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2012* Clinical Practice Guideline on the Evaluation and Management of
von Willebrand Disease (VWD)
Presented by the
American Society of Hematology,adapted from: The Diagnosis, Evaluation, and Management of von Willebrand Disease. National Heart, Lung, and Blood Institute, NIH Pub. No. 08-5832. December, 2007.
*This quick reference guide was revised in 2012.
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I. Evaluation
A. History Ask the following broad questions: • Haveyouorabloodrelativeeverneededmedicalattentionforableeding
problemorbeentoldyouhadableedingproblem? • Haveyoueverhadablooddisorder,orliverorkidneydisease? • Areyoucurrentlytakingorhaveyourecentlytakenanticoagulationor
antiplateletmedications?
If answers to questions above are positive, ask the following questions:
• Doyouhaveabloodrelativewithableedingdisorder? • Haveyoueverhadanyofthefollowingsymptoms? – Bleedingfromtrivialwoundslasting>15minutesorrecurring
spontaneouslyduringthe7daysaftertheinjury – Heavy,prolonged,orrecurrentbleedingaftersurgicalprocedures – Bruisingwithminimalornoapparenttrauma,especiallyifyoucould
feelalumpunderthebruise – Spontaneousnosebleedlasting>10minutesorthatrequiredmedical
attention – Heavy,prolonged,orrecurrentbleedingafterdentalextractionsthat
requiredmedicalattention – Bloodinyourstoolthatrequiredmedicalattentionandwas
unexplainedbyananatomiclesion(stomachulcer,colonpolyp) – Anemiathatrequiredabloodtransfusionorothertypeoftreatment – Heavymensescharacterizedbyclots>1inchdiameter,changinga
padortamponmorethanhourly,orresultinginanemiaorlowiron • Refertothebleedingscoretable(panel2)tohelpdeterminethe
likelihoodofableedingdisorderincludingpossibleVWD.
B. Physical Examination Perform a physical examination to include evaluation for: • Evidenceofbleedingoranemia,includingsize,location,anddistribution
ofecchymoses,hematomas,andpetechiae. • Evidenceofrisksofincreasedbleedingsuchasjaundiceorspider
angiomata,splenomegaly,arthropathy,jointandskinlaxity,andtelangiectasia.
C. Special Considerations for the Laboratory Diagnosis of VWD
• Patientsshouldbeatoptimalbaselineatthetimeoftesting.Unduestress(illness,strugglingorcryinginchildren,anxietyinadults)maytransientlyelevateVWFandFVIIIlevels.
• Veryrecentexercise,acuteinflammationduetosurgeriesorinfection,chronicinflammationsuchasfromautoimmunediseasesordiabetes,pregnancy,andestrogencontainingcontraceptives,mayalsoelevateVWFlevels.
• Atraumaticblooddrawslimittheexposureoftissuefactorfromthesiteandclottingfactoractivation,thusminimizingfalselyhighorlowlevels.
• Carefulhandlingandprocessingofsamplesiscritical.Samplesmustbepromptlyandthoroughlycentrifuged.Samplesthatwillbetransportedtoareferencelaboratorymustbefrozenanddeliveredpromptlyandremainfrozenuntilassayed.
D. Bleeding Score1
Thebleedingscoreisdeterminedbyscoringtheworstepisodeforeachsymptom(eachrow)andthensummingalloftherowstogether.“Consultationonly”referstoapatientconsultingamedicalprofessional(doctor,nurse,dentist)becauseofasymptombutnotreatmentbeinggiven.ForVWD,ableedingscore≥4hasasensitivity=100%,specificity=87%,positivepredictivevalue=0.20,negativepredictivevalue=1.00.Thehigherthebleedingscore,thegreateristhelikelihoodofableedingdisorderincludingpossibleVWD.Formoreinformation,pleasevisit www.path.queensu.ca/labs/james/bq.htm.
-1 0 1 2 3 4Epistaxis - No or trivial
(< 5/year)> 5/year or > 10 mins
Consultation only
Packing or cauterization or antifibrinolytic
Blood transfusion or replacement therapy or desmopressin
Cutaneous - No or trivial(< 1 cm)
>1 cm and no trauma
Consultation only
- -
Bleeding from minor wounds
- No or trivial(< 5/year)
> 5/year or > 5 mins
Consultation only
Surgical hemostasis Blood transfusion or replacement therapy or desmopressin
Oral cavity - No Reported, no consultation
Consultation only
Surgical hemostasis or antifibrinolytic
Blood transfusion or replacement therapy or desmopressin
Gastro-intestinal bleeding
- No Assoc. with ulcer, portal hypertension, hemorrhoids, angiodysplasia
Spontaneous Surgical hemostasis, blood transfusion, replacement ther-apy, desmopressin, antifibrinolytic
-
Tooth extraction
No bleed-ing in ≥ 2 extrac-tions
None done or no bleed-ing in 1 extraction
Reported, no consultation
Consultation only
Resuturing or packing
Blood transfusion or replacement therapy or desmopressin
Surgery No bleed-ing in ≥ 2 surgeries
None done or no bleed-ing in 1 surgery
Reported, no consultation
Consultation only
Surgical hemostasis and antifibrinolytic
Blood transfusion or replacement therapy or desmopressin
Menor-rhagia
- No Consultation only
Antifibrinolytics, oral contracep-tive pill use
Dilation & curet-tage, iron therapy, ablation
Blood transfusion or replacement therapy or desmopressin or hysterectomy
Post-partum hemor-rhage
No bleed-ing in ≥ 2 deliveries
No deliver-ies or no bleeding in 1 delivery
Consultation only
Dilation & curettage, iron therapy, antifi-brinolytics
Blood transfusion or replacement therapy or desmo-pressin
Hysterectomy
Muscle hemoto-mas
- Never Post-trauma, no therapy
Spontaneous, no therapy
Spontaneous or traumatic, requir-ing desmopressin or replacement therapy
Spontaneous or traumatic, requiring surgical intervention or blood transfusion
Hemar-throsis
- Never Post-trauma, no therapy
Spontaneous, no therapy
Spontaneous or traumatic, requir-ing desmopressin or replacement therapy
Spontaneous or traumatic, requiring surgical intervention or blood transfusion
CNS bleeding
- Never - - Subdural, any intervention
Intracerebral, any intervention
Atthetimeofthisreport,thereareseveralbleedingassessmenttoolsinvariousstagesofinvestigationandvalidation.2ThisquickreferenceincludestheCondensedMCMDM-1VWDBleedingQuestionnaire,asthistoolhasbeenwellvalidatedasaresearchtool,isundergoinginvestigationasaclinicaltool,andcanberapidlyadministered.1
1BowmanM,MundellG,GrabellJ,HopmanW,RapsonD,LillicrapD,JamesP.GenerationandValidationoftheCondensedMCMDM1-VWDBleedingQuestionnaire.JThrombHaemost2008;6:2062-6,fromwww.ncbi.nlm.nih.gov/pubmed/18983516.
2RydzNandJamesPD.TheEvolutionandValueofBleedingAssessmentTools.JThrombHaemost2012Sept13[Epubaheadofprint]PMID:22974079,fromwww.ncbi.nlm.nih.gov/pubmed/22974079.
II. Assessment Algorithm Assessment for VWD or Other Bleeding Disorders
Positive Initial Screen by History & Physical Exam
Initial Hemostasis Tests
If bleeding history is strong, consider performing initial VWD assays
OtherAppropriateEvaluation
Initial VWD Assays
Other cause identified, e.g.,extremely low platelets,isolated abnormal PT,
low fibrinogen,abnormal TT
Isolated prolonged PTT thatcorrects on 1:1 mixing study,
or no abnormalities
Consider testing such as:• Factor IX, Factor XI (if PTT prolonged)• Platelet function testing• Factor XIII testing• Evaluation for Ehlers Danlos syndrome
Selected specialized VWD studies such as:• Repeat initial VWD assays if necessary• Ratio of VWF:RCo to VWF:Ag• Multimer distribution• Collagen binding• RIPA or platelet binding• FVIII binding• Platelet VWF studies• DNA sequencing of VWF gene
Abnormal Normal
• CBC and platelet count• PT and PTT• Fibrinogen or TT (optional)
• VWF:Ag• VWF:RCo• FVIII
CBC=completebloodcount,FVIII=factorVIIIactivity,PT=prothrombintime,PTT=partialthromboplastintime,TT=thrombintime,VWF:Ag=VWFantigen,VWF:RCo=VWFristocetincofactoractivity
III. Laboratory DiagnosisLaboratory Values for VWD*
Condition DescriptionVWF:RCo (lU/dL)
VWF:Ag (lU/dL)
FVIIIVWF:RCo/ VWF:Ag Ratio
Type 1 Partial quantitative VWF deficiency
<30** <30** Low or Normal >0.5-0.7
Type 2A Decreased VWF-dependent platelet adhesion with selective deficiency of high-molecular-weight multimers
<30** <30-200**
Low or Normal <0.5-0.7
Type 2B Increased affinity for platelet GPlb; decreased platelets
<30** <30-200**
Low or Normal Usually <0.5-0.7
Type 2M Decreased VWF-dependent platelet adhesion without selective deficiency of high-molecular-weight multimers
<30** <30-200**
Low or Normal <0.5-0.7
Type 2N Markedly decreased binding affinity for FVIII
30-200 30-200 Very Low >0.5-0.7
Type 3 Virtually complete deficiency of VWF
<3 <3 Extremely Low (<10 IU/dL)
Not applicable
“Low VWF”**
30-50 30-50 Normal >0.5-0.7
Normal 50-200 50-200 Normal >0.5-0.7
*Thesevaluesrepresentprototypicalcases.Exceptionsoccur,andrepeattestingmaybenecessary.
**<30IU/dLisdesignatedasthelevelforadefinitivediagnosisofVWD;somepatientswithtype1ortype2VWDhavelevelsofVWF:RCoand/orVWF:Agof30-50IU/dL.
NOTE:30IU/dLisrecommendedasthe“cut-off”forthedefinitediagnosisofVWDforthefollowingreasons:1)highfrequencyofbloodtypeOintheUnitedStates,whichisassociatedwith“low”VWFlevels;2)bleedingsymptomsarereportedbyasignificantproportionofnormalindividuals;3)noabnormalityintheVWFgenehasbeenidentifiedinmanyindividualswhohavemildlytomoderatelylowVWF:RColevels.ThisdoesnotprecludetheuseofagentstoincreaseVWFlevelsinthosewhohaveVWF:RCoof30-50IU/dLandwhomaybeatriskforbleeding.
IV. Selected Recommendations for the Management of VWD
A. Therapies to Elevate VWF: Desmopressin (DDAVP) • AdministrationofDDAVPmaybeIV(0.3mcg/kg)orintranasal
(Stimate®/Octostim®150mcgor1sprayforpersons<50kgand300mcgor2spraysforpersonsweighing≥50kg).
• AtherapeutictrialofDDAVPisrecommendedpriortouse.VWF:RCoandFVIIIactivitiesshouldbemeasuredatbaselineandwithin1hour.Additionaltesting2-4hoursafterDDAVPshouldbeconsideredtoevaluateforshortenedsurvival.
• Mosttype1VWDpatientswillrespondtoDDAVP,althoughpatientswithVWF:RCo<10IU/dLandFVIIIactivity<20IU/dLarelesslikelytohaveaclinicallysignificantresponse.
• Intype2VWD,DDAVPwillincreasetheVWFconcentration,buttheVWFdysfunctionwillstillbepresent.Intype2BVWD,DDAVPmayresultintransientthrombocytopenia.Therefore,DDAVPshouldbeusedwithcautionintype2VWD.
• Sideeffectsincludefacialflushing,transienthyper-orhypotension,headache,abdominalupset,andwaterretention.Patientsshouldlimitfluidintaketomaintenancelevelsfor24hoursfollowingDDAVP.SerumelectrolytesshouldbemonitoredaftersurgeryormultipledosesofDDAVP.
• ConsideralternativetherapiestoDDAVPinyoungchildrenandpatientsatincreasedriskofhyponatremiaandseizures.
• Toavoidtachyphylaxis,DDAVPtherapyistypicallydiscontinuedafter2or3dailydoses.
B. Therapies to Elevate VWF: Factor Products Von Willebrand Factor Replacement Products
(available in United States)
Product VWF:RCo activity (IU/ml)1
FVIII activity (IU/ml)1
Ratio of VWF:RCo to FVIII activity
Humate-P®2 120 50 2.4:1
Wilate®2 90 90 1:1
Product VWF:RCo activity (IU/ml)1
FVIII activity (IU/ml)1
Ratio of VWF:RCo to FVIII activity
Koate DVI® 50 50 1:1
Alphanate SD/HT®2 16-72 40-180 1:21Potencymayvary.Refertoeachindividualcartonorvialpriortoreconstitution.2FDA-approvedforthetreatmentofvonWillebranddisease
C. General Management of VWD Patients • Long-termprophylaxisisrarelyrequired,butshouldbeconsidered
forrecurrentjointbleedingorexcessivemucocutaneousbleedingnotadequatelycontrolledbyothertreatments.
• Avoidaspirin,otherNSAIDs,andotherplatelet-inhibitingdrugs.
D. Notes on Treatment of Minor Bleeding and Prophylaxis for Minor Surgery
• MinorbleedingshouldbetreatedwithintravenousornasalDDAVP,ifsupportedbyresultsofaDDAVPtrial.
• IfresponsetoDDAVPisinadequate,VWFconcentrateshouldbeused,withdosingprimarilybasedonVWF:RCounitsandsecondarilyonFVIIIunits.
• Forminorsurgery,prophylaxisshouldachieveVWF:RCoandFVIIIactivitylevels≥30IU/dL,andpreferably>50IU/dL,for1-5days.
• ManagementofminorbleedingwithDDAVPandproperfluidrestrictioncanbeperformedwithoutelectrolytemonitoringunlessDDAVPisused>3timesin72hours.
• FormildtomoderateVWD,antifibrinolyticscombinedwithDDAVParegenerallyeffectivefororalsurgery.
E. Notes on Treatment of Major Bleeding and Prophylaxis for Major Surgery
• AlltreatmentplansshouldbebasedonobjectivelaboratorydeterminationsofresponseofVWF:RCoandFVIIIactivitylevelstoDDAVPorVWFconcentrate.
• Forseverebleeding(e.g.intracranial,retroperitoneal)orprophylaxisofmajorsurgery,initialtargetVWF:RCoandFactorVIIIactivitylevelsshouldbe>100IU/dL,andlevels>50IU/dLshouldbemaintainedforatleast7-10days.
• InallpatientsreceivingVWFconcentrate,cliniciansshouldperformproperthrombotic-riskassessmentandinstituteappropriatestrategiestopreventthrombosis.
• Todecreaseriskofperioperativethrombosis,VWF:RColevelsshouldnotexceed200IU/dL,andFVIIIactivityshouldnotexceed250IU/dL.
F. Women’s Health and von Willebrand Disease • Hormonalcontraceptivesarethefirst-linetherapyformenorrhagiainthe
adolescentoradultwomanwhodoesnotdesirepregnancy. • Duringchildbirth,womenshouldachieveVWF:RCoandFVIIIlevelsofat
least50IU/dLbeforedelivery,andthoselevelsshouldbemaintainedfor3-5days,withsubsequentsurveillancefordelayedpost-partumbleeding.
G. Acquired von Willebrand Syndrome (AVWS) • DefectsinVWFconcentration,structure,orfunctionthatarenotinherited
directlybutareconsequencesofothermedicaldisorders. • Associatedwithmonoclonalgammopathy,aorticstenosis,
thrombocytosis,myelo-orlymphoproliferativedisorders,hypothyroidism,congenitalheartdisease,andsolidtumors.
• AVWSpatientsundergoingsurgerymaymeritpharmacokinetictrialofDDAVPand/orVWFconcentratetoevaluatepossibleacceleratedclearanceofVWF.
About this Clinical Quick Reference GuideThisquickreferenceguideoriginallysummarizedselectedrecommendationsfromNicholsWL,HultinMB,JamesAH,Manco-JohnsonMJ,MontgomeryRR,OrtelTL,RickME,SadlerJE,WeinsteinM,andYawnBP,The Diagnosis, Evaluation, and Management of von Willebrand Disease.NationalHeart,Lung,andBloodInstitute,NIHPub.No.08-5832.December,2007.However,tobringthisguideup-to-date,anASHworkinggroupledbySarahO’Brien,MD,modifiedseveralareasincooperationwiththeNHLBIexpertpanel.MembersoftheASHworkinggroupincludedCukerA,JamesP,DiPaolaJ,FloodV,KuoK,andKentsisA.
Guidelinesprovidethepractitionerwithclearprinciplesandstrategiesforqualitypatientcareanddonotestablishafixedsetofrulesthatpreemptphysicianjudgment.
Forfurtherinformation,pleaseseethecompleteguidelinesontheNHLBIwebsiteatwww.nhlbi.nih.gov/guidelines/vwdorrefertothePracticeGuidelinessectionoftheASHwebsiteat www.hematology.org/policy/resources/guidelines.YoumayalsocontacttheASHDepartmentofGovernmentRelations,Practice,andScientificAffairsat202-776-0544.
AmericanSocietyofHematology,2021LStreet,NW,Suite900, Washington,DC20036
Freecopiesofthisquickreferenceguideareavailablefordownloadatwww.hematology.org/practice.
AmericanSocietyofHematology2021LStreetNW,Suite900Washington,DC20036www.hematology.org
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