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Approachtotheadultpatientwithableedingdiathesis
OfficialreprintfromUpToDate
www.uptodate.com2014UpToDate
Approachtotheadultpatientwithableedingdiathesis
Author
ReedEDrews,MD

SectionEditor
LawrenceLKLeung,
MD

DeputyEditor
JenniferSTirnauer,
MD

Disclosures:ReedEDrews,MDNothingtodisclose.LawrenceLKLeung,MD
Nothingtodisclose.JenniferSTirnauer,MDEmployeeofUpToDate,Inc.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthe
content.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2014.|Thistopiclastupdated:Nov14,2014.
INTRODUCTIONBleedingthatisspontaneous,excessive,ordelayedinonsetfollowingtissueinjuryresultsfromalocalizedpathologicprocessoradisorderofthe
hemostaticprocess,involvingacomplexinterplayamongvascularintegrity,plateletnumberandfunction,coagulationfactors,andfibrinolysis.Thistopicreviewwilldiscuss
thediagnosticapproachtothepatientwithabnormalbleeding.
Congenitalandacquireddisordersofplateletfunction,aswellasthehemostaticprocessandassociateddisorders,arediscussedseparately.

(See"Overviewofhemostasis".)
(See"Approachtotheadultwithunexplainedthrombocytopenia".)
(See"Congenitalandacquireddisordersofplateletfunction".)
(See"Disordersoffibrinogen".)

PATIENTHISTORYTheclinicalevaluationofapatientwithableedingdisorderbeginswithacarefulhistory.Patientswithinheritedhemostaticdisordersmayreportlittle
bleeding,whileotherswithoutinheritedoracquiredhemostaticabnormalitiesmayreportexaggeratedtendenciestobleed[1,2].Giventhevariabilityinpatients'perceptionsof
bleeding,aswellasthelackofauniformclinicalmeasureofbleedingseverity[3],adialoguebetweenthepatientandphysicianisessentialfortheconsiderationofa
bleedingdiathesis.Acarefulassessmentofthepresentingcomplaintcanprovideimportantcluesastowhereadefectmightresideinthehemostaticprocessandwhether
thedefectisinheritedoracquired,providingarationalapproachtolaboratoryinvestigation(table1).Useofastandardizedbleedingassessmenttoolmayhelpinthe
prospectiveevaluationofpatientsreferredforhemostaticevaluation[4,5].
BleedinghistoryPatientswithasuspectedbleedingdisordershouldbequestionedaboutpastbleedingproblems,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
excludeaninheritedcoagulationdisorder.Asanexample,upto30to40percentofpatientswithhemophiliaAhaveanegativefamilyhistory.(See"Clinicalmanifestations
anddiagnosisofhemophilia",sectionon'Patientandfamilyhistory'.)
MedicationuseAcarefulhistoryofmedicationuseisimportant,includingprescribedmedications,overthecountermedications,andherbalproducts.Drugingestionmay
beassociatedwithableedingdiathesisviaavarietyofmechanisms,suchastheinductionofthrombocytopeniaorplateletdysfunction,aplasticanemia,orvascularpurpura.
Inaddition,somedrugscaninduceorexacerbateacoagulationdisorder.Examplesincludeplateletdysfunctioninducedbyaspirinandothercommonlyusedantiinflammatory
drugs,betalactamantibiotics,clopidogrel,ticlopidine,andthecoingestionofdrugsthatmaypotentiatetheanticoagulanteffectsofwarfarin.(See"NonselectiveNSAIDs:
Overviewofadverseeffects"and"Druginducedthrombocytopenia".)
Anexampleofthecoingestionofdrugspotentiatingtheincidenceofbleedingwasprovidedinastudyofover21,000elderlypatientsrecoveringfromanacutemyocardial
infarction[6].Inthisstudy,theratesofhospitalizationforbleeding(incidencerateper100patientsperyear)forvariouscombinationsofantiplateletagentsandanticoagulants
were[6]:

Aspirinalone3.2
Warfarinalone5.9
Aspirinpluseitherticlopidineorclopidogrel6.8
Aspirinpluswarfarin8.3

Asimilarstudyin27,058olderadultpatientsdischargedfollowingacutemyocardialinfarctionfoundthefollowingratesofhospitalizationforbleedingassociatedwitha
differentcombinationofdrugs(aspirin,clopidogrel,SSRI)[7].(See"Selectiveserotoninreuptakeinhibitors:Pharmacology,administration,andsideeffects",sectionon
'Bleeding'.)

Aspirinalone0.65
Clopidogrelalone1.55
Aspirinplusaselectiveserotoninreuptakeinhibitor(SSRI)1.61
Aspirinplusclopidogrel2.08
ClopidogrelplusSSRI2.43
AspirinplusclopidogrelplusSSRI3.63

CLINICALMANIFESTATIONSClinicalmanifestationsofdisorderedhemostasiscanbedividedintotwomajorcategories:thoseassociatedwithdisordersofblood
vesselsorqualitativeorquantitativeplateletabnormalitiesandthoseassociatedwithdisordersofcoagulation(table1).
DisordersofplateletsorbloodvesselsTheseconditionsareoftenreferredtoasdisordersofprimaryhemostasisorthepurpuricdisorderssincetheyare
characteristicallyassociatedwithmucosalandcutaneousbleeding(picture1).Mucosalbleedingmaybemanifestasepistaxisand/orgingivalbleeding,andlargebullous
hemorrhagesmayappearonthebuccalmucosaduetothelackofvesselprotectionaffordedbythesubmucosaltissue.Bleedingintotheskinismanifestedaspetechiaeor
superficialecchymoses.(See"Immunethrombocytopenia(ITP)inadults:Clinicalmanifestationsanddiagnosis"and"Approachtotheadultwithunexplained
thrombocytopenia".)
Patientswithplateletabnormalitiestendtobleedimmediatelyaftervasculartraumaandrarelyexperiencedelayedbleeding,whichismorecommoninthecoagulation
disorders.Thefollowingarethetypesofbleedingmostoftenassociatedwiththesedisorders:
PetechiaePetechiaearesmallcapillaryhemorrhages.Theycharacteristicallydevelopincropsinareasofincreasedvenouspressure,suchasthedependentpartsof

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thebody.Asaresult,theyaremostdenseonthefeetandankles,fewerarepresentonthelegs(picture1).Petechiaearenotfoundonthesoleofthefootwherethevessels
areprotectedbythestrongsubcutaneoustissue.Theyareasymptomaticandnotpalpable,andshouldbedistinguishedfromsmalltelangiectasias,angiomas,andvasculitic
purpura.
EcchymosesEcchymoticlesionscharacteristicallyarepurpleincolorandaresmall,multiple,andsuperficialinlocation.Theyusuallydevelopwithoutnoticeable
traumaanddonotspreadintodeepertissues.
MenorrhagiaMenorrhagia(menstrualflowthatdoesnottaperaftermorethanthreedays)andmetrorrhagia(bleedinginbetweenperiods)arecommoninwomenwith
bleedingdisordersupto15to20percentofwomenpresentingwithmenorrhagiamayhavesometypeofbleedingdiathesis,suchasvonWillebranddisease,immune
thrombocytopenia(ITP),plateletfunctiondefect[8,9].(See"ClinicalpresentationanddiagnosisofvonWillebranddisease",sectionon'Clinicalpresentation'and"Chronic
menorrhagiaoranovulatoryuterinebleeding".)
CoagulationdisordersThetypicalmanifestationsofbleedinginthecoagulationdisordersarelargepalpableecchymosesandlarge,spreading,deepsofttissue
hematomas.
Hemorrhageintosynovialjoints(hemarthrosis)mostoftenindicatesasevereinheritedcoagulationdisorder,suchashemophilia(table1).Postsurgicalbleedingcanbe
extensive.(See"Clinicalmanifestationsanddiagnosisofhemophilia".)
Insomepatientswithacoagulationdisorder,theonsetofbleedingaftertraumamaybedelayed.Asanexample,bleedingafteratoothextractionmaystop,onlytorecurina
matterofhours.Thereasonforthisphenomenonandfortheabsenceofpetechiaeorbleedingfromsmallcutsorscratchesisthepreservationofnormalplateletfunction.
ThecardiacsurgerypatientEvaluationofthepatientundergoingcardiacsurgerycanbedifficultduetocompetingbleedingandthrombotictendencies.Abnormalities
whichmayoccurinsuchpatientsincludesomeorallofthefollowing[10].

Endothelialdamage/activationwithdisseminatedintravascularcoagulation
Presenceofprostheticvalves,stents,vasculargrafts,assistdevices
Useofantiplateletand/oranticoagulantagents
Intraoperativemetabolicabnormalities(eg,hypothermia,acidosis,anemia,hypocalcemia)
Presenceofassociatedhepaticorrenalfailure

LABORATORYTESTINGLaboratorytestsofprimaryandsecondaryhemostaticmechanismsareusedfortwopurposes:
Generalscreeningtests
Teststodefinespecificplateletorclottingfactorabnormalities
Generalscreeningtestsincludetheplateletcount,bleedingtime(BT),prothrombintime(PT),activatedpartialthromboplastintime(aPTT),andthrombintime(TT).
Specifictestsincludeexaminationoftheperipheralbloodsmear,plateletaggregationinresponsetoADP,epinephrine,collagen,andristocetinplateletreleaseassays,
coagulationfactorassays,andassessmentoffactorXIIIactivityviaclotsolubilitytesting.TestsoffibrinolysisincludethemeasurementoffibrinsplitproductsandDdimer
levels.Assaysforthelesscommonlyseenbleedingdisordersincludealpha2antiplasminactivity,euglobulinclotlysistime,aswellastissueplasminogenactivatorand
plasminogenactivatorinhibitor1antigens.
Appropriateemergencylaboratorytestingforthosewithactivebleedingisdiscussedseparately.(See"Shockinadults:Types,presentation,anddiagnosticapproach",
sectionon'Laboratoryevaluation'.)
PlateletcountingandtheperipheralsmearPlateletsmaybecounteddirectlyorwiththeuseoffullyautomatedelectronicmethods.(See"Automatedhematology
instrumentation".)Whilesomeautomatedmethodsmayflagforthepresenceofunusuallysmallorextremelylargeplatelets,thereisnosubstitutefordirectexaminationof
theperipheralbloodsmearfordetectionofquantitativeaswellasqualitative(ie,abnormalitiesofplateletsize)plateletabnormalities.(See"Congenitalandacquireddisorders
ofplateletfunction",sectionon'CBCandperipheralsmearexamination'.)
Examinationoftheperipheralbloodsmearisessentialinpatientswithlowplateletcountstoexcludethepresenceofpseudothrombocytopeniaduetoinvitroplatelet
agglutinationinthepresenceofEDTA(picture2).Thisphenomenonisthoughttoresultfroma"naturallyoccurring"plateletautoantibodydirectedagainstanormally
concealedepitopeontheplateletmembrane,whichbecomesexposedbyEDTA.Useofalternativeanticoagulants(eg,citrateorheparin),maycircumventthistechnical
problem.
BleedingtimeThebleedingtime(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'.)
ThePlateletFunctionAnalyzerThecommerciallyavailablePlateletFunctionAnalyzer(PFA100)isanalternativetechnologythatassessesplateletfunctionwithgreater
sensitivityandreproducibilitythanthebleedingtime(BT)[15].BecausetheBTisinsensitive,invasive,timeconsuming,andsubjecttovariationduetotechnicalfactors,
manycentershaveadoptedthePFA100inplaceoftheBTastheirscreeningtestofplateletfunction[17].(See"Plateletfunctiontesting",sectionon'Theplateletfunction
analyzer'.)
Thistestmaybeperformedoncitratedsamplesofwholebloodthathavebeenstoredatroomtemperature,andisconsiderablyfastertoperformthanplateletaggregation
studies.NormalPFA100testresultsmayobviatetheneedforfurtherexpensiveplateletfunctiontesting.UnliketheinvivoBT,thePFA100testdoesnotprovideameasure
ofvascularfunction.
ProthrombintimeTheproductionoffibrinviatheextrinsicpathwayandthefinalcommonpathway(commontobothextrinsicandintrinsiccascades)requirestissue
thromboplastin(tissuefactor),factorVII(extrinsicpathway),andfactorsX,V,prothrombin(factorII),andfibrinogen.Thefunctioningofthesepathwaysismeasuredbythe
plasmaprothrombintime(figure1).Thetestbypassestheintrinsicpathwayandusesthromboplastinstosubstituteforplatelets.Withinthiscombinedpathway,factorsVII,
X,andprothrombinarevitaminKdependentandarealteredbywarfarin.Forthisreason,thePTisusedasameasureoftheanticoagulantactivityofwarfarinandother
vitaminKantagonists.(See"Clinicaluseofcoagulationtests",sectionon'Prothrombintime(PT)'.)
ActivatedpartialthromboplastintimeTheactivatedpartialthromboplastintime(aPTT)measurestheintrinsicandcommonpathwaysofcoagulation(figure1).Itis
calledpartialsinceplateletsubstitutesareusedwhichareonlypartialthromboplastinstheyareincapableofactivatingtheextrinsicpathway,whichrequirescompletetissue
thromboplastin(tissuefactor).Intheoriginalmethod,aglasstesttubeprovidedcontactactivation.However,theadditionofactivatorssuchasellagicacidorparticulate
silicatesprovidedbetterandmorestandardizedcontactactivation.ThisactivatedversionofthePTT(aPTT)isnowtheroutineassayusedtoevaluateintrinsiccoagulation
andthedegreeofheparinanticoagulation.(See"Clinicaluseofcoagulationtests",sectionon'Activatedpartialthromboplastintime(aPTT)'.)
TheaPTTissensitivetoinhibitorssuchasheparinandtodeficienciesofallcoagulationfactorsexceptfactorsVIIandXIII.ItislesssensitivethanthePTtodeficienciesof
thecommonpathway(factorsXandV,prothrombin,andfibrinogen)[18].Highlevelsofasinglefactor(eg,factorVIII)canshortentheaPTT.However,anassociation

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betweenashortaPTTandahypercoagulablestateremainscontroversial.
ThrombintimeandreptilasetimeThethrombintime(TT)andreptilasetime(RT)measureconversionoffibrinogentofibrinmonomersandtheformationofinitialclotby
thrombinandreptilase,respectively.Reptilase,athrombinlikesnakeenzyme,differsfromthrombinbygeneratingfibrinopeptideAbutnotfibrinopeptideBfromfibrinogenand
byresistinginhibitionbyheparinviaantithrombin.Fibrinstrandcrosslinking,whichismediatedbyfactorXIII,isnotmeasuredbytheseassays.
Prolongedthrombintimesandreptilasetimesmaybeduetohypofibrinogenemia,structurallyabnormalfibrinogens(dysfibrinogens),orincreasedfibrinsplitproducts[19].
SinceheparinprolongstheTTbutnottheRT,theRTisusefulfordeterminingifheparinisthecauseofaprolongedTT.Alternatively,onecantestforheparinactivityviaits
antifactorXaactivity,orwiththeuseofacommercialheparinase.(See"Clinicaluseofcoagulationtests",sectionon'Thrombintime(TT)'and"Clinicaluseofcoagulation
tests",sectionon'Heparininthesample'and"Disordersoffibrinogen".)
FactordeficienciesandinhibitorsAprolongedaPTTcanbeduetoadeficiency(orabsence)ofacoagulationfactororthepresenceofacoagulationfactorinhibitor.A
factordeficiencyshouldbecorrectablebyadditionofnormalplasmatothetestreactiontube.ThisisnormallydonebyperformingaPToraPTTona1:1mixtureofpatient
andnormalplasma[18].(See"Clinicaluseofcoagulationtests",sectionon'Mixingstudies'.)
SpecificfactordeficienciesarethendeterminedbyassessingthePToraPTTinmixesoftestplasmawithcommerciallyavailableplasmasdeficientinknownfactors.Factor
levelscanbefunctionallyassessedbycomparingtestresultstostandardcurvesgeneratedbymixturesofseriallydilutednormalplasmaandfactordeficientplasma.
Immunologicassayscanalsobeusedtomeasurefactorlevels.Immunologicandfunctionalassaysshouldgiveequivalentresultswhenafactordeficiencyispresent.On
theotherhand,alowfunctionalassaybutnormalimmunologicassayindicatesthepresenceofafunctionallyabnormalfactor.
Thepresenceofafactorinhibitorissuspectedwhentheabnormaltestdoesnotcorrect,oronlypartiallycorrects,followinganimmediateassayofa1:1mixtureofpatient
andnormalplasma.Insomecases,suchasacquiredfactorVIIIantibodies,theaPTTmaycorrectimmediatelyaftermixing,butbecomesprolongedafter60to120minutes
ofincubationat37.(See"Clinicaluseofcoagulationtests",sectionon'Mixingstudies'.)
Inadditiontofactorinhibitors,lupusanticoagulantscanresultinaprolongedaPTTthatisnotcorrectablebytheadditionofnormalplasma.Theeffectoftheseantibodieson
theaPTTcanbeovercomebyaddingexcessplateletphospholipid(particularlyahexagonalphasephospholipid)orbyassessingthedilutedRussell'svipervenomtime[20].
Paradoxically,theantiphospholipidsyndromeisusuallyassociatedwithatendencytothrombosisratherthanbleedingtheprolongedaPTTisanartifactofthe
antiphospholipidphenomenon.(See"Clinicalmanifestationsoftheantiphospholipidsyndrome".)
FibrinogenFibrinogen'sfunctionalactivityismeasuredasthrombincoagulableprotein,whilelevelsofstructuralfibrinogenaremeasuredbyimmunologicassays.
Immunologicandfunctionalassaysoffibrinogenmaybediscordantinpatientswithaninheriteddysfibrinogenemia.(See"Disordersoffibrinogen",sectionon'Diagnosis'.)
UreaclotsolubilityTheinitialfibrinclot,heldtogetherbynoncovalentbonds,issolubleinurea.SubsequenttransglutaminationbyfactorXIIIcovalentlycrosslinks
overlappingfibrinstrands,whichthenbecomeresistanttosolubilization.Theabilityof5MureaormonochloroaceticacidtosolubilizetheclotreflectsdeficiencyoffactorXIII
(figure1).
TestsforfibrinolysisFibrinandfibrinogendegradationproducts(FDP)areproteinfragmentsresultingfromtheactionofplasminonfibrinorfibrinogen,respectively.
Elevatedlevelsareseeninstatesoffibrinolysissuchasdisseminatedintravascularcoagulation(DIC).FDPassaysdonotdifferentiatebetweenfibrindegradationproducts
andfibrinogendegradationproducts.ItispossibletoaccuratelymeasuretheconcentrationoffibrinDdimers,whicharedegradationproductsofcrosslinkedfibrin[21].The
methodofchoiceistheenzymelinkedimmunosorbentassay(ELISA).
Whenfibrinolysisexceedsthrombingeneration,therebyincreasingtheriskofhemorrhageratherthanthrombosis(eg,disseminatedintravascularcoagulationassociatedwith
acutepromyelocyticleukemia),quantitativeFDPlevelsmaybemoresensitivethanDdimerlevelsasanindicationofthedegreeoffibrinolyticactivity.(See"Hematologic
consequencesofmalignancy:Anemiaandbleeding",sectionon'Microangiopathichemolysis'.)
BecauseDdimersspecificallyreflectfibrinolysisofcrosslinkedfibrin(ie,thefibrinclot),assessmentofDdimerlevelssuggeststhrombosismorereliably.Asanexample,in
patientswhohavealowpretestprobabilityofdeepveinthrombosis,thenegativepredictivevalueofDdimersishigh[22].(See"Diagnosisofsuspecteddeepvein
thrombosisofthelowerextremity",sectionon'Ddimer'.)
Theeuglobulinlysistime,whichassessesoverallfibrinolysisislessuseful,sinceresultsfromthistestmayvarysignificantlyinrelationtocalciumionconcentrationsaswell
asplasmalevelsoftissueplasminogenactivatorandplasminogenactivatorinhibitor1[2325].Alpha2antiplasmin,aninhibitoroffibrinolysis,isnotmeasuredinthistest.
Morespecifictestsofthefibrinolyticsystemincludeassaysforplasminogen,tissueplasminogenactivator(tPA),alpha2antiplasmin,plasminogenactivatorinhibitor1(PAI
1),andthrombinactivatablefibrinolysisinhibitor(TAFI).Assaysforalpha2antiplasminareusedclinicallytoidentifypatientswithalpha2antiplasmindeficiency,aninherited
disorderassociatedwithdelayedbleeding.However,specificassaysfortPA,PAI1andTAFIareofuncertainuseclinically.(See"Thromboticandhemorrhagicdisorders
duetoabnormalfibrinolysis".)
DIAGNOSTICAPPROACHInmanypatientswithableedingdiathesis,thelikelydiagnosiswillbeapparentfromthehistoryandphysicalexaminationthediagnosiscan
thenbeconfirmedwiththeappropriatespecifictests(table2).Individualtests(eg,eitherPToraPTTalone)canalsobeusedformonitoringtheeffectofananticoagulantor
assessingpatientswithaknownconditionthathasapredictableeffectoncoagulation.
Whenthediagnosisisnotimmediatelyapparent,threeinitialtestsshouldbeperformedplateletcount,PT,andaPTTbecausedefectsinprimaryorsecondary
hemostasis,includingintrinsic,extrinsic,andcommonpathwaydefects,canallberesponsibleforbleeding(table2).Thepatternofresultsprovidesapresumptivediagnosis
whichcanthenbeconfirmedwithspecifictesting(table3andtable4).
NormalPTandaPTTThrombocytopeniawithanormalPTandaPTTisthemostcommonoftheacquiredbleedingdisorders.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
bleedingtime[15,16].(See"ClinicalpresentationanddiagnosisofvonWillebranddisease",sectionon'Bleedingtime'.)
vonWillebranddiseasevonWillebranddisease(VWD)isthemostcommoninheritedbleedingdisorder,withanestimatedprevalenceofupto1percent.Asmall
numberofpatientshavebeendescribedwithacquiredVWDduetoantibodies,usuallyassociatedwithautoimmuneorclonalproliferativedisorders.(See"Classificationand
pathophysiologyofvonWillebranddisease",sectionon'AcquiredvonWillebranddisease'.)
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".)
PlateletdysfunctionStudiestoconfirmthepresenceofqualitativedisordersofplateletfunctionincludeevaluationofplateletmorphology,andtestsofplatelet
aggregationandfunction.(See"Plateletfunctiontesting".)

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Inheriteddisordersofplateletfunctionarerelativelyrareandinclude:
BernardSouliersyndromecharacterizedbyadefectinanyofthecomponentsoftheglycoprotein(GP)Ib/IX/Vcomplex,giantplatelets,andgreaterthanexpected
bleedingforthedegreeofthrombocytopenia
GlanzmannthrombastheniacharacterizedbyadefectintheGPIIb/IIIacomplex,normalplateletcounts,normalplateletmorphology,andabnormalinvitroplatelet
aggregation.
StoragepooldiseasestheseincludeWiskottAldrichsyndrome,thrombocytopeniawithabsentradiisyndrome,ChediakHigashisyndrome,andHermanskyPudlak
syndrome.Themuchmorecommonacquiredcausesincludeuseofaspirinandnonsteroidalantiinflammatorydrugs,betalactamantibiotics,uremia,and
myeloproliferativeandmyelodysplasticsyndromes.(See"NonselectiveNSAIDs:Overviewofadverseeffects"and"Plateletdysfunctioninuremia"and"Congenitaland
acquireddisordersofplateletfunction".)
CoagulationdisordersCoagulationdisordersleadingtoableedingdiathesismaybeassociatedwithnormalscreeningcoagulationtestsifthefactorisnotinvolvedin
thestepsincoagulationmeasuredbyinvitrotests(figure1),orifthedegreeofdeficiencyismild.
Examplesincludethefollowing:
FactorXIIIdeficiencyFactorXIIIstabilizesandcrosslinksfibrinstrands.FactorXIIIdeficiencymaypresentwithdelayedbleeding,usually24to36hoursafter
surgeryortraumaspontaneousbleedingalsooccurs.CoagulationtestingshowsnormalvaluesforthePT,aPTT,andTT.Thediagnosisismadebymeasurementof
reducedplasmafactorXIIIactivityanimmunoassayforfactorXIIIordemonstrationofclotdissolutionin5molarureaormonochloroaceticacid,althoughclotsolubility
testingmaybepoorlystandardizedandsensitivitymaybelow[29].(See"Rare(recessivelyinherited)coagulationdisorders".)
AbnormalitiesofplasminogenorplasminPlasministheprimaryenzymeresponsibleforfibrinolysisitisproducedfromthecleavageofplasminogen.Rare
abnormalitiesinregulatorsofplasminogenactivationorplasmindegradationhavebeenreportedascausesoffamilialbleedingdisorders(eg,alpha2antiplasmin
deficiency,plasminogenactivatorinhibitor1deficiency).(See"Thromboticandhemorrhagicdisordersduetoabnormalfibrinolysis".)
ThrombomodulinmutationThrombomodulin(TM)isaregulatoryproteinexpressedbyendothelialcells,monocytes,andmegakaryocytes.Bindingofcellsurface
thrombomodulintothrombinconvertsthrombinfromaprocoagulanttoananticoagulant.(See"Overviewofhemostasis",sectionon'Controlmechanismsand
terminationofclotting'.)
AfamilywithanautosomaldominantbleedingdisorderwasfoundtohaveaTMgenemutationthatcreatedaprematurestopcodonandeliminatedtheportionoftheprotein
responsibleforitscellularretention[30].ThisinturncausedextremelyhighlevelsofTMinplasma(100foldgreaterthannormal),whichwasassociatedwithsevere
bleeding.
MildhemophiliaFactoractivitylevelsaboveapproximately15to20percentareoftensufficienttopreventspontaneousbleedingandtoproduceanormalPTand
aPTT,althoughthisvariesbyspecificfactorlevel(table5).However,patientswithmilddeficiencyofacoagulationfactormayhaveincreasedbleedingwithhemostatic
challenges(eg,excessivesurgicalbleeding,menorrhagia).Thismaybeseeninanindividualwhoisheterozygousforacoagulationfactordefect,suchasahemophilia
carrier.(See"Clinicalmanifestationsanddiagnosisofhemophilia",sectionon'Bleedinginfemales/carriers'.)
VascularpurpurasWiththepossibleexceptionofaprolongedbleedingtime,screeningtestsareusuallynormalinpatientswithbleedingdisordersrelatedtovascular
abnormalities(table4).Theseincludestructuralabnormalities(eg,hereditaryhemorrhagictelangiectasia),hereditarydisordersofconnectivetissue(eg,EhlersDanlos
disease,osteogenesisimperfecta),acquiredconnectivetissuedisorders(eg,scurvy,steroidinducedpurpura),smallvesselvasculitis,andpurpuraassociatedwiththe
presenceofparaproteins.(See"Classificationofandapproachtothevasculitidesinadults",sectionon'Smallvesselvasculitis'.)
UnknowncauseSomepatientsareencounteredwithasignificantbleedinghistoryforwhichthereisnoexplanation.Abuse,occasionallyselfinflicted,shouldbe
considered,butitislikelythatsomedisordersofhemostasisescapedetectionwithcurrentlyavailablemethods.Psychogenicpurpuramaybeamongthesedisorders.(See
"Psychogenicpurpura(GardnerDiamondsyndrome)".)
NormalPTandprolongedaPTT
FactordeficienciesAnormalPTandaprolongedaPTTischaracteristicofdisordersoftheintrinsicpathwayofcoagulation(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].
AcquiredinhibitorsAcquiredinhibitorsincludeantiphospholipidantibodieswhich,asnotedabove,maybeassociatedwiththrombosisratherthanbleeding,and
antibodiestofactorVIII(acquiredhemophilia),IX,andXI,whichmaybeassociatedwithcatastrophicbleeding(table3).FactorVIIIinhibitorshavebeendescribedin
associationwithmalignancy,clonallymphoproliferativedisorders,pregnancy,rheumatologicdisorders,aswellasintheabsenceofunderlyingdisease.Acquiredantibodies
tofactorIXandXIarerare.(See"Acquiredinhibitorsofcoagulation".)AcquiredinhibitorsoffactorVmayhavevariableeffectsonthePT,aPTT,andBT(seebelow).
ProlongedPTandnormalaPTTAprolongedPTwithanormalaPTTisindicativeofanabnormalityintheextrinsicpathwayandsuggestsfactorVIIdeficiency,which
canbeinheritedoracquired(table3).
Thispatternismostcommonlyseenfollowingwarfarintherapy,earlyliverdisease,andvitaminKdeficiency,and,lesscommonly,incertain(early)casesofDIC.(See
"TherapeuticuseofwarfarinandothervitaminKantagonists"and"Clinicalfeatures,diagnosis,andtreatmentofdisseminatedintravascularcoagulationinadults"and
"Coagulationabnormalitiesinpatientswithliverdisease",sectionon'Prothrombintime(PT)andtheInternationalNormalizedRatio(INR)'.)
InheritedfactorVIIdeficiencydisplaysconsiderablephenotypicandmolecularheterogeneity,andthereareinconsistenciesbetweentheclinicalpicture,theunderlyingclotting
andmoleculardefects,andtheresponsetoprophylactictreatmentwithrecombinanthumanfactorVIIa[3539].Themanifestationsrangefromnoexcessivebleedingtoa
severehemorrhagictendency[40,41].(See"Rare(recessivelyinherited)coagulationdisorders".)
AcquiredinhibitorsoffactorVIIarerare.(See"Acquiredinhibitorsofcoagulation",sectionon'FactorVIIinhibitors'.)
ProlongedPTandaPTTProlongationofboththePTandtheaPTTindicatesaninheriteddisorderofthecommonpathwayoramorecomplexacquireddisorderinvolving
multiplepathways(table3).
InheriteddisordersincludedeficiencyoffactorX,factorV,prothrombin(factorII),orfibrinogen(factor1).Thesedeficienciesareextremelyrare.(See"Rare(recessively
inherited)coagulationdisorders".)
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
ofvitaminKstatusandthisfactorisnotmanufacturedbyhepatocytesfactorVIIIlevelsareusuallynormalorincreasedinliverdisease.Thus,lowlevelsoffactorVIII
wouldfavoradiagnosisofDICinthissetting.(See"Coagulationabnormalitiesinpatientswithliverdisease",sectionon'Testsofcoagulationinliverdisease'.)
AcquiredinhibitorsoffactorVhavebeendescribed,attimesinassociationwithtopicalbovinethrombintherapy.Acquiredantibodiestobovinethrombinand/orfactorV
contaminatingbovinethrombinpreparationsmaycrossreactwithendogenoushumanfactorVaswellaswithhumanthrombin.EffectsoftheseantibodiesonPT,
aPTT,andTTtestingcanvary,andassociatedrisksofbleeding,whichcanbesevere,areunpredictable.(See"Acquiredinhibitorsofcoagulation",sectionon'FactorV
inhibitors'.)
ThefirststepintheevaluationofpatientswithaprolongedPTandaPTTshouldbetoexcludeoridentifyanabnormalityoffibrinogen.Thiscanbeachievedbymeasurement
oftheplasmafibrinogenconcentrationandthethrombintime,andtestingforincreasedamountsofDdimerorfibrin/fibrinogendegradationproducts(FDP).Inpatientswithan
inheritedcoagulationdisorderandnormalamountsoffibrinogen,deficienciesoffactorV,factorX,andprothrombincanbediagnosedbyspecificfactorassays.Inpatients
withanacquireddisorder,thelikelydiagnosis,intheabsenceofheparin,warfarin,andfibrinogenabnormalities,isvitaminKdeficiencyorliverdisease.
AcquiredinhibitorstoprothrombinandfactorXareextremelyrare.AcquiredfactorXdeficiencymaybeseeninpatientswithprimaryamyloidosis,andresultsfromthe
bindingoffactorXtoamyloidfibrils.(See"Pathogenesisofimmunoglobulinlightchain(AL)amyloidosisandlightandheavychaindepositiondiseases".)
SUMMARYANDRECOMMENDATIONS
Bleedingthatisspontaneous,excessive,ordelayedinonsetfollowingtissueinjuryresultsfromoneormoreofthefollowing:
Alocalizedpathologicprocess
Disordersinvolvingvascularintegrity
Disordersofplateletnumberand/orfunction
Disordersofthevariouscoagulationfactors
Increasedfibrinolysis
Acarefulassessmentofthepresentingcomplaintandthepatient'sbleedinghistorycanprovideimportantcluesastowhereadefectmightresideinthehemostatic
processandwhetherthedefectisinheritedoracquired(table1).(See'Patienthistory'aboveand"Preoperativeassessmentofhemostasis",sectionon'Theclassic
approach'and"Approachtotheadultwithunexplainedthrombocytopenia",sectionon'Overviewofourapproach'.)
Thephysicalexaminationishelpfulindeterminingthetypeofbleedingpresent,aswellasfordetectingotherconditionsthatmightbepresent.(See'Clinical
manifestations'aboveand"Preoperativeassessmentofhemostasis",sectionon'Thephysicalexamination'and"Approachtotheadultwithunexplained
thrombocytopenia",sectionon'Physicalexamination'.)
Inmanypatientsthelikelydiagnosiswillbeapparentfromthehistoryandphysicalexaminationalonethediagnosiscanthenbeconfirmedwiththeappropriatespecific
tests.
Whenthediagnosisisnotimmediatelyapparent,threeinitialtestsshouldbeperformed:plateletcount,prothrombintime(PT),andactivatedpartialthromboplastintime
(aPTT)(table2).(See'Laboratorytesting'aboveand"Clinicaluseofcoagulationtests".)
Thepatternofresultsprovidesapresumptivediagnosiswhichcanthenbeconfirmedwithspecifictesting(table3andtable4).(See'Diagnosticapproach'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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