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Bleeding Disorders: Characterization,Dental Considerations and ManagementSara Israels,MD, FRCPC;Nora Schwetz,RN, BSc;Ron Boyar,RM, DMD, MSc; Archie McNicol,BSc, PhD

ABSTRACT

Hemostasis is a fnely balanced process in which an insult to a blood vessel wall, either byinjury or surgical intervention, stimulates a pair o parallel, yet associated, pathways thatlead to the termination o blood loss. The coagulation cascade is initiated by the inter-action between exposed subendothelial tissue actor and circulating blood and includesa series o amplifcation steps that result in thrombin generation. Concurrently, exposedsubendothelial collagen stimulates platelets, which, in the presence o thrombin, areconsolidated by fbrin to orm a blood clot, thus terminating blood loss. Multiple inher-ited and acquired abnormalities in these pathways can seriously compromise hemostasis.Furthermore, several drugs, including over-the-counter preparations, also adverselya ect hemostasis. These present signifcant concerns to the dentist conducting inva-sive procedures as they can prolong postoperative bleeding, impair wound healing andincrease risk o in ection. In this article, we review the current knowledge o bleedingabnormalities and discuss preoperative systemic precautions and intraoperative hemo-static measures.

MeSH Key Words:blood coagulation/physiology; blood coagulation disorders/complications

Dental procedures, such as extractionsand periodontal surgery, are amongthe most common invasive proceduresin Canada. Many dental procedures are as-sociated with postoperative bleeding, which,in most cases, is sel -limiting and nonprob-

lematic. However, a small but signi cant seg-ment o the population has an increased risk o bleeding due to inherited bleeding disorders,in which even relatively minor invasive pro-cedures can precipitate a prolonged bleedingepisode. Excessive bleeding in these patientsis not only distressing or the patient, butalso hinders the completion o the procedure(e.g., suture insertion) and can compromisewound healing. More common are patientswith hemostatic de ects secondary to under-lying disease or medication. Te dental man-

agement o such indiviuals presents a signi -icant challenge; however, the onus is very much on the dental practitioner to maintainclear and requent communication with thepatients primary physician, hematologist orboth to assess the risk and plan appropriate

management.

Normal HemostasisUnder normal conditions, hemostasis (or

the arrest o bleeding) occurs through 2 in-dependent, but related processes: the coagula-tion cascade (Fig. 1)1 and the platelet activationpathway (Fig. 2).2 Blood vessels are lined with acontinuous layer o endothelial cells that allow the passage o gases, soluble nutrients, etc., butprevent contact between blood componentsand the subendothelial matrix and interstitial

Dr. McNicol Email: [email protected]

J Can Dent Assoc 2006; 72(9):827This article has been peer reviewed.

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tissues. However, when the in-tegrity o the endothelial layeris compromised, the interactiono the blood with previously in-accessible stimuli initiates botharms o the hemostatic process.

In the rst arm, the stimulusis the glycoprotein tissue actor,which is expressed on the sur-ace o subendothelial cells. 3 Following an insult to the endo-thelial layer, the subendothelialtissue actor comes into contactwith circulating blood ( Fig. 1).Additional tissue actor is ex-pressed on the sur ace o endo-thelial cells ollowing injury and on macrophages ollowing

stimulation by soluble actors,such as cytokines and bacterialproducts. Te presence o smallamounts o tissue actor initi-ates a succession o proteolyticevents, termed the coagulationcascade the sequential activation o a series o soluble en-zymes. Ampli cation at eachstep results in the generationo large amounts o importanthemostatic proteins ( Fig. 1).1

Initially, tissue actor inter-acts with Factor VII, leadingto its conversion to the activeorm, Factor VIIa. Te tissueactorFactor VIIa complex

proteolytically converts FactorsIX, X and additional VII totheir active orms IXa, Xa andVIIa. Factor Xa then convertsFactor II (or prothrombin) tothrombin, which has severalcritical unctions. 4 First,

thrombin proteolytically activates Factors V (to Va), VIII(to VIIIa) and XI (toXIa), ampli ying steps inthe coagulation cascade.Second, thrombin convertsbrinogen to the brin mono-mer and activates Factor XIII(to XIIIa), which catalyzesthe cross-linking o ibrin,both crucial steps in theconsolidation o the hemostatic

Figure 1: Coagulation cascade initiated by vascular damage leads to the expressiono tissue actor and culminates in the generation o thrombin and cross-linked fbrin.EC = endothelial cells; Lum. = lumen; Mac. = macrophage; Mat. = ;Plt. = platelet; SE = subendothelial matrix; SM = smooth muscle.

Figure 2: Platelet activation, initiated by vascular damage exposing subendothelial vonWillebrand actor and collagen, culminates in platelet aggregation. ADP = adenosine diphos-phate; COX = cyclooxygenase; 5-HT = serotonin; TxA = thromboxane A.

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plug. Finally, thrombin is a power ul, locally producedplatelet activator. 4

Te second hemostatic pathway engaged ollowing vascular injury is the platelet activation process ( Fig. 2).Platelets are the smallest cells in circulating blood; de-rived rom megakaryocytes, 5 their turnover rate is 1012days. Structurally, they are anucleate, but they containseveral types o storage granules, notably alpha granulesand dense granules. 2,6 Alpha granules contain a range o proteins, including adhesive material, such as brinogenand von Willebrand actor (vWF), several coagulationactors and growth actors. Te dense granules containsoluble platelet-activating molecules such as ADP andserotonin (5-H ). Platelets also possess sur ace receptorsthat mediate platelet adhesion and activation. 2,6

Damage to the endothelial lining initiates the adhesiono platelets to, and their activation by, a number o com-ponents o the subendothelium ( Fig. 2). vWF is a largeadhesive protein stored in endothelial cells ( rom whichit is secreted into the subendothelial space) and platelets. 7 Under the high shear stress in the microvasculature, sub-endothelial vWF binds to, and stimulates, platelets via theglycoprotein IbVIX complex on the platelet sur ace. Inlarger vessels, subendothelial matrix proteins, notably col-lagen, are exposed, which activates platelets via the 2 1receptor on the platelet sur ace. 2

Once activated, platelets undergo signi cant struc-tural and unctional changes. Te contents o bothdense and alpha granules are expelled. Dense granule-derived 5-H and ADP act on their respective receptorsto stimulate production o additional platelets and re-cruit them to the site o injury, whereas alpha-granule-derived vWF and brinogen both serve to solidi y plateletplatelet interactions. 2,6 Activated platelets synthe-size, by the cyclooxygenase 1 (COX-1) pathway, throm-boxane A2 ( xA 2) which acts as a soluble platelet agonistresponsible or signi cant ampli cation o the platelet

response and as a vasoconstrictor, reducing local bloodfow and, there ore, blood loss at the site o injury. 2,6

Following activation, platelets shed phosphatidylserine-rich, negatively charged membrane ragments or micro-particles (Fig. 2), which provide the necessary plat ormor the activities o components o the coagulation cascade(Fig. 1).8

Te principle receptor that mediates plateletplatelet

interaction is the IIb3 integrin.9

Tis glycoprotein ispresent on the sur ace o circulating platelets, but in aclosed orm. Following activation by any platelet agonist,the structure o the IIb3 complex is rearranged intoan open con guration that promotes the binding o sev-eral adhesive proteins, most notably cross-linked brin(Fig. 2), which mediate plateletplatelet aggregation. Teend result o these processes is that the initially ragileadherent platelet monolayer ormed at the site o injury isconsolidated by additional platelets and the cross-linkingaction o brin into a stable clot ( Fig. 2).

Inherited Coagulation isordersVon Willebrand DiseaseVon Willebrand disease (vWD) is considered the most

common inherited bleeding disorder, a ecting up to 1%o the general population and resulting in mucocutaneousand operative bleeding. Easy bruising, epistaxis, menor-rhagia and bleeding with oropharyngeal surgery are themost common mani estations. 10 vWD results rom quanti-tative or qualitative de ects in vWF, an important proteinin hemostasis (see above). vWF is also the carrier o FactorVIII in plasma; its de ciency may, there ore, result in low levels o Factor VIII.11

Table 1 Classi ication o von Willebrand disease

Type 1 Partial de ciency (80% o thosewith vWD)

Type 2 Qualitative de ectsA Decreased unction; absent medium

and HMW multimersB Increased a nity or platelet GPIb;

decreased HMW multimersM Decreased unction; variable

multimer patternN Decreased a nity or FVIII

Type 3 Severe de ciency; autosomal recessive

Table 2 Classi ication o hemophilia

Severe < 0.01 IU/mLor < 1%

Spontaneous joint,muscle and internalbleeding; exces-sive bleeding withtrauma or surgery

Moderate 0.010.05 IU/mLor 1% to 5%

Bleeding into jointsor muscles withminor trauma;excessive bleedingwith surgery

Mild 0.050.35 IU/mLor 5% to 35%

No spontaneousbleeding; delayedonset bleedinga er trauma or

surgery or dentalextractions

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Inherited vWD is subdivided into 3 categories:ypes 1 and 3 represent partial and complete de ciency o vWF, respectively; ype 2 variants represent qualitativeabnormalities o vWF ( Table 1 ). ype 1 vWD is the mostcommon, occurring in 80% o vWD patients; it is usually inherited in an autosomal dominant mode, although vari-able penetrance can result in some amily members beingasymptomatic. 10,11

Diagnosis o vWD, particularly ype 1, can be chal-lenging because laboratory diagnosis requires a bat-tery o tests, the interpretation o which is limited by the heterogeneity o the disease, physiologic variation inlevels o vWF and Factor VIII and the limitations o theavailable laboratory assay. Personal and amily bleedinghistory are important in assigning patients a diagnosis o vWD. Laboratory testing includes quantitative measureso vWF, unctional assays o vWF (the ristocetin co actorassay, ristocetin-induced platelet aggregation or collagen-binding assay) and multimer analysis. Te results o theseassays help to make the diagnosis and de ne the subtype.Discrimination among the subtypes is important because

o the clinical and therapeutic implications. Repeat testingis o en required to con rm a diagnosis, particularly inype 1 patients with mild de ciencies, as their plasmalevels o vWF may fuctuate. 10

Te approach to treatment will depend on the sub-type o vWD. Most ype 1 and some ype 2A and2M patients respond well to desmopressin acetate, asynthetic analogue o vasopressin, which stimulates re-lease o vWF rom storage pools in endothelial cells,transiently raising plasma levels o vWF and FactorVIII by 35- old, or 812 hours and improvingprimary hemostasis. 12 Desmopressin can be admin-

istered intravenously, subcutaneously or as an in-tranasal spray. he onset o action is immediateand reaches maximum at 3060 minutes. 13,14 Side e ects areprimarily the result o vasodilation and include fushing,tachycardia, hypotension and headache. Other side e -ects include hyponatremia (water intoxication in severecases) resulting rom desmopressins antidiuretic e ectsand thrombosis in patients with pre-existing risk actors.Patients or whom desmopressin is being considered as theprimary therapeutic or prophylactic therapy should have atrial period to con rm a hemostatic response.

For patients who do not respond to desmopressin andthose with ype 2B and ype 3 vWD, vWF replacementis required. Te currently available replacement is vWF-containing Factor VIII concentrates derived rom pooledhuman plasma and pasteurized to inactivate viruses. 1416 As the hal -li e o vWF is long, once a day dosing is ad-equate or most bleeding episodes or surgical procedures.

HemophiliaHemophilia is an inherited X-chromosome-linked

bleeding disorder caused by de ciencies o either FactorVIII (hemophilia A) or Factor IX (hemophilia B). Teprevalence o hemophilia is 1 in 5,000 males; 85% to90% have type A disorder and 10% to 15% have typeB. Hemophilia A and B are not clinically distinguish-able; they are characterized by easy bruising, spontan-eous muscle and joint hemorrhage and excessive bleedingollowing trauma and surgical procedures. Diagnosismust be con rmed by speci c laboratory assay. Teseverity o bleeding is related to the measured residualactor concentration and is classi ed as mild, moderate

Table 3 Rare coagulation abnormalities a

efciencyPrevalence o severe

defciency ( 10 -6)b Treatment options

Fibrinogen 1 CryoprecipitateFibrinogen concentrate

Prothrombin 0.5 Fresh rozen plasmaProthrombin complex concentrate

Factor V 1 Fresh rozen plasma

Factor VII 2 Factor VII concentrateRecombinant Factor VIIa

Factor X 10 Fresh rozen plasma

Factor XI 1 Fresh rozen plasmaFactor XI concentrate

Factor XIII 0.5 Factor XIII concentrateCryoprecipitate or plasma

aData rom Bolton-Maggs,17 Peyvandi,20 Di Paolo21bFactor concentrations < 10%

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or severe (Table 2 ). Tis classi cation o en predicts thebleeding risk and the required therapy. 17

Factors VIII and IX are both initially required or the

activation o Factor X in the coagulation cascade that leadsto ormation o a brin clot. Te pivotal role played by these 2 actors is underlined by the signi cant hemorrhagicdiathesis caused by de ciency o either protein ( Fig. 1).

De ects in the Factor VIII gene include deletionsand point mutations; intrachromosomal inversion o in-tron 22 is present in almost 50% o patients with severehemophilia A. More than 250 missense mutations in theFactor VIII gene have been identi ed. 18 De ects in theFactor IX gene may also be due to either large deletions orpoint mutations. Patients with large deletions and absentprotein may be at risk o anaphylaxis when treated withFactor IX replacement. Mutations in the Factor VIII orIX genes mani est as hemophilia in males and as the car-rier state in emales. In carrier emales, the levels o FactorsVIII and IX vary widely and may sometimes be low enoughto result in clinical bleeding problems.

reatment or hemophilia is by intravenous re-placement o Factor VIII or IX using puri ed plasma-derived concentrates or, pre erably, recombinant actorconcentrates. Te required dose, requency and dur-ation o therapy depends on the severity o the bleedingepisode.17,18 For surgical procedures, patients receivepreoperative doses o actor concentrate to raise plasmaconcentrations to hemostatic levels. Tese are thenmaintained postoperatively by repeated intermittent dosesor by continuous in usion.

In mild hemophilia A only, desmopressin can be usedto raise levels o Factor VIII to approximately twice base-line, which may result in adequate hemostasis or minorbleeds or procedures.

Inhibitors (allo-antibodies) develop in up to 20% to30% o patients with hemophilia A and 5% o those withhemophilia B, usually as an immune response to actorreplacement therapy. Inhibitors are seen more requently in patients with severe hemophilia, particularly those withlarge gene deletions. Te risk o inhibitor development is

also infuenced by inherited di erences in the immune re-sponse.19 Te presence o inhibitors complicates treatment,as simple actor replacement is o en not e ective and

alternative bypassing agents, such as recombinant FactorVIIa, are used to promote hemostasis. Immune modula-tion, with continuous exposure to the actor in conjunc-tion with immunosuppressive drugs, is used to induceimmune tolerance and reduce inhibitor titres. 17,18

Rare Coagulation Factor DefcienciesCongenital de ciencies in coagulation actors, other

than Factor VIII and Factor IX, are very rare. FactorXI de ciency in the Ashkenazi Jewish population hasa prevalence o 1 in 1,000; however, the prevalences o brinogen, prothrombin and Factors V, VII, X andXIII de ciencies are in the order o only 1 in 0.51 million.Tese disorders are inherited as autosomal recessive traitsand mani est clinically in homozygotes or compoundheterozygotes. 20 Although, with some exceptions, thebleeding mani estations in these disorders are less severethan hemophilia, patients may require coagulation actorreplacement be ore dental surgery. Speci c actor concen-trates are available or some de ciencies (e.g., Factor VII);resh rozen plasma is used as the source or others (e.g.,Factor V) (Table 3 ).20,21

Acquired Coagulation AbnormalitiesPatients on long-term anticoagulation therapy with

either war arin or heparin are at increased risk o bleed-ing with trauma or surgical procedures. Te risk o bleeding is relative to the intensity o anticoagulation. Incases o acute bleeding or in preparation or major surgery,these anticoagulants may need to be discontinued tempor-arily. However, their role in the treatment or preventiono thromboembolic disease should be care ully consid-ered be ore interruption o therapy, as the patients may be placed at a signi cantly increased risk o a thromboticevent.

War arin is a vitamin K antagonist, inhibiting the-carboxylation o glutamic acid residues on the clot-

Table 4 Inherited thrombocytopenias

Small platelets Normal-sized platelets Large platelets

Wiskott-Aldrich SyndromeX-linked thrombocytopenia

Glanzmann thrombocytopeniaFamilial platelet disorder associated with

a predisposition to myelodysplastic

syndromesCongenital amegakaryocytic

thrombocytopeniaTrombocytopenia with absent radiiAutosomal dominant thrombocytopenia

Bernard Soulier syndromeVelocardio acial syndromeMediterranean thrombocytopenia

Paris- rousseau-JacobsenssyndromeMay-Haegglin anomaly Sebastian syndromeFechtner syndromeEpstein syndromeGray platelet syndromeMontreal platelet syndrome

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ting actor zymogens II, VII, IX and X. Te absence o this modi cation inhibits calcium-dependent bindingto anionic phospholipid, which is required or as-

sembly o the coagulation enzyme complexes on cellsur aces ( Fig. 1).22 War arins e ect is monitored by theinternational normalized ratio (INR; a standardizationo the prothrombin time assay). Te therapeutic INR range varies depending on the indication, but is 2.03.0or most patients requiring protection rom venous orarterial thromboembolism. 23

Heparin is a proteoglycan that unctions as a co actoro the naturally occurring anticoagulant antithrombin,accelerating inhibition o the serine proteases o the co-agulation cascade, particularly Factors IIa and Xa. Becausethe hal -li e o un ractionated heparin (3kD to 30kD) isshort (1 hour), therapeutic levels are maintained by intravenous bolus ollowed by in usion. Te therapeutic rangeis usually monitored by appropriate prolongation o theactivated partial thromboplastin time (aP ). Low mo-lecular weight heparin (LMWH) (5kD) exerts its anti-coagulation e ects via antithrombin, particularly onFactor Xa with less e ect on IIa. It has a longer hal -li e than un ractionated heparin and, there ore, can bedelivered subcutaneously only once or twice a day. 24 Most patients on long-term therapy do not require lab-oratory monitoring; when monitoring is required, ananti-Xa assay is used, as aP is not prolonged. 25

Platelet isordersTe large number o platelet-related de ects, both inher-

ited and acquired, can be broadly categorized as de ects o number (thrombocytopenia) or o unction. Tis classi ca-tion is somewhat arbitrary as some platelet disorders arecharacterized by both decreased number and unction.

TrombocytopeniasBlood platelet levels normally all within the broad

range o 150400 109/L, although or any given personthe range is much narrower. 26 Tese levels are preservedby the ne balance between synthesis o platelets in the

bone marrow and their removal by the spleen. Disturbingthis balance by reducing production or increasing removal(either by splenic uptake or platelet activation) results in

thrombocytopenia, which may be considered mild (100150 109/L), moderate (50100 10 9/L ) or severe (< 50 109/L).26 In general, thrombocytopenias all into 2 cat-egories: inherited ( Table 4 )26,27 and acquired ( Table 5 ).26 Inherited thrombocytopenias are rare, are o en associatedwith alterations in platelet size and, in many cases, areconsidered to be 1 component o a syndrome. 27

Acquired thrombocytopenias can be classi ed asthose o immune origin and those o nonimmune origin.O the immune causes, immune thrombocytopenicpurpura (I P) is likely the most common and can occurin association with in ection or as part o an auto-immunesyndrome. Nonimmune acquired thrombocytopenias aremost o en secondary to drug toxicity or another under-lying disease.26 In particular, most chemotherapeuticagents can cause thrombocytopenia, and aggressive multi-agent regimens routinely cause myelosuppression, o whichthrombocytopenia can be the dose-limiting actor.

Increased bleeding is rarely an issue unless plateletcounts are < 50 109/L. Te management will vary depending on the etiology o the thrombocytopenia, butplatelet counts can usually be raised transiently to sup-port hemostasis i necessary or surgical procedures.Patients receiving chemotherapy should have plateletcounts evaluated immediately be ore dental proceduresto ensure that there has been bone marrow recovery be ore proceeding.

Adhesion De ectsTe primary platelet adhesive receptor is GPIbVIX,

a complex o 4 proteins: GPIb, GPIb, GPV and GPIX, 6 each the product o an individual gene. 28 Bernard Souliersyndrome (BSS) is an autosomal recessive disorder causedby genetic de ects in GPIb, GPIb or GPIX. 29 It is char-acterized by giant platelets and thrombocytopenia andsymptoms include mucosal bleeding, easy bruising andsurgical bleeding.28 Several molecular de ects have been

Table 5 Acquired thrombocytopenias

Immune-related

Nonimmune-related

Impaired production estructive

Immune thrombocytopenicpurpura

Drug-induced thrombocytopeniaNeonatal immune

thrombocytopeniaPost-trans usion purpura

Drug-induced bone marrow depression

Viral or bacterial in ectionsAlcoholismAplastic anemiaMyelodyplastic syndromesLeukemia, lymphoma, myelomaSolid tumour in ltrating bonemarrow

Disseminated intravascularcoagulopathy

Trombotic thrombocytopenicpurpura

Hemolytic uremic syndromeHeparin-induced thrombocytopeniaSplenomegaly, splenic sequestration

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associated with BSS, but almost all result in a de ciency in the expression o the mature, unctional GPIbVIXcomplex.28,29

Management o bleeding episodes or preparation orsurgery usually requires platelet trans usion, although theuse o an activated coagulation actor concentrate, recom-binant Factor VIIa, has been use ul in some patients. 30

Aggregation De ectsGlanzmann thrombasthenia (G ) is an autosomal

recessive disorder caused by qualitative or quantitativede ects in 1 o the proteins in the IIb3 integrin, the com-plex whose structural reorganization ollowing plateletactivation is critical to plateletplatelet interaction andclot ormation. Essential diagnostic eatures are a normalplatelet count and morphology, but the absence o plateletaggregation in response to stimulants in vitro. 28 In addi-tion to compromising plateletplatelet interaction, clotretraction is also a ected which contributes to delayedwound healing.

Te signs o G occur early in li e and include easy bruising, epistaxis and prolonged bleeding rom relatively minor injuries. Epistaxis, menorrhagia, post-partumbleeding and surgical bleeding can be li e-threatening. 31,32

At a molecular level, G is an extremely complex, hetero-geneous condition with multiple deletions and mutationso the genes encoding the IIb3 integrin. 28,31,32

Management o bleeding episodes in G patients usu-ally requires platelet trans usion, the use o recombinantFactor VIIa or both. Ancillary therapies include anti b-rinolytics and hormonal therapy, and topical measuresmay be required or speci c local sites (see below). 30,31

Granule De ectsAs outlined above, platelets contain 2 important types

o storage granules, alpha granules and dense granules,

whose released contents ollowing platelet activation arecritical to a competent hemostatic system. De ciencies inboth granule types have been reported and they have sig-ni cant negative e ects on hemostasis.

Gray platelet syndrome is mainly an autosomal reces-sive condition characterized by large platelets and reducedlevels o alpha granules. 29 Patients with this syndromeo en have mucocutaneous bleeding and associated mildthrombocytopenia. Quebec platelet disorder is an auto-somal dominant condition marked by delayed post-trau-matic bleeding and associated with a de ciency o alphagranule contents including Factor V, possibly secondary toabsence o a binding protein termed multimerin. 33 Severaldense granule de ciencies have been identi ed. An isolatedautosomal dominant orm and a variant orm, character-ized by a dual de ciency o dense and alpha granules, areboth associated with prolonged mucocutaneous bleeding,likely due to the absence o secreted ADP. 34

In several other situations, dense granule de ciency is a single element in a multi-component syndrome, suchas Hermansky-Pudlak syndrome and Chediak-Higashisyndrome, autosomal recessive conditions in which thedense granule de ciency is accompanied by a pigmentabnormality or albinism. 34 Bleeding associated with milderplatelet granule de ects o en responds to treatment withdesmopressin, but cannot be predicted; a trial o desmo-pressin is warranted to evaluate response in patients orwhom this is being considered as prophylaxis or surgery.For nonresponders, platelet trans usion may be required.

Drug-induced Platelet De ectsA variety o prescribed drugs and over-the-counter

preparations are known to have signi cant adverse e -ects on platelet number and unction ( Table 6 ). O drugs a ecting platelet number, heparin-induced throm-bocytopenia (HI ), which occurs in an estimated 5% to

Table 6 Common drugs a ecting platelets

Functional impairment Thrombocytopenia

AspirinNSAIDsiclopidine, clopidogrelricyclic antidepressantsClo brateSulphinpyrazoneDipyridamolePropranololHistamine H 1 antagonistsPenicillinAmpicillinNitroglycerin

Heparin or analoguesChemotherapeutic agentsQuinidineQuininerimethoprimsul amethoxazoleMethyldopaFurosemideAcetaminophenCephalosporinsVancomycinCarbamazapineValproic acidChlorpropamide

DigoxinDiclo enacIndomethacinPhenylbutazoneIsoretinoinGoldProcainamideHydrochlorothiazideRanitidineDiphenylhydantoin

NSAIDs = nonsteroidal anti-infammatory drugs

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40% o patients to whom it is administered, 35 is the mostcommon. O the others, quinidine, gold and the trimetho-primsulphamethoxazole combination are most requently associated with the development o thrombocytopenia. 36

A large number o drugs attenuate platelet activity. Temost common is aspirin, which acetylates COX, thereby blocking xA 2 release rom activated platelets. As this isan irreversible e ect, the activity o the platelet is com-promised or the li e o the platelet. Tis accounts bothor the prolonged e ect (several days) that a single as-pirin can have on bleeding and the antithrombotic ac-tion o aspirin. Other nonsteroidal anti-infammatory drugs (NSAIDs), such as ibupro en, naproxen, ketorolacand indomethacin, also inhibit COX, but in contrast toaspirin, the inhibition is reversible and the antiplatelete ects are present only as long as the NSAID is in con-tact with the platelet. ADP antagonists, such as ticlopi-dine and clopidogrel, and phosphodiesterase inhibitors,such as dipyridamole, are clinically used antiplatelet

agents and may also increase the risk o clinical bleeding.Several over-the-counter preparations, particularly rst-generation histamine H 1 antagonists, can also a ectplatelet unction.

Management or ental ProceduresSystemic Terapies

Te choice o appropriate systemic therapy or dentalprocedures should be made in consultation with the pa-tients hematologist. Decisions regarding the need or,and type o , coagulation actor replacement will dependon the speci c hemostatic diagnosis, the severity o the

bleeding diathesis and the type o dental procedure (majoror minor). Table 7 outlines systemic replacement therapy options or vWD and hemophilia. 37 Some patients may re-quire urther laboratory testing be ore dental surgery, suchas a trial o desmopressin to con rm adequate response, orscreening or inhibitors. Te choice o actor replacementor individuals with rare coagulation disorders should bemade in consultation with a hematologist amiliar withthe replacement products and local availability (as someare unlicensed).

Appropriate prophylaxis or platelet disorders will de-pend on both the speci c de ect and the nature o theplanned dental surgery ( Table 8 ). Mild thrombocytopeniaor mild unctional disorders may require no speci c sys-temic therapy other than the use o local hemostatic meas-ures and anti brinolytic agents. More severe disorders willrequire measures that transiently raise the platelet countor improve unction. Choice o the appropriate prophyl-axis should be made in consultation with the patientsphysician.

Use o Antifbrinolytic AgentsAminocaproic acid and tranexamic acid are synthetic

derivatives o the amino acid lysine. Tey inhibit b-rinolysis by blocking the binding o plasminogen to brinand its subsequent activation to plasmin. Te oral mucosais rich in plasminogen activators, and saliva has signi cantbrinolytic activity. Tese agents are use ul in preventingclot lysis ollowing oral surgery or dental extraction. Tey are used as adjuncts to speci c systemic therapy that cor-rects the coagulation actor or platelet abnormality. In

Table 7 Management o patients with coagulation actor de iciencies, who require dental extraction or complex procedures

Bleeding disorderPretreatment or extraction or

nerve blockPostextraction treatmentor all bleeding disorders

vWD, ype 1 Desmopressin, 0.3 g/kg (maximumdose 20 g) IV over 2030 minutes or

subcutaneously

Anti brinolytic agents(e.g., tranexamic acid, 25 mg/kg

t.i.d.) or 35 days

So diet or 7 days

Within 24 hours, assess needor repeat treatment

vWD, ypes 2A and 2M Desmopressin, as above, i testedresponse orHumate-P, 50 IU o vWF:RCoF/kg

vWD, ypes 2B and 3 Humate-P, 50 IU o vWF:RCoF/kg

Hemophilia A (mild) Desmopressin, as above, i testedresponse is adequate

Hemophilia A (moderate orsevere)

Recombinant Factor VIII concentrate,2025 IU/kgRe-evaluate postprocedure

Hemophilia B (mild, moderateor severe)

Recombinant Factor IX concentrate,4060 IU/kgRe-evaluate postprocedure

RCoF = ristocetin co actor; t.i.d. = 3 times daily; VWF = von Willebrand actor

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hemophilia, or example, they have been shown to reduceboth the risk o delayed bleeding and the amount o clot-ting actor replacement therapy required. 38,39 Oral dosingstarts be ore the surgery and continues or several daysa er or until the socket is healed ( Table 7 ). Tese agentscan also be used locally as a mouthwash and may make itpossible to per orm dental procedures in patients on oralanticoagulation therapy without reducing or withholdingthe anticoagulant. 40

Patients Receiving Antithrombotic Terapy Most patients on long-term anticoagulation or anti-

platelet therapy do not have to discontinue their medi-cation be ore surgical procedures. Although commonpractice has been to discontinue war arin or at least2 days be ore procedures, and in high-risk patients replacethis with heparin, a series o studies now demonstratesthat, with attention to local hemostatic measures, the risk o serious bleeding is minimal and patients may be atgreater risk o thromboembolic events i they are not ad-equately protected. 4143 In a review o 950 patients receivinganticoagulation therapy, Wahl 44 showed that ewer than1.3% required other than local measures or management

o bleeding. Proceeding with most dental procedures i INR 3.5 has been recommended, although 1 study suggeststhat bleeding risk does not correlate with the INR. 42,45

Patients receiving prophylactic doses o either un rac-tionated heparin or LMWH should be able to proceed withdental surgery without discontinuing their prophylaxis.Patients receiving therapeutic LMWH may have to oregothe dose be ore dental surgery and restart ollowing theprocedure.

Tere is less in ormation about the risk o antiplateletdrugs, although 1 small study o patients taking 100 mgo aspirin a day showed no increased risk o bleeding

ollowing dental extractions compared with control pa-tients. 46 In all studies, attention to good local hemostaticprocedures was the most important measure in preventinghemorrhage.

reatment ConsiderationsTe dental management o people with bleeding dis-

orders must take into consideration not only the natureand severity o the disorder, but also the type, location andextent o the intervention. Management decisions then de-pend on a usion o the local and systemic considerations.

Te risk o the intervention will depend on the access-ibility o the surgical site or local control o hemostasis.For example, simple exodontia usually allows ready accessto the potential sites o postoperative hemorrhage or ap-plication o local hemostatic measures, such as pressureor topical agents. In contrast, deep spatial or cavity (e.g.,sinus) surgery and some fap surgery may a ord little orno access to the bleeding sites postoperatively. Te morelimited the access to these sites, the more important sys-temic, rather than local, measures to control postoperativehemorrhage become.

Surgical location is also important with regard to pos-

sible postoperative sequence o hemorrhage. Speci cally,hemorrhage and hematoma ormation that may causeairway obstruction must be controlled by systemicmeasures.

Not only is the nature and location o the surgicalprocedure important to the potential or local or sys-temic management o hemorrhage, but injection o localanesthetic also poses various degrees o risk. Nerve-block injections (in erior alveolar and posterior superioralveolar) can cause airway obstruction. Te greater risk is presented in the in erior alveolar nerve block situa-tion, although such risks rom mandibular blocks can

Table 8 Management o patients with platelet disorders, who require dental procedures

Platelet disorder Preprocedure Postprocedure

Trombocytopenia I platelet count < 50 10 9/L, considermeasures that will raise platelet counttransiently

(therapy depends on etiology)

Anti brinolyt ic agents (e.g.,tranexamic acid, 25 mg/kgt.i.d.) or 35 days

So diet or 7 days

Within 24 hours, assess needor repeat treatment

Glanzmann thrombastheniaBernard Soulier syndrome

Platelet trans usion orRecombinant Factor VIIa

Non-speci c aggregationabnormalities

Desmopressin, 0.3 g/kg (maximumdose 20 g) IV over 2030 minutes orsubcutaneously

Granule de ects Desmopressin, as above, i testedresponse to desmopressin or,i necessary, platelet trans usion

t.i.d. = 3 times daily

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be reduced by using the Gow-Gates technique. Te needor nerve blocks must be considered preoperatively and,i possible, an alternative technique should be employed(e.g., local in ltration, periodontal ligament injection).I these alternatives cannot provide satis actory paincontrol, the need or systemic methods o hemostasis mustbe considered even or nonsurgical dental procedures.

Local Measures to Limit and Control HemorrhageTe method o pain control has already been discussed.

Tat is, choosing techniques and injection sites least likely to result in hematoma ormation causing airway obstruc-tion. Consideration may be given to alternative or ad- junctive means o pain control to limit or avoid injectioninto vulnerable areas. Examples o this are sedation tech-niques or even general anesthesia. Hypnosis has been usedas an adjunct in pain control in these circumstances.

Surgical techniques may be modi ed or re ned some-

what to minimize both intraoperative and postoperativeleeding.Some suggestions in this regard are:

minimize trauma (e.g., elective sectioning o di cultextract ions, limiting the number o teeth to be removedat a time depending on the severity o the bleedingde ect)

avoid faps, as they provide a much greater bleedingarea that is harder to control with local measures

choose surgical and closure techniques that permiteasy access or packing, suturing, cautery, etc.

strive to obtain primary surgical closure remove all granulation tissue rom areas o chronic

infammation.

Depending on the nature and severity o the bleedingdisorder, it may be important to consider alternatives tosurgery, including treatment decisions that would be un-usual under normal circumstances. For example, it mightbe pre erable to per orm endodontic treatment on teeth orroots that are not restorable to retain them without symp-toms or risk, rather than remove them. In some circum-stances, simply opening root canals and leaving them openinde nitely, so that there is no acute in ection, may be areasonable option i surgery is a risk. Tis technique has

been used success ully in circumstances where medicalmanagement is not readily available.Various adjuncts to hemostasis can be employed at the

surgical site to enhance hemostasis, aid in vascular closureand prevent clot breakdown. Gel oam (P zer, Markham, Ont.) is an absorbable gel-

atin sponge material that holds many times its weightin blood and provides a stable sca old or clot or-mation. It is placed in tooth sockets in the orm o tapered cones rolled rom the sheet material. Gel oamis absorbed within 46 weeks with little or no scartissue ormation. It should not be used under epithelial

incisions or faps because it inhibits healing o the epi-thelial edges.47

Bleed-X (QAS, Orlando, Fla.) is a hemostatic productcontaining microporous polysaccharide hemispheres(potato starch) that dehydrate blood and accelerateclotting. It can be applied to all types o surgical sites,including tooth sockets. It has been used success-ully when Gel oam cones have been rolled in the dry powder and placed in sockets. Tere are no knowncontraindications to its use. 48

isseel (Baxter, Mississauga, Ont.) is a brin sealantthat acts both through its adhesive action and by directcontribution o brin to clot ormation. isseel is tech-nique sensitive and requires special preparation justbe ore application. It is expensive and is probably bestreserved or particularly complicated or di cult dentalsituations. 49

Cyklokapron (tranexamic acid) (P zer) has also been

used success ully in the orm o a mouthwash a eroral surgical procedures to inhibit postoperativebleeding episodes. As outlined above, it is an inhibitoro brinolysis that can be administered parenterally. Inaddition, the intravenous preparation can be diluted toa 4.8% aqueous solution and used as a mouthwash (4times daily or 7 days). In controlled trials, it markedly decreased postoperative bleeding episodes in patientson anticoagulant therapy. 40

Electrocautery is a use ul tool to slow intraoperativebleeding and stem postoperative episodes. However,it must be used cautiously to avoid excessive tissue

necrosis. Not only will the necrosis delay healing butit may also become a source o postoperative bleedingwhen the necrotic tissue sloughs. 50

Suturing is worthwhile i signi cant apposition o sotissue can be achieved or i it retains a pack such asGel oam. However, suturing may provide additionaltraumatic puncture points that contribute to post-operative bleeding episodes and may cause con usionover the nature and source o the hemorrhage. 51

Amicar (aminocaproic acid) (Wyeth, Markham, Ont.),a popular anti brinolytic agent, and Trombostat(P zer), a dry thrombin powder, are no longer avail-able or topical use.

Te use o pre ormed splints to protect and enhancethe placement o pressure on sockets is a valuable adjunctin multiple extraction procedures. It is a technique thatshould be considered or complicated situations where sys-temic management is required, but is di cult or expensiveto deliver. Te most popular material is so , mouthguardtype material. Te teeth to be extracted are cut rom theworking model be ore the splint is abricated. Great caremust be taken to ensure that there are no abrasive oroverextended areas on the splint that will traumatize sotissue. Splints enhance the ormation o rm, well-or-

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ganized clots and prevent them rom being dislodged ortraumatized. Splints also shield the clots rom saliva andthe brinolytic substances it contains. Tey are quick andsimple to abricate. Tey must be removed and cleanedonce a day. A er the second day, competent patients may do this themselves. It is recommended that they be worn

or 47 days.51 Te most e ective and o en underrated method

or achieving hemostasis is pressure. Pressure must beapplied at the appropriate location, and gauze should beprewetted to prevent the clot rom adhering to it. Patientsshould be told that the pressure must be maintained or atleast 30 minutes, and pre erably or an hour, as requentinterruption o pressure will cause bleeding to continue.

Management o Postoperative HemorrhageOne o the allacies surrounding patients with bleed-

ing disorders is that they will have uncontrollablehemorrhage. However, when the diagnosis is clear, ap-propriate precautions are taken and preoperative prepara-tions are carried out, this is highly unlikely. Nevertheless,postoperative bleeding episodes should be anticipated andmanaged appropriately. 43

An important aspect o treating any patient with thepotential or excessive bleeding is to in orm him or hero the risk and describe plans or intervention shouldexcessive bleeding occur. oo o en, patients assume thatany amount o bleeding is abnormal. 52 Tey are reassuredwhen they are given a 24-hour a day contact and next-day reassessment is prearranged. Te requency and durationo reassessment is determined by the signi cance o thebleeding problem and by the extent and nature o thesurgery.

echniques or managing postoperative bleeding epi-sodes are: Reapplication o pressure packs. O en patients do not

do this properly. Te technique must be demonstratedto the patient to ensure that this simple technique ise ective. Pressure packs must be kept in place at least30 minutes without checking them be ore the need orother intervention is determined.

Packing or repacking sockets with Gel oam is usually the second step, with pressure packs replaced over the

resh Gel oam. 47 Reinjection o local anesthetic with epinephrine can

help slow hemorrhage and allow vessel constriction,platelet plug ormation and stable clot ormation.However, a er epinephrine rebound, vasodilation canoccur, which may lead to signi cant hemorrhage.

Any large, exophytic clots should be removed down tothe level o the socket as they may provide a pathway or continued bleeding and prevent application o ad-equate pressure to the site.

Te use o astringents may be considered, especially onincisions and raw areas. Te old tea-bag trick re ers

to the practice o using a tea bag as a pressure pack. Tetea contains the astringent tannic acid. Commercialpreparations containing aluminum chloride produce asimilar result. 53

Patients should be instructed to limit physical exertion,to sit or sleep in a semi-sitting position and to avoid

smoking and alcohol consumption. 54

Choosing the Best CourseTe dentist must be prepared to provide the physician

with a clear picture o the treatment proposed and thelocal measures that the dentist can employ to control hem-orrhage. Te physician must be made aware o the degreeo risk associated with serious sequelae, such as airway compromise. 55 ogether, the dentist and physician shouldchoose the least traumatic course o management a ordingthe minimum amount o risk. 44 Ten the patient should becare ully in ormed o the options. Te patient must under-stand what role he or she has and agree to and be able toul ll those obligations. 56 Finally, the circumstances mustbe care ully controlled and the procedure carried out inthe least traumatic way possible. 53

A patient may have a diagnosed bleeding disorder, butis not currently being ollowed by a hematologist. Dentistscan obtain expert advice and consultation throughbleeding disorders programs across Canada. A list o theseprograms is available on the Canadian Hemophilia Society website (www.hemophilia.ca).

Postoperatively, monitoring by the dentist and theability o the patient to contact him or her or help orreassurance are essential. Even patients without bleedingdisorders requently turn up in emergency departmentsbelieving they are having a serious problem because they were not well in ormed and because they cannot contacttheir dentist. Being prepared to deal with bleeding epi-sodes in a calm, competent manner will result in minimalmorbidity or the patient. 51

ConclusionsIn the last decade, studies have shown a remarkable

degree o complexity associated with the hemostatic pro-cess. Cellular and soluble components act in a highly or-chestrated manner to stop blood loss rapidly at the site o

injury. Dentists are acing an ever-increasing number o conditions inherited, acquired and drug-related as-sociated with abnormal hemostatic unction. Tese raisethe possibility o excessive blood loss, poor wound healingand in ection. In this review, we have described many o these conditions and discussed both systemic and localmanagement o bleeding. Further in ormation on a var-iety o bleeding disorders, or both dentists and patients,is available on the Canadian Hemophilia Society website(www.hemophilia.ca).

Te dentist must maintain clear and open communi-cation, not only with the patient, but also with his or her

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physician or hematologist. Tis will ensure that the den-tist obtains complete and, most important, contemporary in ormation on the severity and control o the patientscondition and advice on management o the patient be oreand a er surgery. Te dentist must be prepared to dealwith intraoperative hemorrhage, should it occur, in a calm

and e cient manner. a

THE AUTHORS

Dr. Israels is a pro essor in the department o pediatricsand child health and a senior investigator at the ManitobaInstitute o Cell Biology, University o Manitoba, Winnipeg, Manitoba.

Ms. Schwetz is the nurse coordinator o the Bleeding DisordersProgram, Health Sciences Centre, Winnipeg, Manitoba.

Dr. Boyar was ormerly an associate pro essor in the department o dental diagnostic and surgical sciences, University o Manitoba, Winnipeg, Manitoba.

Dr. McNicol is a pro essor in the department o oral biology and in the department o pharmacology and therapeutics,University o Manitoba, Winnipeg, Manitoba.

Correspondence to: Dr. Archie McNicol, Department o Oral Biology,780 Bannatyne Avenue, Winnipeg, MB R3E 0W2.

Te authors have no declared nancial interests in any company manu ac-turing the types o products mentioned in this article.

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