype of surgery, including dental sur-gery. Different herbs possess specificsafety windows that range from 24hours (ephedra) to 7 days to 14 days(garlic and ginseng) prior to undergo-ing surgery.20 Patients taking herbalsupplements that possess anticoagulantand/or antiplatelet properties should beadvised to discontinue use at least 2weeks prior to having a surgical pro-cedure until more is definitively knownabout the potential for bleeding com-plications.6,29 This 2 week to 3 weeksafety window is suggested by theAmerican Society of Anesthesiologists(ASA).20 It is important to note that thesafety window also takes into accountother herbal side effects that mayincrease surgical risk, such as the abil-ity to recover from general anesthesia.A discussion of these and other effectsis beyond the scope of this paper. Thereader is referred to Ang-Lee et al(2001) for a detailed discussion ofthese considerations

Despite careful planning and pre-cautions, the potential for an unex-pected bleeding event always existsfor patients taking these medications.Therefore, it is essential that dentalprofessionals have access to localhemostatic agents for use in the oper-atory. There are a variety of pharma-cologic agents that are available forthis purpose; however, a complete dis-cussion about these products isbeyond the scope of this paper. Thereader is referred to Burrell and Glick

(2003) for a review of hemostaticagents used in dentistry.129 Invasiveprocedures should be performed withas minimal trauma to the tissues aspossible. Careful post-surgical moni-toring is advised.6

To determine whether increased gin-gival bleeding is caused by a medica-tion side effect, or is a manifestation ofgingival disease, a thorough oral exam-ination should be performed at eachvisit. Patients should be taught properoral hygiene techniques to decrease eti-ologic bacteria that cause gingivalinflammation. Manual plaque removalmay be improved through the use ofpower-assisted toothbrushes, floss aids,and oral irrigators. Chemotherapeuticagents that exhibit antimicrobial prop-erties are useful adjuncts to kill residualorganisms that brushing and flossingmay leave behind. Broad- spectrumantimicrobial agents, such as chlorhex-idine, essential oil mouthrinse, and tri-closan toothpaste, have demonstratedefficacy in reducing supragingivalplaque and gingivitis, and resultant gin-gival bleeding. Improving oral hygienereduces gingival inflammation, thuseliminating the primary etiologic factorfor gingival bleeding. It is important to

teach patients that gingival bleeding isnot “normal,” as so many patients mis-takenly believe, so that gingival bleed-ing as a complication of medicationtherapy can be quickly and accuratelyidentified.

Dental hygienists possess animportant role in educating patientsabout bleeding effects that may affectthe oral cavity and the provision oforal health care services. Patientsshould be taught about the importanceof accurately reporting their medica-tion and herbal use, compliance withtheir medication regimens, and rou-tine monitoring with blood tests asprescribed by their physicians. Patienteducation may also include dispellingmyths about the need to discontinuemedication use prior to undergoingroutine oral care. Many patients dis-continue their medications on theirown, without consulting their physi-cians or dental professionals, becausethey are worried about a bleedingcomplication. It is important to edu-cate patients about how bleeding isadequately managed in the oral healthcare setting, provide reassurance, andhow, if needed, their medicationsshould be discontinued.

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mary prevention of cardiovascular events: recommenda-tion and rationale. Ann Intern Med. 2002;136:157-160.

4. Manton KG, Corder L, Stallard E. Chronic disability trendsin elderly United States populations: 1982-1994. Proc NatlAcad Sci USA. 1997;94:2593-2598.

5. Little JW, Miller CS, Henry RG, McIntosh BA. Antithrom-botic agents: implications in dentistry. Oral Surg Oral MedOral Pathol Oral Radiol Endod. 2002;93:544-551.

6. Lockhart PB, Gibson J, Pond SH, Leitch J. Dental man-agement considerations for the patient with an acquiredcoagulopathy. Part 2: Coagulopathies from drugs. Brit DentJ. 2003;195:495-501.

7. Wahl MJ. Myths of dental surgery in patients receiving anti-coagulant therapy. JADA. 2000;131:77-81.

8. Jeske AH, Suchko GD. Lack of a scientific basis for routinediscontinuation of oral anticoagulation therapy before den-tal treatment. JADA. 2003;134:1492-1497.

9. Mulligan R, Weitzel KG. Pretreatment management of thepatient receiving anticoagulant drugs. JADA. 1988;117:479-483.

10.Ziffer AM, Scopp IW, Beck J, Baum J, Berger AR. Profoundbleeding after dental extractions during dicumarol therapy.N Engl J Med. 1957;256:351-353.

11.Scopp IW, Fredrics H. Dental extractions in patients under-going anticoagulant therapy. Oral Surg Oral Med OralPathol. 1958;11:470-474.

12.World Health Organization Expert Committee on BiologicalStandardization. Thirty-third report. World Health OrganTech Rep Ser. 1983;687:81-105.

13.Spolarich AE. Understanding pharmacology: the pharma-cologic history. Access. 1995;9:33-35.

14.Spolarich AE. Understanding pharmacology: risk assess-ment. Access. 1996;10:36-39.

It is essential that dental professionals have access to local hemostatic agents for use in

the operatory.


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