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