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24/11/2014 Approachtotheadultpatientwithableedingdiathesis OfficialreprintfromUpToDate www.uptodate.com ©2014UpToDate ®

Approachtotheadultpatientwithableedingdiathesis

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Approachtotheadultpatientwithableedingdiathesis

® ® Approachtotheadultpatientwithableedingdiathesis Author SectionEditor DeputyEditor ReedEDrews,MD

Disclosures:ReedEDrews,MDNothingtodisclose.LawrenceLKLeung,MD

Nothingtodisclose.JenniferSTirnauer,MDEmployeeofUpToDate,Inc.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby

vettingthroughamulti­levelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe

content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.

Literaturereviewcurrentthrough:Oct2014.|Thistopiclastupdated:Nov14,2014.

INTRODUCTION—Bleedingthatisspontaneous,excessive,ordelayedinonsetfollowingtissueinjuryresultsfromalocalizedpathologicprocessoradisorderofthe

hemostaticprocess,involvingacomplexinterplayamongvascularintegrity,plateletnumberandfunction,coagulationfactors,andfibrinolysis.Thistopicreviewwilldiscuss

thediagnosticapproachtothepatientwithabnormalbleeding.

Congenitalandacquireddisordersofplateletfunction,aswellasthehemostaticprocessandassociateddisorders,arediscussedseparately.

PATIENTHISTORY—Theclinicalevaluationofapatientwithableedingdisorderbeginswithacarefulhistory.Patientswithinheritedhemostaticdisordersmayreportlittle

bleeding,whileotherswithoutinheritedoracquiredhemostaticabnormalitiesmayreportexaggeratedtendenciestobleed[1,2].Giventhevariabilityinpatients'perceptionsof

bleeding,aswellasthelackofauniformclinicalmeasureofbleedingseverity[3],adialoguebetweenthepatientandphysicianisessentialfortheconsiderationofa

bleedingdiathesis.Acarefulassessmentofthepresentingcomplaintcanprovideimportantcluesastowhereadefectmightresideinthehemostaticprocessandwhether

thedefectisinheritedoracquired,providingarationalapproachtolaboratoryinvestigation(table1).Useofastandardizedbleedingassessmenttoolmayhelpinthe

prospectiveevaluationofpatientsreferredforhemostaticevaluation[4,5].

Bleedinghistory—Patientswithasuspectedbleedingdisordershouldbequestionedaboutpastbleedingproblems,ahistoryofiron­responsiveanemia,bleedingoutcomes

followingsurgicalproceduresandtoothextractions,historyoftransfusion,characterofmenses,anddietaryhabitsorantibioticusewhichmightpredisposetovitaminK

deficiency.Thepatientshouldalsobequestionedconcerningthepresenceofthyroid,liver,andkidneydisease.Complaintssuchashematuria,melena,andmenorrhagiaare

oftenlesshelpful,sincestructuralcausesaremorecommonlyresponsiblethanableedingdiathesis.

Theresponsetotraumaisanexcellentscreeningtest.Ahistoryofsurgicalproceduresortoothextractionsorsignificantinjurywithoutabnormalbleedingisgoodevidence

againstthepresenceofaninheritedhemorrhagicdisorder.

Aninheriteddisorderissuggestedbytheonsetofbleedingshortlyafterbirthorduringchildhoodandapositivefamilyhistorywithaconsistentgeneticpattern.Thus, hemophiliaA(factorVIIIdeficiency)andhemophiliaB(factorIXdeficiency)arecharacterizedbyX­linkedrecessiveinheritance.However,anegativefamilyhistorydoesnot

Medicationuse—Acarefulhistoryofmedicationuseisimportant,includingprescribedmedications,over­the­countermedications,andherbalproducts.Drugingestionmay

beassociatedwithableedingdiathesisviaavarietyofmechanisms,suchastheinductionofthrombocytopeniaorplateletdysfunction,aplasticanemia,orvascularpurpura.

Inaddition,somedrugscaninduceorexacerbateacoagulationdisorder.Examplesincludeplateletdysfunctioninducedbyaspirinandothercommonlyusedantiinflammatory

Anexampleoftheco­ingestionofdrugspotentiatingtheincidenceofbleedingwasprovidedinastudyofover21,000elderlypatientsrecoveringfromanacutemyocardial

infarction[6].Inthisstudy,theratesofhospitalizationforbleeding(incidencerateper100patientsperyear)forvariouscombinationsofantiplateletagentsandanticoagulants

were[6]:

Aspirinalone–3.2

Warfarinalone–5.9

Aspirinpluseitherticlopidineorclopidogrel–6.8

Aspirinpluswarfarin–8.3

Asimilarstudyin27,058olderadultpatientsdischargedfollowingacutemyocardialinfarctionfoundthefollowingratesofhospitalizationforbleedingassociatedwitha

Aspirinalone–0.65

Clopidogrelalone–1.55

Aspirinplusaselectiveserotoninreuptakeinhibitor(SSRI)–1.61

Aspirinplusclopidogrel–2.08

ClopidogrelplusSSRI–2.43

AspirinplusclopidogrelplusSSRI–3.63

CLINICALMANIFESTATIONS—Clinicalmanifestationsofdisorderedhemostasiscanbedividedintotwomajorcategories:thoseassociatedwithdisordersofblood

vesselsorqualitativeorquantitativeplateletabnormalities;andthoseassociatedwithdisordersofcoagulation(table1).

Disordersofplateletsorbloodvessels—Theseconditionsareoftenreferredtoasdisordersofprimaryhemostasisorthepurpuricdisorderssincetheyare

characteristicallyassociatedwithmucosalandcutaneousbleeding(picture1).Mucosalbleedingmaybemanifestasepistaxisand/orgingivalbleeding,andlargebullous

hemorrhagesmayappearonthebuccalmucosaduetothelackofvesselprotectionaffordedbythesubmucosaltissue.Bleedingintotheskinismanifestedaspetechiaeor

Patientswithplateletabnormalitiestendtobleedimmediatelyaftervasculartraumaandrarelyexperiencedelayedbleeding,whichismorecommoninthecoagulation

disorders.Thefollowingarethetypesofbleedingmostoftenassociatedwiththesedisorders:

Petechiae—Petechiaearesmallcapillaryhemorrhages.Theycharacteristicallydevelopincropsinareasofincreasedvenouspressure,suchasthedependentpartsof

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thebody.Asaresult,theyaremostdenseonthefeetandankles,fewerarepresentonthelegs(picture1).Petechiaearenotfoundonthesoleofthefootwherethevessels

areprotectedbythestrongsubcutaneoustissue.Theyareasymptomaticandnotpalpable,andshouldbedistinguishedfromsmalltelangiectasias,angiomas,andvasculitic

purpura.

Ecchymoses—Ecchymoticlesionscharacteristicallyarepurpleincolorandaresmall,multiple,andsuperficialinlocation.Theyusuallydevelopwithoutnoticeable

traumaanddonotspreadintodeepertissues.

Menorrhagia—Menorrhagia(menstrualflowthatdoesnottaperaftermorethanthreedays)andmetrorrhagia(bleedinginbetweenperiods)arecommoninwomenwith

bleedingdisorders;upto15to20percentofwomenpresentingwithmenorrhagiamayhavesometypeofbleedingdiathesis,suchasvonWillebranddisease,immune

Coagulationdisorders—Thetypicalmanifestationsofbleedinginthecoagulationdisordersarelargepalpableecchymosesandlarge,spreading,deepsofttissue

hematomas.

Hemorrhageintosynovialjoints(hemarthrosis)mostoftenindicatesasevereinheritedcoagulationdisorder,suchashemophilia(table1).Postsurgicalbleedingcanbe

Insomepatientswithacoagulationdisorder,theonsetofbleedingaftertraumamaybedelayed.Asanexample,bleedingafteratoothextractionmaystop,onlytorecurina

matterofhours.Thereasonforthisphenomenonandfortheabsenceofpetechiaeorbleedingfromsmallcutsorscratchesisthepreservationofnormalplateletfunction.

Thecardiacsurgerypatient—Evaluationofthepatientundergoingcardiacsurgerycanbedifficultduetocompetingbleedingandthrombotictendencies.Abnormalities

whichmayoccurinsuchpatientsincludesomeorallofthefollowing[10].

● Endothelialdamage/activationwithdisseminatedintravascularcoagulation

● Presenceofprostheticvalves,stents,vasculargrafts,assistdevices

● Useofantiplateletand/oranticoagulantagents

● Intraoperativemetabolicabnormalities(eg,hypothermia,acidosis,anemia,hypocalcemia)

● Presenceofassociatedhepaticorrenalfailure

LABORATORYTESTING—Laboratorytestsofprimaryandsecondaryhemostaticmechanismsareusedfortwopurposes:

● Generalscreeningtests

● Teststodefinespecificplateletorclottingfactorabnormalities

Generalscreeningtestsincludetheplateletcount,bleedingtime(BT),prothrombintime(PT),activatedpartialthromboplastintime(aPTT),andthrombintime(TT).

Specifictestsincludeexaminationoftheperipheralbloodsmear,plateletaggregationinresponsetoADP,epinephrine,collagen,andristocetin;plateletreleaseassays, coagulationfactorassays,andassessmentoffactorXIIIactivityviaclotsolubilitytesting.TestsoffibrinolysisincludethemeasurementoffibrinsplitproductsandD­dimer

levels.Assaysforthelesscommonlyseenbleedingdisordersincludealpha­2­antiplasminactivity,euglobulinclotlysistime,aswellastissueplasminogenactivatorand

plasminogenactivatorinhibitor­1antigens.

Examinationoftheperipheralbloodsmearisessentialinpatientswithlowplateletcountstoexcludethepresenceofpseudothrombocytopeniaduetoinvitroplatelet

agglutinationinthepresenceofEDTA(picture2).Thisphenomenonisthoughttoresultfroma"naturallyoccurring"plateletautoantibodydirectedagainstanormally

concealedepitopeontheplateletmembrane,whichbecomesexposedbyEDTA.Useofalternativeanticoagulants(eg,citrateorheparin),maycircumventthistechnical

problem.

Bleedingtime—Thebleedingtime(BT)isameasureoftheinteractionofplateletswiththebloodvesselwall.Aprolongedbleedingtimemayoccurinthrombocytopenia

(plateletcountusuallybelow50,000/microL),qualitativeplateletabnormalities(eg,uremia),vonWillebranddisease(VWD),somecasesofvascularpurpura,andsevere

fibrinogendeficiency,inwhichitisprobablytheresultofplateletdysfunction.Amongpatientswithanormalplateletcountwhoarenottakingaspirin,thebleedingtimeis

usedprimarilytoscreenpatientsforinheriteddisordersofplateletfunction[11,12].Anabnormaltestinapatientwithmucocutaneousbleedingwouldjustifyfurthertestingfor

plateletdysfunctionorspecifictestsforvonWillebranddisease(VWD).However,anormalvaluefortheBTshouldnotprecludetestingforVWD[13,14].Aswillbe

discussedbelow,thePlateletFunctionAnalyzerismoresensitivefordetectionofVWDthanistheBT(seebelow)[15,16].

AnormalBTdoesnotpredictthesafetyofsurgicalprocedures,nordoesanabnormalBTpredictforexcessivebleeding.SinceassessmentoftheBTissubjectto

considerablevariationduetotechnicalfactorsinexecutingthetest,anormalrangeforthetestvariesfromlaboratorytolaboratory,andcannotbegeneralizedhere.Of

importance,theBTisnotrecommendedasapreoperativescreeningtest.Becauseofconsiderablevariationduetotechnicalfactorsinexecutingthetest,theBTplaysa

limitedrole,ifany,inevaluatinghemostaticdefects.(See"Preoperativeassessmentofhemostasis",sectionon'Bleedingtime'.)

ThePlateletFunctionAnalyzer—Thecommercially­availablePlateletFunctionAnalyzer(PFA­100)isanalternativetechnologythatassessesplateletfunctionwithgreater

sensitivityandreproducibilitythanthebleedingtime(BT)[15].BecausetheBTisinsensitive,invasive,timeconsuming,andsubjecttovariationduetotechnicalfactors,

Thistestmaybeperformedoncitratedsamplesofwholebloodthathavebeenstoredatroomtemperature,andisconsiderablyfastertoperformthanplateletaggregation

studies.NormalPFA­100testresultsmayobviatetheneedforfurtherexpensiveplateletfunctiontesting.UnliketheinvivoBT,thePFA­100testdoesnotprovideameasure

ofvascularfunction.

Prothrombintime—Theproductionoffibrinviatheextrinsicpathwayandthefinalcommonpathway(commontobothextrinsicandintrinsiccascades)requirestissue thromboplastin(tissuefactor),factorVII(extrinsicpathway),andfactorsX,V,prothrombin(factorII),andfibrinogen.Thefunctioningofthesepathwaysismeasuredbythe

plasmaprothrombintime(figure1).Thetestbypassestheintrinsicpathwayandusesthromboplastinstosubstituteforplatelets.Withinthiscombinedpathway,factorsVII,

X,andprothrombinarevitamin­Kdependentandarealteredbywarfarin.Forthisreason,thePTisusedasameasureoftheanticoagulantactivityofwarfarinandother

Activatedpartialthromboplastintime—Theactivatedpartialthromboplastintime(aPTT)measurestheintrinsicandcommonpathwaysofcoagulation(figure1).Itis

calledpartialsinceplateletsubstitutesareusedwhichareonlypartialthromboplastins;theyareincapableofactivatingtheextrinsicpathway,whichrequirescompletetissue

thromboplastin(tissuefactor).Intheoriginalmethod,aglasstesttubeprovidedcontactactivation.However,theadditionofactivatorssuchasellagicacidorparticulate

silicatesprovidedbetterandmorestandardizedcontactactivation.ThisactivatedversionofthePTT(aPTT)isnowtheroutineassayusedtoevaluateintrinsiccoagulation

TheaPTTissensitivetoinhibitorssuchasheparinandtodeficienciesofallcoagulationfactorsexceptfactorsVIIandXIII.ItislesssensitivethanthePTtodeficienciesof

thecommonpathway(factorsXandV,prothrombin,andfibrinogen)[18].Highlevelsofasinglefactor(eg,factorVIII)canshortentheaPTT.However,anassociation

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betweenashortaPTTandahypercoagulablestateremainscontroversial.

Thrombintimeandreptilasetime—Thethrombintime(TT)andreptilasetime(RT)measureconversionoffibrinogentofibrinmonomersandtheformationofinitialclotby

thrombinandreptilase,respectively.Reptilase,athrombin­likesnakeenzyme,differsfromthrombinbygeneratingfibrinopeptideAbutnotfibrinopeptideBfromfibrinogenand

byresistinginhibitionbyheparinviaantithrombin.Fibrinstrandcross­linking,whichismediatedbyfactorXIII,isnotmeasuredbytheseassays.

Prolongedthrombintimesandreptilasetimesmaybeduetohypofibrinogenemia,structurallyabnormalfibrinogens(dysfibrinogens),orincreasedfibrinsplitproducts[19].

SinceheparinprolongstheTTbutnottheRT,theRTisusefulfordeterminingifheparinisthecauseofaprolongedTT.Alternatively,onecantestforheparinactivityviaits

Factordeficienciesandinhibitors—AprolongedaPTTcanbeduetoadeficiency(orabsence)ofacoagulationfactororthepresenceofacoagulationfactorinhibitor.A

factordeficiencyshouldbecorrectablebyadditionofnormalplasmatothetestreactiontube.ThisisnormallydonebyperformingaPToraPTTona1:1mixtureofpatient

SpecificfactordeficienciesarethendeterminedbyassessingthePToraPTTinmixesoftestplasmawithcommerciallyavailableplasmasdeficientinknownfactors.Factor

levelscanbefunctionallyassessedbycomparingtestresultstostandardcurvesgeneratedbymixturesofseriallydilutednormalplasmaandfactor­deficientplasma.

Immunologicassayscanalsobeusedtomeasurefactorlevels.Immunologicandfunctionalassaysshouldgiveequivalentresultswhenafactordeficiencyispresent.On

theotherhand,alowfunctionalassaybutnormalimmunologicassayindicatesthepresenceofafunctionallyabnormalfactor.

Thepresenceofafactorinhibitorissuspectedwhentheabnormaltestdoesnotcorrect,oronlypartiallycorrects,followinganimmediateassayofa1:1mixtureofpatient

andnormalplasma.Insomecases,suchasacquiredfactorVIIIantibodies,theaPTTmaycorrectimmediatelyaftermixing,butbecomesprolongedafter60to120minutes

Inadditiontofactorinhibitors,lupusanticoagulantscanresultinaprolongedaPTTthatisnotcorrectablebytheadditionofnormalplasma.Theeffectoftheseantibodieson

theaPTTcanbeovercomebyaddingexcessplateletphospholipid(particularlyahexagonalphasephospholipid)orbyassessingthedilutedRussell'svipervenomtime[20].

Paradoxically,theantiphospholipidsyndromeisusuallyassociatedwithatendencytothrombosisratherthanbleeding;theprolongedaPTTisanartifactofthe

Fibrinogen—Fibrinogen'sfunctionalactivityismeasuredasthrombin­coagulableprotein,whilelevelsofstructuralfibrinogenaremeasuredbyimmunologicassays.

Immunologicandfunctionalassaysoffibrinogenmaybediscordantinpatientswithaninheriteddysfibrinogenemia.(See"Disordersoffibrinogen",sectionon'Diagnosis'.)

Ureaclotsolubility—Theinitialfibrinclot,heldtogetherbynoncovalentbonds,issolubleinurea.SubsequenttransglutaminationbyfactorXIIIcovalentlycrosslinks

overlappingfibrinstrands,whichthenbecomeresistanttosolubilization.Theabilityof5MureaormonochloroaceticacidtosolubilizetheclotreflectsdeficiencyoffactorXIII

Testsforfibrinolysis—Fibrinandfibrinogendegradationproducts(FDP)areproteinfragmentsresultingfromtheactionofplasminonfibrinorfibrinogen,respectively. Elevatedlevelsareseeninstatesoffibrinolysissuchasdisseminatedintravascularcoagulation(DIC).FDPassaysdonotdifferentiatebetweenfibrindegradationproducts

andfibrinogendegradationproducts.ItispossibletoaccuratelymeasuretheconcentrationoffibrinD­dimers,whicharedegradationproductsofcross­linkedfibrin[21].The

methodofchoiceistheenzyme­linkedimmunosorbentassay(ELISA).

Whenfibrinolysisexceedsthrombingeneration,therebyincreasingtheriskofhemorrhageratherthanthrombosis(eg,disseminatedintravascularcoagulationassociatedwith

BecauseD­dimersspecificallyreflectfibrinolysisofcross­linkedfibrin(ie,thefibrinclot),assessmentofD­dimerlevelssuggeststhrombosismorereliably.Asanexample,in

Theeuglobulinlysistime,whichassessesoverallfibrinolysisislessuseful,sinceresultsfromthistestmayvarysignificantlyinrelationtocalciumionconcentrationsaswell

asplasmalevelsoftissueplasminogenactivatorandplasminogenactivatorinhibitor­1[23­25].Alpha­2antiplasmin,aninhibitoroffibrinolysis,isnotmeasuredinthistest.

Morespecifictestsofthefibrinolyticsystemincludeassaysforplasminogen,tissueplasminogenactivator(t­PA),alpha­2antiplasmin,plasminogenactivatorinhibitor­1(PAI­

1),andthrombin­activatablefibrinolysisinhibitor(TAFI).Assaysforalpha­2antiplasminareusedclinicallytoidentifypatientswithalpha­2antiplasmindeficiency,aninherited

DIAGNOSTICAPPROACH—Inmanypatientswithableedingdiathesis,thelikelydiagnosiswillbeapparentfromthehistoryandphysicalexamination;thediagnosiscan

thenbeconfirmedwiththeappropriatespecifictests(table2).Individualtests(eg,eitherPToraPTTalone)canalsobeusedformonitoringtheeffectofananticoagulantor

assessingpatientswithaknownconditionthathasapredictableeffectoncoagulation.

Whenthediagnosisisnotimmediatelyapparent,threeinitialtestsshouldbeperformed—plateletcount,PT,andaPTT—becausedefectsinprimaryorsecondary

hemostasis,includingintrinsic,extrinsic,andcommonpathwaydefects,canallberesponsibleforbleeding(table2).Thepatternofresultsprovidesapresumptivediagnosis

whichcanthenbeconfirmedwithspecifictesting(table3andtable4).

NormalPTandaPTT—ThrombocytopeniawithanormalPTandaPTTisthemostcommonoftheacquiredbleedingdisorders.Inthepresenceofsignificant

thrombocytopenia,thebleedingtimeisprolongedandclotretractionisdeficient.MeasurementofthebleedingtimeorPFA­100(see'Bleedingtime'above)isnotnecessaryin

patientswhohaveplateletcountsbelow50,000/microL.(See"Approachtotheadultwithunexplainedthrombocytopenia".)

ThebleedingtimeorPFA­100test(see'ThePlateletFunctionAnalyzer'above)shouldbemeasuredinpatientswithahistoryofmucocutaneousbleedingwhohaveanormal

plateletcount,PT,andaPTT.AprolongedbleedingtimeorPFA­100justifiesfurtherplateletfunctiontesting,includingassaystoevaluatevonWillebranddisease(VWD)and

plateletaggregationstudies[26].(See"Plateletfunctiontesting".)

However,anormalbleedingtimeshouldnotprecludeevaluationforVWD,especiallysincethePFA­100testhassubstantiallyhighersensitivityfordetectingVWDthanthe

vonWillebranddisease—vonWillebranddisease(VWD)isthemostcommoninheritedbleedingdisorder,withanestimatedprevalenceofupto1percent.Asmall

MostpatientswithVWDpresentwithmoderatetoseveremucocutaneousbleedingduetoreducedlevelsofvonWillebrandfactor(VWF).TheymayhaveaprolongedaPTT

duetoamildtomoderateconcordantdeficiencyoffactorVIII(table4)[27].Insomepatients,however,theclinicalmanifestationsaremild,theaPTTisnormal,andfurther

studiesarenecessarytomakethediagnosis.ThisisparticularlytruewhenfactorsthatincreaseVWFandfactorVIIIlevels(eg,pregnancy,oralcontraceptiveuse,liver

disease)arepresent.

InitialscreeningtestsforVWDincludefactorVIIIactivitylevel,immunoassayofVWFantigen,andristocetincofactoractivity.Repeatedtestingmayberequiredtoestablish

thediagnosisofVWD,becausetestresultsmayvaryovertime[28].(See"ClinicalpresentationanddiagnosisofvonWillebranddisease".)

Plateletdysfunction—Studiestoconfirmthepresenceofqualitativedisordersofplateletfunctionincludeevaluationofplateletmorphology,andtestsofplatelet

aggregationandfunction.(See"Plateletfunctiontesting".)

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Inheriteddisordersofplateletfunctionarerelativelyrareandinclude:

● Bernard­Souliersyndrome—characterizedbyadefectinanyofthecomponentsoftheglycoprotein(GP)Ib/IX/Vcomplex,giantplatelets,andgreaterthanexpected

bleedingforthedegreeofthrombocytopenia

● Glanzmannthrombasthenia—characterizedbyadefectintheGPIIb/IIIacomplex,normalplateletcounts,normalplateletmorphology,andabnormalinvitroplatelet

aggregation.

● Storagepooldiseases—theseincludeWiskott­Aldrichsyndrome,thrombocytopeniawithabsentradiisyndrome,Chediak–Higashisyndrome,andHermansky­Pudlak

syndrome.Themuchmorecommonacquiredcausesincludeuseofaspirinandnonsteroidalantiinflammatorydrugs,beta­lactamantibiotics,uremia,and

Coagulationdisorders—Coagulationdisordersleadingtoableedingdiathesismaybeassociatedwithnormalscreeningcoagulationtestsifthefactorisnotinvolvedin

thestepsincoagulationmeasuredbyinvitrotests(figure1),orifthedegreeofdeficiencyismild.

Examplesincludethefollowing:

FactorXIIIdeficiency–FactorXIIIstabilizesandcrosslinksfibrinstrands.FactorXIIIdeficiencymaypresentwithdelayedbleeding,usually24to36hoursafter

surgeryortrauma;spontaneousbleedingalsooccurs.CoagulationtestingshowsnormalvaluesforthePT,aPTT,andTT.Thediagnosisismadebymeasurementof

reducedplasmafactorXIIIactivity;animmunoassayforfactorXIII;ordemonstrationofclotdissolutionin5molarureaormonochloroaceticacid,althoughclotsolubility

testingmaybepoorlystandardizedandsensitivitymaybelow[29].(See"Rare(recessivelyinherited)coagulationdisorders".)

Abnormalitiesofplasminogenorplasmin–Plasministheprimaryenzymeresponsibleforfibrinolysis;itisproducedfromthecleavageofplasminogen.Rare

abnormalitiesinregulatorsofplasminogenactivationorplasmindegradationhavebeenreportedascausesoffamilialbleedingdisorders(eg,alpha­2antiplasmin

deficiency,plasminogenactivatorinhibitor­1deficiency).(See"Thromboticandhemorrhagicdisordersduetoabnormalfibrinolysis".)

Thrombomodulinmutation–Thrombomodulin(TM)isaregulatoryproteinexpressedbyendothelialcells,monocytes,andmegakaryocytes.Bindingofcellsurface

AfamilywithanautosomaldominantbleedingdisorderwasfoundtohaveaTMgenemutationthatcreatedaprematurestopcodonandeliminatedtheportionoftheprotein

responsibleforitscellularretention[30].ThisinturncausedextremelyhighlevelsofTMinplasma(100foldgreaterthannormal),whichwasassociatedwithsevere

bleeding.

Mildhemophilia–Factoractivitylevelsaboveapproximately15to20percentareoftensufficienttopreventspontaneousbleedingandtoproduceanormalPTand

aPTT,althoughthisvariesbyspecificfactorlevel(table5).However,patientswithmilddeficiencyofacoagulationfactormayhaveincreasedbleedingwithhemostatic

challenges(eg,excessivesurgicalbleeding,menorrhagia).Thismaybeseeninanindividualwhoisheterozygousforacoagulationfactordefect,suchasahemophilia

Vascularpurpuras—Withthepossibleexceptionofaprolongedbleedingtime,screeningtestsareusuallynormalinpatientswithbleedingdisordersrelatedtovascular

abnormalities(table4).Theseincludestructuralabnormalities(eg,hereditaryhemorrhagictelangiectasia),hereditarydisordersofconnectivetissue(eg,Ehlers­Danlos

disease,osteogenesisimperfecta),acquiredconnectivetissuedisorders(eg,scurvy,steroid­inducedpurpura),smallvesselvasculitis,andpurpuraassociatedwiththe

Unknowncause—Somepatientsareencounteredwithasignificantbleedinghistoryforwhichthereisnoexplanation.Abuse,occasionallyself­inflicted,shouldbe

considered,butitislikelythatsomedisordersofhemostasisescapedetectionwithcurrentlyavailablemethods.Psychogenicpurpuramaybeamongthesedisorders.(See

NormalPTandprolongedaPTT

Factordeficiencies—AnormalPTandaprolongedaPTTischaracteristicofdisordersoftheintrinsicpathwayofcoagulation(figure1andtable3).Inheriteddisorders

includedeficienciesoffactorsVIII(hemophiliaA,vonWillebranddisease),IX(hemophiliaB),andXI.HemophiliaAandBarethemostcommon.Inonestudyinsixstates,

theage­adjustedprevalenceofhemophiliain1994was13.4cases/100,000males(10.5forhemophiliaAand2.9forB)[31].Patientswiththesedisorderspresentwithlife­

longrecurrentsofttissueandjointbleeding,generallyrequiringfrequentfactorreplacementtherapy(table1).

FactorXIdeficiency,whichisrelativelycommoninAshkenaziJews,butcanbeseeninavarietyofethnicgroups,presentswithavariableandunpredictablebleeding

history[32,33].Bleedinginthesepatients,whenpresent,ismostcommonlyseenfollowingsurgicalprocedures.(See"FactorXIdeficiency".)

TherearealsoavarietyofdisordersthatprolongtheaPTTbutarenotassociatedwithexcessivebleeding.TheseincludeinheritedoracquiredfactorXIIdeficiency,aswell

asdeficienciesofprekallikreinorhighmolecularweightkininogen[34].

Acquiredinhibitors—Acquiredinhibitorsincludeantiphospholipidantibodieswhich,asnotedabove,maybeassociatedwiththrombosisratherthanbleeding,and

antibodiestofactorVIII(acquiredhemophilia),IX,andXI,whichmaybeassociatedwithcatastrophicbleeding(table3).FactorVIIIinhibitorshavebeendescribedin

associationwithmalignancy,clonallymphoproliferativedisorders,pregnancy,rheumatologicdisorders,aswellasintheabsenceofunderlyingdisease.Acquiredantibodies

tofactorIXandXIarerare.(See"Acquiredinhibitorsofcoagulation".)AcquiredinhibitorsoffactorVmayhavevariableeffectsonthePT,aPTT,andBT(seebelow).

ProlongedPTandnormalaPTT—AprolongedPTwithanormalaPTTisindicativeofanabnormalityintheextrinsicpathwayandsuggestsfactorVIIdeficiency,which

canbeinheritedoracquired(table3).

Thispatternismostcommonlyseenfollowingwarfarintherapy,earlyliverdisease,andvitaminKdeficiency,and,lesscommonly,incertain(early)casesofDIC.(See

InheritedfactorVIIdeficiencydisplaysconsiderablephenotypicandmolecularheterogeneity,andthereareinconsistenciesbetweentheclinicalpicture,theunderlyingclotting

andmoleculardefects,andtheresponsetoprophylactictreatmentwithrecombinanthumanfactorVIIa[35­39].Themanifestationsrangefromnoexcessivebleedingtoa

AcquiredinhibitorsoffactorVIIarerare.(See"Acquiredinhibitorsofcoagulation",sectionon'FactorVIIinhibitors'.)

ProlongedPTandaPTT—ProlongationofboththePTandtheaPTTindicatesaninheriteddisorderofthecommonpathwayoramorecomplexacquireddisorderinvolving

multiplepathways(table3).

Inheriteddisorderswithalowfibrinogenlevelincludeafibrinogenemia,arareautosomalrecessivedisorderwithmucocutaneousbleedingepisodesthatmayabatein

severitywithageandthataretreatablewithfibrinogenreplacement,andthedysfibrinogenemias,aheterogeneousgroupofautosomaldominantdisordersoccasionally

associatedwitheitherableedingorthromboticdiathesis.(See"Disordersoffibrinogen",sectionon'Congenitalafibrinogenemia/hypofibrinogenemia'.)

● SupratherapeuticdosesofwarfarinorheparincancauseprolongationofboththePTandaPTT.ItiscommontoseeprolongationofboththePTandaPTTwhenheparin

andwarfarinareemployedsimultaneously,asintheinitialtreatmentofvenousthromboembolicdisease.

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● AcquireddisorderswithmultipleabnormalitieswhichproducethispatternincludevitaminKdeficiency,liverdisease,disseminatedintravascularcoagulation,and

fibrinolysis.Differentiatingamongthesepossibilitiesmaybedifficult.Thefollowingmayhelpindistinguishingamongtheseconditions:

InbothliverdiseaseandvitaminKdeficiency,thereisdeficientsynthesisoffactorsII,VII,IXandX.SincefactorVproductionisindependentofvitaminKstatus,low

factorVlevelscanbeusedasevidenceforeitherreducedhepaticsyntheticfunctionorincreasedconsumption,asinDIC.SincefactorVIIIproductionisindependent

ofvitaminKstatusandthisfactorisnotmanufacturedbyhepatocytes;factorVIIIlevelsareusuallynormalorincreasedinliverdisease.Thus,lowlevelsoffactorVIII

● AcquiredinhibitorsoffactorVhavebeendescribed,attimesinassociationwithtopicalbovinethrombintherapy.Acquiredantibodiestobovinethrombinand/orfactorV

contaminatingbovinethrombinpreparationsmaycross­reactwithendogenoushumanfactorVaswellaswithhumanthrombin.EffectsoftheseantibodiesonPT,

ThefirststepintheevaluationofpatientswithaprolongedPTandaPTTshouldbetoexcludeoridentifyanabnormalityoffibrinogen.Thiscanbeachievedbymeasurement

oftheplasmafibrinogenconcentrationandthethrombintime,andtestingforincreasedamountsofD­dimerorfibrin/fibrinogendegradationproducts(FDP).Inpatientswithan

inheritedcoagulationdisorderandnormalamountsoffibrinogen,deficienciesoffactorV,factorX,andprothrombincanbediagnosedbyspecificfactorassays.Inpatients

withanacquireddisorder,thelikelydiagnosis,intheabsenceofheparin,warfarin,andfibrinogenabnormalities,isvitaminKdeficiencyorliverdisease.

AcquiredinhibitorstoprothrombinandfactorXareextremelyrare.AcquiredfactorXdeficiencymaybeseeninpatientswithprimaryamyloidosis,andresultsfromthe

SUMMARYANDRECOMMENDATIONS

● Bleedingthatisspontaneous,excessive,ordelayedinonsetfollowingtissueinjuryresultsfromoneormoreofthefollowing:

• Alocalizedpathologicprocess

• Disordersinvolvingvascularintegrity

• Disordersofplateletnumberand/orfunction

• Disordersofthevariouscoagulationfactors

• Increasedfibrinolysis

● Acarefulassessmentofthepresentingcomplaintandthepatient'sbleedinghistorycanprovideimportantcluesastowhereadefectmightresideinthehemostatic

● Thephysicalexaminationishelpfulindeterminingthetypeofbleedingpresent,aswellasfordetectingotherconditionsthatmightbepresent.(See'Clinical

● Inmanypatientsthelikelydiagnosiswillbeapparentfromthehistoryandphysicalexaminationalone;thediagnosiscanthenbeconfirmedwiththeappropriatespecific

tests.

● Whenthediagnosisisnotimmediatelyapparent,threeinitialtestsshouldbeperformed:plateletcount,prothrombintime(PT),andactivatedpartialthromboplastintime

(aPTT)(table2).(See'Laboratorytesting'aboveand"Clinicaluseofcoagulationtests".)

● Thepatternofresultsprovidesapresumptivediagnosiswhichcanthenbeconfirmedwithspecifictesting(table3andtable4).(See'Diagnosticapproach'above.)

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REFERENCES

24/11/2014

Approachtotheadultpatientwithableedingdiathesis

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