medical issues 01-acquired hemophilia

186 Pages·2014·2.34 MB·English

MEDICAL ISSUES
01-ACQUIRED HEMOPHILIA
Measurementofanti-porcineFVIIIantibodytiters TheeconomicandclinicalburdenofacquiredhemophiliaA(AHA)
HERBERTGRITSCH,1PETERWOJCIECHOWSKI,2CHEE VINCENTW.LIN,1AARONNOVACK,1 DEBORAH TESTA2 and
KONGLAI,2 CLAUDIAAPOSTOL1andPETERL.TURECEK1 JOSHUA EPSTEIN1
1BaxterInnovationsGmbH,Vienna,Austria;and2BaxterBioScience,Milford, 1BaxterHealthcare,WestlakeVillage,CA,USA;and2IndependentConsultant,
Massachusetts,USA WestlakeVillage,CA,USA
Introduction and Objectives: OBI-1 (Baxter Healthcare) is a recombinant FVIII Introduction: Acquired hemophilia A (AHA) is a severe autoimmune disease
concentrate with porcine factor VIII sequence, which typically possesses lowcross- characterizedbythespontaneousdevelopmentofautoantibodiesagainstcoagulation
reactivity to anti-human factor VIII (FVIII) antibodies. This would make it a factorVIII(FVIII).Duetotherarityofthedisease(approximately1.5casesmillion
treatmentoptionforpatientswithhemophiliaAandinhibitorstoFVIIIorpatients peryear),theburdenofAHAhasnotbeenextensivelydescribed.Thegoalofthis
withacquiredhemophilia.ForeffectivetreatmentwithOBI-1thelevelofanti-porcine studyistodeterminetheeconomicandclinicalburdenofAHApatientstreatedin
FVIII antibodies is relevant. Therefore in a field study, the accuracy and between U.S.hospitals.
laboratory precision of anti-human FVIII and anti-OBI-1 antibody assays was Methods:AretrospectivecohortstudyusingthePremierPerspectivedatabasefrom
investigated. January 2011 to March 2013 was conducted. This repository of hospital
Materials and Methods: Samples with known anti-porcine FVIII antibody titers administrativedataincludesapproximatelyone-sixthofallhospitalizationsintheU.S.
(approximately 3 BU/mL and 19 BU/mL respectively) and a negative control were HospitaladmissionsforAHAwereidentifiedintwoways.Thefirstwasaninpatient
providedtothe15participatinglaboratories.Antibodieswereknowntohavecross- admissionwithICD-9code 286.82 (AHA), withany recordof a hemostaticagent
reactivitywithhumanFVIII.ThelabsusedtheirownBethesdamethodstoanalyze (rFVIIa, aPCC, FVIII, or DDAVP) or an immunosuppressant (rituximab,
theanti-humanFVIIIantibodytiters.Anti-porcinetiterswereanalyzedwiththesame cyclophosphamide,steroid).TocapturecaseswithnonAHAspecificcoding,wealso
methodsexceptthatnormalhumanplasmawasreplacedbyOBI-1pre-dilutedwith identifiedinpatientadmissionwithICD-9code286.0(hemophiliaA),withanyrecord
human FVIII-deficient plasma (“normal porcine plasma”). FVIII activities were of an immunosuppressant (rituximab or cyclophosphamide. Steroid use was not
measuredwithaone-stageclottingassay. includedduetoitswideuse).Totalinpatientcosts,hospitallengthofstay,thrombotic
Results: Fourteen sites returned acceptable results for anti-porcine FVIII antibody events,andmortalityduringtheinpatientvisitwereassessed.
titers,sevensitesreportedacceptableanti-humanFVIIIdata.Onaveragetheantibody Results:Atotalof72inpatientadmissionswereidentified.Themeanageofadmitted
titersfoundinthelocallaboratorieswereinthesamerangeasfoundinthecentral patientswas64(SD=23.4).Thirty(41.6%)admissionsweremalepatients.Thetotal
laboratory,intra-laboratorycoefficientofvariation(CV)rangedfrom30%to57% cost for all 72 inpatient admissions was $9,543,384. Cost per inpatient admission
for samples with inhibitors. The negative control was found negative in all variedwidely($22,880to$1,392,785).Thecostofhemostaticagentswasthelargest
laboratories. contributortototalinpatientcost(75.8%)forthese72inpatientadmissions.Patients
Conclusion:Theresultsindicatethatthedegreeofvariabilityinresultsobtainedfrom treated with rFVIIa during an inpatient admission incurred the highest hemostatic
assaysforporcineinhibitorsissimilartothatseenwithassaysforhumaninhibitors. agent cost (mean=$213,781, SD=$286,221, median=$96,865, min=$4,038, max=
Differencesinassaymethodandstandardsusedmayaffectsensitivity,accuracy,and $946,492).Themeanlengthofstayinahospitalwas11.1days(SD=10,median9,
variabilityofresults. min=1,max=45).Five(6.9%)deathsoccurredduringinpatientadmissionafterAHA
treatment. Thrombotic events occurred during three (4.2%) admissions (one
cerebrovascularaccident,onemyocardialinfarction,andonedeepveinthrombosis).
Conclusion:TheeconomicburdenoftreatingbleedingepisodesforpatientswithAHA
RecombinantporcinesequencefactorVIII(OBI-1):Resultsfroma usingcurrent therapiesishigh.Furthermore,AHApatientsface significantrisks of
prospectiveclinicalstudyinvestigatingthetreatmentofseriousbleedsin thrombotic events and mortality. With an aging population, these burdens are
patientswithacquiredhemophiliaA expectedtoincreaseinthefuture.
KRUSE-JARRESR,1ST-LOUIS J,2GREISTA,3SHAPIROA,3
SMITHH,4CHOWDARY P,5 DREBESA,5GOMPERTS E,6
CHAPMANM,6 MO,M,6NOVACKA6 andFARINH6
1LouisianaCenterforBleedingandClottingDisorders,NewOrleans,LA,US; ThromboticandemboliceventsassociatedwiththeuseofFEIBAin
2DivisionofHematology,Ho^pitalMaisonneuve-Rosemont,UniversityofMontreal, AcquiredHaemophilia:Acumulativereview
Montreal,QC,Canada;USA;3HemophiliaandThrombosisCenter,Indianapolis,IN, ROGERBERG,1 ALESSANDROGRINGERI,2
USA;4DivisionofHematology/Oncology,TuftsNewEnglandMedicalCenter, ELISABETHFU€LLENHALS1andARMINJ.REININGER2
Boston,MA,USA;5RoyalFreeHospital,London,UK;and6BaxterHealthcare,USA 1GlobalPharmacovigilance,BaxterInnovationsGmbH,Vienna,Austria;and2Global
MedicalAffairsHaemophilia,BaxterInnovationsGmbH,Vienna,Austria
Introduction and Objectives: Acquired hemophilia A (AHA) is a rare bleeding
disorder, resulting from auto-antibodies to human factor VIII (hFVIII). Currently Introduction and Objectives: The management of bleeding episodes in acquired
approvedtherapieslacklaboratorymethodsthatallowforobjectivemeasurementsof hemophilia often requires the use of bypassing agents such as rFVIIa or activated
efficacy and safety, which complicates the treatment of bleeding in this typically prothrombincomplexconcentrate(FEIBA-FVIIIinhibitorbypassingactivity;Baxter,
elderly population with significant co-morbidities. A recombinant, highly pure, B- Deerfield,ILUSA).Treatment-associatedthromboticandembolicevents(TEEs)have
domaindeleted,porcinesequenceFVIII(OBI-1)thatisnotgenerallysusceptibletothe beennotedforbothagentswithasimilarincidenceinarecentlypublishedregistry
inhibitoryactivityofanti-humanFVIIIantibodiesaffordsaphysiciantheopportunity (EACH2).Thesmallsizeofobservationalstudiesinacquiredhemophilialimitsthe
tomonitorFVIIIactivitylevels,thusprovidingareproducibleandobjectivesurrogate capability to ascertain risk factors for FEIBA-associated TEEs. The present review
predictorofhemostasis.Intheeventofableedingepisode,thisadditionalmonitoring providesacomprehensiveoverviewofallTEEsassociatedwiththeuseofFEIBAin
capabilityofFVIIIactivitylevelscanbeofbenefit. acquiredhaemophiliadocumentedinBaxter’sglobalsafetydatabase.
MaterialsandMethods:ThisfirstprospectivestudyinAHAisaglobal,prospective, MaterialsandMethods:TheglobalsafetydatabasewasreviewedforallAEreportsof
multi-centrephase2/3openlabelclinicaltrialinvestigatingtheefficacyandsafetyof FEIBA received from 1975 through July 2013, addressing patient demographics,
OBI-1inthetreatmentofseriousbleedsinadultswithAHA.Theprimaryefficacy dosingregimens,andrisk factorsdeemed relevantfor thedevelopmentof TEEsin
endpointwas‘hemostasis’assessedat24hoursaftertheinitialinfusion.Secondary associationwithFEIBAtreatment.
efficacy outcomes were described including FVIII activity levels and by ultimate Results:Overall24TEEwerereportedforpatientswithacquiredhemophilia(thereof
successful OBI-1 treatment. Safety was assessed by adverse events and analyses of 20spontaneousreports),aged53–88years(mean74,median77).Ofthese24reports
immunogenicityprofiles. including one or more TEEs, 3 were reported as deep vein thrombosis and/or
Results:Subjectswhohavecompletedthestudytodate(N=28)presentedwitha pulmonaryembolism (DVT/PE;age 57–86, mean 70, median66),5 asmyocardial
seriousbleed,wereallhospitalizedandweretreatedwithaninitialdoseofOBI-1 infarctionorstroke(MI;age65–76,mean70,median70)and13asdisseminated
(200U/kg),followedbyadditionaldosesbasedonthesubject’sobservedfactorVIII intravascularcoagulation(DIC;age56–88,mean77,median80).Fiveof24reports
activitylevelandclinicalassessments.Inall28subjects,apositivetreatmentresponse includedrFVIIaasconcomitantmedication(2DVT/PE,1MI,2DIC).
defined as effective/partially effective, not effective was observed at 24hours after Conclusion:ThelowandstablereportingrateofTEEsinacquiredhaemophiliaover
initialOBI-1treatment.Apositiveresponseat24hourswasassociatedwitheventual almost40yearsofuseconfirmsthelong-timesafetyprofileofFEIBA.Moreover,the
successful treatment of bleeding episodes. No related serious adverse reactions majorityofTEEsoccurredinthepresenceofadditionalriskfactorssuchasageor
occurred during the study. Some subjects demonstrated a positive anti-porcine comorbidities.ThereviewofclinicaldetailsofallTEEsreportedinassociationwith
inhibitor titer at some point after first being infused with this agent without a theuseofFEIBAisavaluableresourceforunderstandingandperhapspreventingin
demonstrableeffectonefficacy. TEEsinpatientsathighrisk.
Conclusion: Data from this prospective study demonstrate OBI-1 as a safe and
effective treatment of bleeding episodes in patients with AHA, with the added
advantageoverothertherapiesbyallowingFVIIIactivitytobemonitoredthroughout
thetreatmentandhealing/recoveryphase. PharmacokineticsofOBI-1,arecombinantporcinesequenceFVIII
product,inmacaquesandhemophilicdogs
WERNERHOELLRIEGL,ALEXANDRASCHIVIZ,
CHRISTINAPISKERNIK, PETERLEIDENMUEHLER and
EVA-MARIA MUCHITSCH
BaxterInnovationsGmbH,Vienna,Austria
Introduction and Objectives: Acquired hemophilia A is a rare bleeding disorder in
which subjects without a history of hemophilia develop autoantibodies against
©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd 1
2 ACQUIRED HEMOPHILIA
endogenous FVIII. These antibodies neutralize the circulating FVIII, creating a reference.Standardtoxicologyparametersincludingeffectoncoagulationvariables,as
deficiency of FVIII procoagulant activity. OBI-1, a recombinant porcine sequence wellassafetypharmacologyparameters,wereassessed.Nochangesinthemacaques’
FVIII product, is being developed for the treatment and prevention of bleeding behavior, serum chemistry, hematological or safety pharmacology parameters were
episodesinadultswithacquiredhemophiliaA. observed. No test item-related changes were observed in macro- and microscopic
MaterialsandMethods:Thepharmacokinetics(PK)ofOBI-1wereassessedinanimal examination of tissues. As expected after repeat administration of an exogenous
speciestoinvestigatetheefficacyandsafetyofthecompound.Hyate:C,aformerly protein,inhibitoryantibodiesagainstporcineFVIIIdevelopedinallgroups,including
marketedplasma-derivedporcineFVIII,wasusedasareference. Hyate:C-treatedanimals.Cross-reactivitywithendogenousFVIIIledtoanincreased
Results:SingledosePKstudieswereconductedinmacaquesandhemophiliaAdogs. bleedingtendencyandaslightprolongationofaPTTinOBI-1-treatedmacaques.
Dogsreceived3,25or100U/kgofOBI-1orHyate:C.SystemicexposuretoFVIII Conclusion:OBI-1showedafavourablesafety/toxicityprofileinbothanimalspecies
activityincreasedwithhigherdoses,butwaslessthandose-proportional.Exposureto used.Thenoobservedadverseeffectlevel(NOAEL)wassettothehighestdosetested
OBI-1(meanAUC0-inf:157,1356,3399U*h/dL;meanCmax:20.9,125.5,466U/dL) ineachstudy.
wasconsistentlyhigherthanthattoHyate:C(meanAUC0-inf:63.1,315.5,1220U*h/ Allauthorsarefull-timeemployeesofBaxterInnovationsGmbH,Vienna,Austria.
dL;meanCmax:8.6,37.9,143U/dL).Monkeysreceived49.5or77U/kgOBI-1or
100U/kgHyate:C.Asseenindogs,plasmaexposuretoOBI-1(meanAUC0-inf:944,
1433U*h/dL;meanCmax:107,169U/dL)washigherthanthattoHyate:C(mean
AUC0-inf:512.9U*h/dL;meanCmax:78.7U/dL)duetoalowerclearanceofOBI-1 AcquiredHemophiliaAwithImmuneThrombocytopeniainadolescent
(0.056and0.085vs.0.599dL/kg/h).ThehigherexposureofOBI-1comparedwith patient
Hyate:Cwasconfirmedinrepeatdosetoxicokineticstudiesconductedinmacaques: HYOSUNKIM,1 JUNGWOOHAN,1JAE-WOO SONG,4
OBI-1wasadministeredover4,28or90daysatdosesof40-1000U/kg,while100 SEUNGMIN HAHN,1YOONJUNGSHIN,1 SUNHEEKIM,1
U/kgHyate:Cwasadministeredfor4or90days.Onbothdaysoneandfour,plasma MOONKYU KIM,2 KUNSOOLEE3 andCHUHL JOOLYU
FVIIIlevels werehigher forOBI-1 thanfor Hyate:C. Ondays 28and90, plasma 1DepartmentofPediatricHematologyandOncology,YonseiUniversityHealth
FVIIIlevelsweremarkedlyreducedinallmonkeysduetothedevelopmentofanti- System,Seoul,Korea;2CHABundangMedicalCenter,CHAUniversity,Seongnam,
porcineFVIIIinhibitorantibodies–afindingexpectedaftermultipleadministrations Korea;3KyungpookNationalUniversitySchoolofMedicine,Daegu,Korea;and
ofexogenousproteins. 4DepartmentofLaboratoryMedicine,YonseiUniversityCollegeofMedicine,Seoul,
Conclusion:TheexposureofOBI-1washigherthanthatofHyate:Cinbothspecies Korea
and at all doses tested. All authors are full-time employees of Baxter Innovations
Introduction and Objectives: Acquired hemophilia A (AHA) is rare autoimmune
GmbH,Vienna,Austria.
disordercausedbyautoantibodieswhichactagainstcoagulationfactorVII(FVIII)in
the nonhemophilic population. The age distribution of autoantibodies is typically
biphasic, with a small peak between the ages of 20 and 30 (mainly postpartum
EfficacyofOBI-1,arecombinantporcinesequenceFVIIIproduct,in inhibitors)andamajorpeakinpatientsaged70to80years.TheincidenceofAHA
animalmodelsofhemophiliaA in children is very rare. Indeed, the incidence in children under 16years has been
estimatedtobe0.045permillion/yearcomparedwith14.7permillion/yearinthose
ALEXANDRASCHIVIZ,CHRISTINAPISKERNIK,
over 85years of age. Also, immune thrombocytopenia is an acquired immune-
PETERLEIDENMUEHLER,EVA-MARIAMUCHITSCHand
mediated disorder caused by increased destruction of platelets opsonized by anti-
WERNERHOELLRIEGL
plateletautoantibodies.WeexperiencedacaseofAHAwiththrombocytopeniacaused
BaxterInnovationsGmbH,Vienna,Austria
by autoantibody in an 18-year-old boy. He had no previous bleeding history and
Introduction and Objectives: Acquired hemophilia A is a rare bleeding disorder in presentedwitheasybruisingonthelowerextremitiesandwasdiagnosedwithAHA.
which subjects without a history of hemophilia develop autoantibodies against Aninitialactivatedpartialthromboplastintime(APTT)was136seconds,thelevelof
endogenousFVIII.TheseantibodiesneutralizethecirculatingFVIII,thuscreatinga FVIII was 0.6 % and FVIII inhibitor was measured at13.1 Bethesda Units (BU).
deficiency of FVIII procoagulant activity. OBI-1, a recombinant porcine sequence Moreover,plateletcountswerelow(34,000/uL),andweobservedplatelet-associated
FVIII product, is being developed for the treatment and prevention of bleeding autoantibody. Other autoimmune diseases were ruled out. He was immediately
episodesinadultswithacquiredhemophiliaA. treatedwithoralprednisolone(1mg/kg/d)andoneweeklateroralcyclophosphamide
Materials and Methods: The aim of the presented studies was to determine the (2mg/kg/d)wasaddedduetoelevatedFVIIIinhibitor(14.7BU)levels.Aboutseven
efficacyofOBI-1inmiceanddogswithhemophiliaA.Hyate:C,aformerlymarketed weeks later, after treatment, FVIII inhibitor had disappeared and APTT was
plasma-derivedporcineFVIII,wasusedasareference. normalized, we started tapering off the medication. During treatment of inhibitor
Results:Sixdogsweretreatedwitheachproductatdosesof3,25,or100U/kgina eradication, platelet counts were also increased and normalized. We report our
randomizedcrossovercuticlebleedingtime(CBT)study.OBI-1effectivelydecreased experienceasthefirstsuccessfulsimultaneousantibodyeradicationforFVIIIinhibitor
CBTbyanaverageof6.6minin7of9studies,correctingCBTtonormalrangein5 andplatelet-associatedautoantibodyinanadolescentAHApatient.
ofthese7.WithHyate:C,CBTwasshortenedin3of9experiments.FourteenFVIII
knock out (ko) mice were treated with varying doses of OBI-1 (10-190 U/kg) or
Hyate:C (10-109 U/kg). Vehicle-treated FVIII ko mice (n=7) served as negative
controls, C57BL/6 mice (n=7) were used as healthy controls. A tail transection Non-clinicalimmunogenicityassessmentofanewrecombinantporcine
mortality protocol was modified to obtain results from which the estimated dose sequenceFVIII(OBI-1)
producing 50% survival after 24h could be established. Following a standardized PETERALLACHER,FRANKHORLING,
tail-sniphemorrhagicinsult,anestimatedED50of89U/kgOBI-1(95%CI:65-120 CHRISTINAPISKERNIK, PETERLEIDENMU€HLERand
U/kg)produced50%survival.Thisefficacydidnotdiffersignificantlyfromthatof BIRGITREIPERT
Hyate:C(64U/kg;95%CI:34-87U/kg). BaxterBioScience,Vienna,Austria
Conclusion: Administration of OBI-1 dose-dependently reduced blood loss in
IntroductionandObjectives:AcquiredhemophiliaA(AHA)isararebleedingdisorder
hemophilicmiceanddogs.TheefficacyofOBI-1wascomparabletoHyate:Cinmice
causedbycirculatingauto-antibodiesthatneutralizefactorVIII(FVIII)activity.Inthe
and appeared to be more effective in correcting the in vivo hemophilic bleeding
past,plasmaderivedporcineFVIII(Hyate:C)wassuccessfullyusedforthetreatment
tendency in dogs.These results demonstrate that OBI-1 has a favorable preclinical
of patients with AHA. Since the discontinuation of the commercial production of
efficacy profile, predictive of a comparable effect to that of the formerly licensed
Hyate:C in 2004, no alternative porcine FVIII has been available. A new product,
comparator product in humans. All authors are full-time employees of Baxter
recombinant porcine sequence FVIII (OBI-1) is currently in development. The
InnovationsGmbH,Vienna,Austria.
objectiveofthisstudywastoassesstheimmunogenicityofOBI-1incomparisonto
Hyate:CinE16hemophiliaAmiceandinCynomolgusmonkeys.
MaterialsandMethods:E16hemophiliaAmicewerepretreatedwith5intravenous
PreclinicalsafetyofOBI-1,arecombinantporcinesequenceFVIII (i.v.) doses of recombinant human FVIII (100 U/kg) to induce antibodies against
product humanFVIII.Subsequently,micereceived4weeklyi.v.doses(1,10or100U/kg)of
eitherOBI-1orHyate:C.Developmentofanti-porcineFVIIIantibodieswasanalyzed
ALEXANDRASCHIVIZ,WERNERHOELLRIEGL,
twoweeksafterthelastdose.CynomolgusmonkeysreceivedeitherOBI-1(40and
CHRISTINAPISKERNIK,PETERLEIDENMUEHLER,
100U/kg) or Hyate:C (100IU/kg) twice daily for 4days. Anti-porcine FVIII
EVA-MARIAMUCHITSCHandBARBARADIETRICH
antibodies were analyzed on days 8, 15, 29, 43 and 57. Total binding antibodies
BaxterInnovationsGmbH,Vienna,Austria
againstporcineFVIIIandhumanFVIIIwereanalyzedbyELISA.Neutralizinganti-
Introduction and Objectives: Acquired hemophilia A is a rare bleeding disorder in porcineFVIIIantibodies(inhibitors)wereanalyzedusingamodifiedBethesdaassay.
which subjects without a history of hemophilia develop autoantibodies against Results:Noneofthemonkeystreatedwith40U/kgOBI-1,2of5monkeystreated
endogenousFVIII.TheseantibodiesneutralizethecirculatingFVIII,thuscreatinga with100U/kgOBI-1and2of6monkeystreatedwith100U/kgHyate:Cdeveloped
deficiency of FVIII procoagulant activity. OBI-1, a recombinant porcine sequence anti-porcineFVIIIinhibitors.HemophiliaAmicedevelopedinhibitorsaftertreatment
FVIII product, is being developed for the treatment and prevention of bleeding withporcineFVIIIinadose-dependentmanner.Themaximumresponsewasseenat
episodesinadultswithacquiredhemophiliaA. thehighestdoseof100U/kgwith81%and94%micedevelopinginhibitorswhen
MaterialsandMethods:ThepotentialtoxicityofOBI-1wasassessedinmacaquesand given OBI-1 or Hyate:C, respectively. No significant differences in titers of anti-
hemophilia A dogs. Acute and subchronic studies included cardiovascular and porcineFVIIIinhibitorswerefound.BindingantibodiesagainstporcineFVIII,assessed
respiratory safety pharmacology assessment (dogs only). Hyate:C, a formerly inhemophilicmice,werehigherinmicetreatedwith10or100U/kgHyate:Cthanin
marketedplasma-derivedporcineFVIII,servedasreference. micetreatedwiththesamedosesofOBI-1.Pre-inducedtitersofantibodiesagainst
Results:SingledosetoxicitywasevaluatedinhemophiliaAdogsreceivingdosesupto human FVIII did not influence the subsequent development of antibodies against
100U/kgOBI-1andmacaquesreceivingupto77U/kg.Hyate:Cwasadministeredat porcineFVIII.
100 U/kg in both species. A single injection of OBI-1 did not induce any adverse Conclusion: Non-clinical immunogenicity assessment indicates that the new
effects.Noadverseeffectsontherespiratoryorcardiovascularsystemswereobserved. recombinant porcine sequence FVIII (OBI-1) expresses a similar immunogenicity
Ina28-daydoseescalationstudy,thetolerabilityandpotentialimmunogenicityof profileastheporcineplasma-derivedFVIIIHyate:C.
ascendingdosesofupto1000U/kgOBI-1inmacaques(n=2)wereevaluatedwhen
injectedintravenouslyoncedailywithdoselevelsincreasingevery7days.Apivotal
90-dayrepeatdosetoxicitystudyincludingdailydosesupto825U/kgwasconducted
inmacaques(n=12).Inthelatterstudy,100U/kgHyate:Candvehicleservedasa
Haemophilia(2014),20(Suppl.3),1--186 ©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd
ACQUIRED HEMOPHILIA 3
AcquiredHemophiliaA:Presentationof5cases 10months:thepatienthasalarge,post-traumaticbruiseonthebackoftheright
SVETLANASTANKOVIKJ,1TATJANASMILEVSKA,1 hand,andahematomaintherightcalfrequiringinfusionofrVII(Novoseven)at
VIOLETADEJANOVA,2 SANJATRAJKOVA,1 90ug/kg, in 3 injection for 2days, with a good clinical improvement. A test for
DUSKO DUKOVSKI1andMARIJAPOPOVA1 circulatingantibodiesfoundUB32VACandaresidualfactorVIIIoflessthan1%.
1UniversityClinicofhematology,Skopje,Macedonia;and2Institutefortransfusion Discussion:Thoughapositivediagnosisissimpletoconduct,Hemophiliaisrelatively
medicine,Skopje,Macedonia rare and not often seen in a clinical setting. The therapeutic strategy has two
componentsinthiscase:1-Controlthehemorrhagicsyndrome:differenthemorrhagic
Introduction and Objectives: Acquired hemophilia A can be defined as a bleeding episodes were controlled by the rVIIa ( Novoseven ) with very good efficacy. 2 -
disorder caused by generation of auto-antibodies towards factor VIII. In untreated Eradicate inhibitor with either corticosteroids, cyclosporine, or more recently
patients,itoftenleadstoalife-threateninghemorrhage. rituximab.Ourpatientwastreatedwithcorticosteroidswithtotaleradicationofthe
MaterialsandMethods:ThisreportpresentsfivecaseswithacquiredhemophiliaA antibody,whichreappearedsixmonthslaterwithanaetiologyotherthanpostpartum.
treatedattheUniversityClinicofHematology,Skopjefrom2006to2012.Themen- Conclusion: Acquired hemophilia, despite its rarity, should be suspected in any
womenratiowas1-4respectively.Theaverageageofpatientswas56years(24– postpartum bleeding issue. This is another situation where research and
80years). The risk factors for development of auto-antibodies included: puerperal multidisciplinarycollaborationisvitalforpatients.
period,lungcancer,andurolithiais.However,intwoofthepatientstheetiologywas
notdefined.
Results:Clinicalexaminationdemonstratedextensivehematomasthroughoutthebody
and limbs in four of the patients, and hematuria in two of them. Laboratory EffectofOBI-1,arecombinantFVIIIproductwithporcineFVIII
evaluationshowedinitialelevationofAPTT(activatedpartialthromboplastintime)in sequence,onthrombingenerationandclotstructureinplasmafrom
allpatients;average64.8secwithcontrol22.0sec.Thequalitativetestwithmixture hemophiliaApatientswithinhibitors
ofnormalandpatient-derivedplasmawaspositiveinallpatients.Initially,theaverage CLAUDENEGRIER,1JOHANNESOLDENBURG,2
valueforfactorVIIIandtheinhibitors’titerwere1.2%and19.7B.E.respectively, BERNDPOETZSCH,2JEAN-CLAUDE BORDET,1
outofwhichthreeofthepatientswerelowresponders,withinhibitortiterbelow5 RAEDALDIERI,3YESIMDARGAUD,1COENHEMKER,3
B.E.andtwoofthemwerehighresponders,withinhibitortiterover5B.U.Theacute MARTINLEE4andPETERL.TURECEK5
hemorrhagewas treated with high doses of factor VIII concentrate (Coate) in two 1Ho^pitalEdouardHerriot,Lyon,France;2InstituteofExperimentalHematologyand
patients,fresh-frozenplasma(FFP)inonepatientandactivatedrecombinantfactor TransfusionMedicine,Bonn,Germany;3SynapseBV,Maastricht,TheNetherlands;
VII (Novoseven) in two patients. In addition, the patients were treated with 4InspirationBiopharmaceuticals,LagunaNiguel,CA,USA;and5BaxterInnovations
immunosuppressive therapy including corticosteroids only, or corticosteroids in GmbH,Vienna,Austria
combinationwithCyclophosphamideand/orRituximab.Thehemorrhagewasstopped
andclinicalremissionwasachievedinallpatientsforapproximately60days(18to Introduction and Objectives: Current treatment of patients with hemophilia A is
180). replacement therapy with factor VIII (FVIII) concentrates. A major clinical
Conclusion:AcquiredHemophiliaAisaveryrarediseasethatmayleadtoalife- complication is the development of neutralizing anti-FVIII inhibitors making factor
threateninghemorrhage.However,earlydiagnosisandsuitabletreatmentcanprevent replacement therapy ineffective due to interaction with epitopes critical for FVIII
afataloutcome. activity.OBI-1(BaxterHealthcare)isarecombinantFVIIIconcentratewithporcine
FVIII sequence, which may possess low cross reactivity to human FVIII inhibitors.
Therefore OBI-1 might be beneficial for the treatment of patients with acquired
hemophilia and in individuals with congenital hemophilia A with inhibitors. The
PlasmaderivedfactorVIIIproductsinduceinvitroosteoblastapoptosis purpose of this multicenter study was to evaluate in vitro restoration of thrombin
MARTIN FBRODDE,ANJA MU€LLERandBEATEE KEHREL2 generation(TGA)inplasmafrompatientswithhemophiliaAandinhibitorstoFVIII
1OxProtectGmbH,Mu€nster,Germany;and2UniversityofMu€nster,Mu€nster, afteradditionofOBI-1.
Germany Materials and Methods: From those patients with hemophilia A and inhibitors to
FVIIIconsentingtothestudy,a20mLbloodsamplewasobtained.VariousOBI-1
IntroductionandObjectives:Inapreviousstudy,bloodcellproteinsandcomplement concentrations(equivalentupto400U/kgbodyweight)wereadded,FVIIIactivitywas
activation have been identified in several plasma derived factor VIII (pdFVIII) measuredwithaone-stageclottingmethod,anti-humanFVIIIandanti-porcineFVIII
products. Whether or not these impurities induce cellular stress in osteoblasts was neutralizing antibodies were analyzed with an assay based on the Nijmegen
examinedbyinvestigatingtheirimpactonosteoblastapoptosis. modification of the Bethesda assay. Thrombin generation was analyzed with the
Methods:PrimaryhumanosteoblastswereculturedandFVIIIconcentrates,dissolved CalibratedAutomatedThrombogram(CAT)assay.Inaddition,clotswereobserved
insterileaquaforinjectionforafinalFVIIIconcentrationofupto0,5IU/ml.The withascanningelectronmicroscope(SEM),thenumberoffibrinfiberswascounted
influence of FVIII products on human osteoblasts was investigated by microscopy. andfibrinfiberdiameteranddensityweredetermined.
ApoptosiswasevaluatedusingtheEnzChekCaspase-3Assay2(MolecularProbes) Results:AllpatientshadseverehemophiliaA,theinhibitortiterscoveredthelow,mid
adaptedforflowcytometry.Phosphatidylserineexposureonosteoblastswasdetected andhightiterrange.AfterinvitroadditionofvariousconcentrationsofOBI-1adose
bystainingwithFITCconjugatedAnnexinVbyflowcytometry. dependentcorrectionofthethrombingenerationparameterswasobservedforpatients
Results: After 48h incubation with medium containing pd FVIII (0,5U/ml) many withlowandmidanti-OBI-1titers(<10BU/mL).Thecorrectionwasdependenton
osteoblastsweredead,butallcellsveryhealthywhenincubatedwithrFVIII(0,5IU/ theanti-OBI-1inhibitortitersbutnotontheanti-humanFVIIIantibodytiter.Infive
ml) in the presence or absence of rvWf (0,5IU/ml). Osteoblasts maintained their out of nine samples with high OBI-1 inhibitor titers (≥10 BU/mL), five samples
characteristic morphology after treatment with rFVIII. The number of apoptotic showed little or no response to OBI-1, one showed a partial response, and three
osteoblastsasshownbycaspase3activityasbyAnnexinVbinding,didnotchange showedacompleteresponse.Thecorrectionofthrombingenerationparametersand
by coincubation of the cells with rFVIII. In contrast, several pFVIII concentrates changes observed in clot structure were mainly dependent on anti-OBI-1 inhibitor
inducedcaspase3activityandAnnexinVbindinginlowconcentrations(0,25U/ml). titer.
BothpdFVIIIandrFVIIIproductsdidnotinduceosteoblastnecrosisascellsdidnot Conclusion:OBI-1correctsthrombingenerationinvitrowhenaddedtohemophiliaA
takeuppropidiumiodide. plasma with low and mid OBI-1 inhibitor titers. However, even for a portion of
Conclusion: Stress to osteoblasts, leading to apoptosis by the tested pdFVIII plasma samples from patients with high titers (< 10 BU/mL), full correction of
concentrates,mayleadtoanenhanceddestructionofbone,whilethetestedrFVIII thrombingenerationwasobserved.Theinvitrodatasuggestthatthiscorrectionis
concentratesdonotinduceosteoblastapoptosis. onlydependentontheOBI-1inhibitortiterandnotontheanti-humanFVIIIinhibitor
titer.SimilartoTGA,theclotstructurewasalsoimprovedafteradditionofOBI-1.
Acquiredhemophiliapostpartum
R.MESSAOUDI, A.BENSAHLI,A. CHERIF-HOSNI,Y.RAHAL, AcquiredFactorVIIIinhibitorinchildren:Experienceinasingleinstitute
D.BELALDJandH.TOUHAMI DARINTRSOSOTHIKUL,KORAMITSUPPIPATand
UniversityHospitalOran,DepartmentsofHematologyandH(cid:2)emiobiology,Algeria PANYASEKSARN
Introduction:Acquiredhemophiliaisararediseasewithanincidenceof1to1.5cases DepartmentofPediatrics,FacultyofMedicine,ChulalongkornUniversity,King
permillioninhabitants.Itistypicallyseverein80%ofcases.Thepostpartumperiod ChulalongkornMemorialHospital,Bangkok,Thailand
represents15%ofcasesAsperthefindingsofDelgadoetal.,theantibodies-FVIII IntroductionandObjectives:AcquiredfactorVIII(FVIII)inhibitorisararebleeding
betweenoneandfivemonthsaftergivingbirth.Mostoftenitoccursafterthefirst disorder caused by an autoantibody against FVIII, with potential life-threatening
pregnancy.Thesearchforacontext-associateddiseaseisoftenfruitless,andinabout complications. In this study, we report three cases of acquired FVIII inhibitor in
two-thirdsofthecases,noassociatedconditioncanbefound. childrentreatedatKingChulalongkornMemorialHospitalfrom1995to2013.
Observation: A patient, aged 36years, primipara, and with no particular medical Results:
history, was seen in hematology postpartum. Following a cesarean section, in Case I: A 13-year-old girl presented with fever, large bruises on both legs, and
December2012,thepatientshowedthefollowing:Day4:hemoperitoneumingreat bleedingfromherlipfor2weeks.Physicalexaminationsshowedhemorrhagicblebs
abundanceDay6:occurrenceofhematemesisofabout200cc.Day7:Anexploratory at left arm and flamed-shape hemorrhage at retina. An uncorrectable APTT
laparotomywasunremarkable.Day8:abdominalbloating,furthersurgerytocheck prolongation with plasma mixing study and a deficiency in FVIII (0.95%) with
thelocalhemostasis,withthedrainbackofmorethanoneliterofblood.Theresults presence of FVIII inhibitor (1.8 BU/ml) were found. She was treated with oral
of standard coagulation and observation of circulating antibodies confirmed the corticosteroidandFVIIIinhibitordisappearedwithin1weekoftreatment.CaseII:A
diagnosisofacquiredhemophilia.ThecoagulationtestsfoundanelongatedAPTT.TP 10-year-oldgirl,who hadbeen diagnosedas SLE8monthsago,came with severe
:100%APTT:81.5sec(T:30sec),FVIII:1%FIX:46%,FXI:.78%Thetest epistaxis, gingival bleeding and multiple ecchymoses on both legs for 10days.
correction : APTT uncorrected 80.3 Dry Index Rosner 61, residual FVIII: 5%. UncorrectableAPTTprolongationswithplasmamixingstudyanddeficiencyinFVIII
Screening for positive anti- VIII, high > 32 Bethesda units / ml. A second test, in (0.25%) with presence of FVIII inhibitor (7.9 BU/ml) were found. FVIII inhibitor
March2013,found200BethesdaUnits.Atthreemonths:renalcolicwithhematuria. disappearedandbleedingstoppedafter2weeksofsteroidadministration.CaseIII:A
3months:Hematomaoftheforearmwithdifficultybending,requiringtheinfusion 10-year-oldgirlpresentedwithlargesubcutaneoushematomasofbotharmsandleft
rVII ( Novoseven ) at 90ug/kg, 3 injection for 2days, with the introduction of legfor2days.Shehadhistoryoffeverwithrash1weekbeforethisbleedingepisode.
corticosteroidtreatmentat1mg/kg/dayfor4weekswithgradualreduction.Atthe UncorrectableAPTTprolongationwithplasmamixingstudyandadeficiencyofFVIII
endof6weeksoftreatment,antibodyscreeningwasnegativeat0Bethesdaunits. (1.1%)withpresenceofFVIIIinhibitor(7.7BU/ml)werefound.HighdoseofFVIII
©2014TheAuthors Haemophilia(2014),20(Suppl.3),1--186
Haemophilia©2014JohnWiley&SonsLtd
4 ACQUIRED HEMOPHILIA
concentrateweregivenduetoearlysignofcompartmentsyndromeofbothherarms, Conclusion:Thesetwocasesrepresentthewiderangeinseveritypatternsofacquired
followedbysteroidadministration.Threeweekslater,FVIIIinhibitordisappearedand hemophilia.Thehigherantibodytiterscanbeassociatedwithfalsepositiveantibodies
bleedingwasresolved.TwoofthethreecasesinourseriesaresecondarytoSLEand tootherfactorsandfalsereductionofallPTT-basedfactorassays.
thethirdcaseislikelytobeapostinfectiousprocess.
Conclusion:TheoutcomeofacquiredFVIIIinhibitorinchildrenseemstobemore
favourablethaninadults,withgoodresponsivetocorticosteroids.HighdoseofFVIII
concentrate was required only in the third case ,due to impending compartment ThetreatmentofacquiredHaemophiliaAintheelderly:Lostgameor
syndromeinherextremities. winningcombination?
DANIJELALEKOVIC,1MIRJANAMITROVIC,1
MIRJANA SRETENOVIC,1 DARKOANTIC,1,2
PREDRAGMILJIC1,2andIVOELEZOVIC1,2
CaseReportofararebleedingdisorder:AcquiredhemophiliaAand 1ClinicforHematology,ClinicalCenterofSerbia,Belgrade,Serbia;and2Facultyof
acquiredFXIIIdeficiency Medicine,UniversityofBelgrade,Belgrade,Serbia
MARTIN HENDELMEIER,1 INGE SCHARRER,2
GEORGGOLDMANN,1 NATASCHA MARQUARDT1and IntroductionandObjective:AcquiredhaemophiliaA(AHA)isanautoimmunedisease
JOHANNES OLDENBURG1 causedbyaninhibitoryantibodytofactorVIII.Themortalityishighduetobleeding
1UniversityHospitalBonn,InstituteofExperimentalHematology,Bonn,Germany; andthetoxiceffectsofimmunosuppressivetherapy.Therefore,thereisnostandard
and2UniversityMedicalCenterMainz,DepartmentofMedicine3,Mainz,Germany treatment for AHA, especially in the elderly. The objective of our reports was to
presentthetreatmentoftwoelderlypatientswithAHAandseverecomorbidities.
IntroductionandObjectives:AcquiredhemophiliaA(AHA)isararebleedingdisorder Case reports: 1. A female patient, 76years, ECOG 3, with arterial hypertension,
causedbythedevelopmentofspecificautoantibodiesthatarecapableofinhibitingthe severebronchialasthmaandsevereosteoporosis,washospitalizedwithmassiveskin
action of naturally occurring Factor VIII (FVIII). Patients present with prominent bleedingandanemia(Hb84g/L).LaboratoryanalysesshowedaPTTat97.4s,FVIII
subcutaneous hematomas as well as bleeding elsewhere. Unlike with classic at0.31%,FVIIIInhibitorat803BJ.Severalepisodesofactivebleedinginsofttissue
hemophilia,hemarhtrosesarerare.ThereisprolongationoftheaPTT,whichdoesnot weresuccessfullystoppedafterusingFEIBAatadoseof75j/kg/12h. Eradication
correctfollowinginvitroadditionofnormalplasma.TheFVIIIlevelisreduced,but therapywasstartedwithprednisone1mg/kg/dailyfor3weeks.Duetothepersistence
rarelytolessthan2%.TheBethesdaassaydemonstratesaninhibitorbutthedegree ofhighlevelofinhibitor,treatmentwaschangedwithonecycleof5-dayCOP.After
ofbleedingisoftenmoreseverethansuggestedbytheinhibitorlevel.AcquiredFactor a transient neutropenia, treatment was continued with prednisone and
XIII(FXIII)deficiencyremainsadoubtfulentity.CoagulationfactorXIII,thatbelongs cyclophosphamide, until the complete eradicationof inhibitor was achieved and of
to a family of transglutaminases, is the last enzyme to be activated in the blood FVIIIlevelreturnedto120%andHbto130g/Lafter12weeks.
coagulationpathwayandfunctionstocross-linka-andμ-fibrinchains,resultingina 2 A male patient, 87years, ECOG 3, with thrombosis of aortic aneurysm and
stronger clot with an increased resistance to fibrinolysis. The standard laboratory arrhythmia absoluta, was admitted to hospital with edema and severe skin
clottingtests(PT,aPTT,fibrinogenlevel,plateletcounts,bleedingtime)arenormalin hemorrhageoftheupperextremities.Laboratoryanalyseswereasfollows:Hb60g/L;
isolatedFXIIIdeficiency. aPTT58.7s;FVIII6%,FVIIIinhibitor18BJ.Initially,thepatientwastreatedwith
Materials and Methods: We report about a 76-year-old man who presented with prednisone1mg/kg/dailyfor2weeks,thencyclophosphamidewasaddedat2mg/kg/
spontaneoushaematomasafteroperationofainguinalherniaandintheabsenceof daily.FEIBAwasusedinareduceddoseof75j/kg/24h,duetoaorticthrombosis.
personal or family history of bleeding disorders. His past medical history included After3weeksoftreatmentacompleteremissionofthebleedingwasobservedwitha
arterialhypertension,prostatecancer,andhyperlipoprotein(a). return of FVIII levels and a decrease of FVIII inhibitor to 4 BJ. There were no
Results: Coagulation tests showed a prolonged aPTT (91sec) with normal PT and complicationsoftheimmunosuppressivetherapy.
INR. aPTT was not modified after mixing tests, lupus anticoagulant was negative, Conclusion: Treatment goals of AHA are bleeding control and autoantibody
FVIIIwas4%,andFVIIIinhibitorwas72BethesdaUnits(BU),leadingtodiagnosis eradication.Inpresentedpatients,FEIBAwashighlyeffectiveincontrollingbleeding
AHA.FactorIX,factorX,factorXIIandvonWillebrandfactorwerenormal.Several inpatientswithAHA,eveninalowerdoseduetoriskforthrombosis.Accordingto
transfusions with packed red blood cells were required due to anemia and the our experience in AHA patients with high titers of inhibitors, addition of
persistenthaemorrhagictendency,andarecombinantfactorVIIa(rFVIIa)90μg/kg cyclophosphamidetoprednisoneresultsinhighremissionrates,evenintheelderly,
i.v.boluswasadministered,andrepeatedafterthreehours,withtemporarycessation butthefrequentmonitoringisneeded.
ofbleeding.Prednisonewasimmediatelystartedatdosesof1mg/kg/day.Severaldays
later,hepresentedagainwithadecreaseinhaemoglobinlevel.Thepatientreceived
packed red blood cells and another rFVIIa bolus. Further investigation led to the
exclusion of other malignant or autoimmune diseases. During admission, he AcquiredFactorVIIIInhibitorsinthePostpartumPeriod
experienced other episodes of bleeding with significant reduction of haemoglobin ANASTAZIAKEEGAN,GEOFFREYKERSHAWand
levels<6g/dl.Afterfurtherlaboratorytestingofhaemostasis,afactorXIIIdeficiency SCOTTDUNKLEY
was detected and the patient was treated with FXIII concentrates. The further InstituteofHaematology,RoyalPrinceAlfredHospital,Sydney,Australia
treatment was aimed at stopping the acute bleeding and eliminating the inhibitor.
Introduction and Objectives: The development of acquired Factor VIII inhibitors
AcutebleedsweresuccessfullytreatedwithrFVIIaandFXIIIconcentrates.
associatedwithpregnancyisarareandpotentiallylife-threateningcomplicationthat
Conclusion:Therarecoagulationdisordermaypresentwithseriousandlife-threating
manifests with abnormal bleeding post partum. Despite an often severe clinical
bleeding.Promptinvestigationandrecognitionofthesedisordersareessentialsothat
phenotype, these patients have an excellent chance of eradication of the inhibitor,
theappropriatetreatmentcanbeinstigated.AHAandFXIIIdeficiencyisaserious
both spontaneously and with immunotherapy. We present two cases of acquired
risk and may have catastrophic consequences. Hematologists need to work closely
Factor VIII inhibitors postpartum where bleeding was controlled with FEIBA
withcolleaguesfromotherdisciplinestorecognizethesedisorders.
prophylaxisuntilinhibitoreradicationbyRituximab.
MaterialsandMethods:Theclinicalnotesofthesecaseswereretrospectivelyreviewed
from diagnosis to last clinical review. Laboratory testing included APTT, mixing
Aggressiveimmunosuppressionmayberequiredforoptimalmanagement studies,1-stageandchromogenicFactorVIIIassayandinhibitorquantificationusing
ofAcquiredHemophilia theNijmegen/Bethesdamethod.
Results:
AJMSALEH,TAREK OWAIDAH, WALIDRASHEED,
Case 1: A 32-year-old G3P2 woman had an uncomplicated caesarian delivery but
SAIDMOHAMEDandHAZZAAALZAHRANI
subsequentlypresentedwithabnormalbruisingseveralweekslater.HerFactorVIII
KingFaisalSpecialistHospital&ResearchCentre
level at presentation was 3 U/dL with an inhibitor titre of 5.0 BU/mL. She was
Introduction:Thetreatmentofacquiredhemophiliaincludescontrolofbleedingand initiallytreatedwithFEIBAandgivenatrialofprednisone.Herinhibitortiterpeaked
suppressionofinhibitors.Herewearepresenting2caseswithdifferentpatternsof at 11.4 BU/mL 116days after diagnosis, correlating with an increase in clinical
severity. bleeding,andresultingintheadditionofRituximabimmunotherapy.Bleedingwas
Patients: controlledbyFEIBAprophylaxis.TheFactorVIIIinhibitortiterfellafter2months
Case-I:A41-year-oldlady,withahistoryofrepeatedabortions,wasreferredtous andwassuccessfullyeradicatedafter199days.
withthighhematomameasuring32.4x8.5x8.8cmandPTTof62.5seconds,two Case2:A36-year-oldG2P1womanhadanemergencycaesariandeliveryfollowing
monthsafteranabortion.Autoimmuneandmalignancyscreeningwerenegative.Her failed trial of forceps, complicated by primary and secondary postpartum
FVIII,FIX,FXIactivitywerelowandinhibitortoFVIIIandFIXwere1779BU/ml haemorrhage requiring a total abdominal hysterectomy. Her Factor VIII level at
and 12 BU/ml respectively. She was initially treated with FEIBA with a good but presentation was 4 U/dL with an inhibitor titer of 3.1 BU/mL. She was initially
unsustained response. She had multiple relapses requiring aggressive courses of treatedwithrFVIIaandthenplacedonregularFEIBAprophylaxis,andstartedon
immunosuppressive therapy including methylprednisone, IVIg, Vincristine, high-doseprednisoneandRituximabimmunotherapywitharesponse6weekslater
CyclophosphamideandRituximab.HerfactorVIIIinhibitorcamedownfrom>2000 followedbyinhibitoreradication.Nothromboticeventsoccurredineitherpatient.
BU/mlto7.5BU/ml(graph).AfalsepositiveforFactorIXandXIinhibitordisappeared Conclusion:ThedevelopmentofFactorVIIIinhibitorsduringthepostpartumperiod
afterreductionoffactorVIIIinhibitor. is a rare disorder with significant morbidity and mortality. Immunotherapy with
Case-II: A 28year-old woman with insignificant past history presented one month Rituximabhaslowtoxicityandmayresultinearlierinhibitorseradication.Herewe
post-partum with multiple spontaneous bruises. She also experienced a heavy usedprophylacticFEIBAtopreventbleedinguntilinhibitoreradication.Despitethe
menstruallossinherfirstpost-partummenstrualcyclebutrequirednotreatment.On higherthromboticriskpostpartum,nothromboticcomplicationswereseen.
thisoccasion,shedevelopedprolongedbleedingafterdentalextractionandwasfound
tohaveaPTTof74sec,FVIIIlevel<0.01U,withaninhibitorlevelof14.7BU/ml.
ShewastreatedwithPrednisone,tranexamicacidandasingledoseofFEIBA.She
hadanexcellentresponsewithnormalizationofcoagulationtests.
Haemophilia(2014),20(Suppl.3),1--186 ©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd
AGEING 5
02-AGEING
Cardiacriskfactorsinolderpatientswithhemophilia:Reportoftheage Riskassessmentforcoronaryheartdiseaseinadultpatientswith
relatedcardiovasculardiseaseinhemophiliaepidemiologicresearch hemophiliaisinfluencedbyhepatitisCstatus
(archer)study AFRAHS.SAIT,ANN KUO, RICKIBETTENCOURT,
LEONARDMINUK,1,2ERINNE DILWORTH,2 JACLYN BERGSTROMandANNETTEVONDRYGALSKI
SHANNONJACKSON,3ALFONSO IORIO,4MAN-CHIUPOON,5 UniversityofCaliforniaSanDiego,SanDiego,USA
ROBERTCARD,6IRUMRIZWAN7andMARTHA LOUZADA1
1UniversityofWesternOntario,London,Canada;2LondonHealthSciencesCentre, Introduction and Objectives: People with hemophilia (PWH) in the US have more
London,Canada;3UniversityofBritishColumbia,Vancouver,Canada;St.Pauls hypertension and cardiovascular death than the general population. Therefore, we
Hospital,Vancouver,Canada;4McMasterUniversity,HamiltonHealthSciences investigated coronary heart disease (CHD) risk in PWH compared to the general
Centre,Hamilton,Canada;5UniversityofCalgary,Calgary,Canada;Foothills population.
MedicalCentre,Calgary,Canada;6UniversityofSaskatchewan,Saskatoon,Canada; Materials and Methods: Retrospective assessment of 10-year Framingham risk
RoyalUniversityHospital,Saskatoon,Canada;and7McMasterUniversity,Hamilton, (cceonmteprocsoitheoortfsoyfstPoWlicHbl≥oo2d0pyreeassrusre(n[S=B8P9],).agLee,veglesndoefr,rissmkowkeinreg,dliepfiindesd)inas:a<s1in0g%le
Canada (low),10-20%(intermediate),and>20%(high).ResultswerecomparedtotheUS
Introduction and Objectives: Improvements in hemophilia care have increased life representativesampleprovidedbyNationalHealthandNutritionExaminationSurvey
expectancy in persons with hemophilia (PWH). The aging population presents (NHANES).
management challenges as they develop age related comorbidities such as Results:Meanageinbothcohortswas~42years.WhileSBPwashigherinPWH,a
cardiovasculardisease(CVD).MinimaldataexistsontheepidemiologyofCVDin higher proportion of PWH were low risk compared to NHANES (77.5% versus
PWHnoristheremuchevidenceguidingappropriatemanagement. 61.0%;p=0.005); severe PWH were at lower risk than non-severe PWH (88.6%
MaterialsandMethods:Aretrospective,multicentrechartreviewwascarriedoutat versus66.7%;p=0.02).Surprisingly,lipidprofilesinPWHwerebettercomparedto
five Canadian Hemophilia Treatment Centres (London, Hamilton, Saskatoon, NHANES,andtrackedwithHepatitisCstatusandseverehemophilia(75%hepatitis
Calgary,andVancouver)fromJanuary2000toDecember2011.WeincludedPWH Cpositive).SeverePWHtendedtohavelowercholesterol(165.3mg/dL)andlower
(AandB)>35-years-oldandextracteddataoncardiovascularriskfactorsandCVD lowdensitylipoproteins(LDL)(85.2mg/dL)thannon-severePWH(cholesterol180.3,
events. p=0.08; LDL 103, p=0.01). Similarly, Hepatitis C positive PWH had lower
Results: 294 patients were analyzed (222 hemophilia A, 72 hemophilia B) with a cholesterol(163.7mg/dL)andLDL(85.4mg/dL)comparedtoHepatitisCnegative
median age at enrolment of 48 (range 35–90). Median follow up duration was PWH (cholesterol 185.5; LDL 105.3; p<0.01). All other risk factors were
5.86years. The majorityof the study populationhad non-severe hemophilia (56% comparable. Those with detectable viral load had the lowest serum lipids (mean
mild, 19% moderate, 25% severe). Cardiovascular risk factors were common: cholesterol[152mg/dL],LDL[78mg/dL]andtriglycerides[110mg/dL])comparedto
hypertension 31.3%, diabetes mellitus 10.5%, smoking 21.8%, obesity 27.6%, HepatitisCnegativePWHorthosewithundetectableviralload(cholesterol~190;
dyslipidemia 22.4%, family history 8.5%, antiretroviral therapy 12.2%. Many LDL~140;triglycerides~105;allp<0.001).ByHepatitisCstatus,theproportionof
patientshadmultipleriskfactorswith37.4%ofpatientshavingtwoormorerisk patients classified as high risk was lower for Hepatitis C positives compared to
factorsandonly24.5%havingnoriskfactors.Therewere24CVDeventswitha NHANES(5.7%versus17.3%;p=0.03),andthosewithdetectableviralloadhad
medianageateventof63years(range46–83).Eventsconsistedofcoronaryartery thehighestproportionofpatientsatlowrisk(80%,NHANES61%,p=0.07).
disease(CAD),14;cerebrovasculardisease,4;andatrialfibrillation(AF)7.Allbut Conclusion:Despitehypertension,themajorityofPWHwereclassifiedlowCHDrisk,
oneeventoccurredinpatientswithnon-severehemophilia.ForthepatientswithAF, driven by favorable lipid profiles associated with Hepatitis C. Hepatitis C is not
3weretreatedwithASAand1withavitaminKantagonist.CADwastreatedwith cardioprotectiveandcompositescoresmaynotbeappropriatetodetermineCHDrisk
coronaryarterybypassgraftingin3patientsandpercutaneouscoronaryintervention ininfectedPWH.
withstentingin9patients.CVDeventswerecomplicatedbyfourbleedingevents(1
minorand3major)occurringinthreepatientsandnoneofthesebleedswerefatal.
Conclusion:CardiovascularriskfactorsarecommoninPWH.Severehemophiliamay
beprotectiveagainstCVDeventsbutpatientswithnon-severehemophiliaarestillat Agingwithhemophilia:Enhancingdialoguewithourpatients
risk.PWHcanbesafelytreatedforCVDeventswithsimilarproceduresasthenon- GERARDDOLAN,MD,1RUUDBOS,2 RANDALL CURTIS,3
PWHpopulationwiththeuseoffactorprophylaxis,thoughspecificprotocolsarenot KARINLINDVALL,4 KAREN WULFF5andNICHANZOURIKIAN6
welldefined. 1NottinghamUniversityHospitals,UK;2UMCUtrecht/VanCreveldClinic,the
NationalHemophiliaCenter,theNetherlands;3FactorVIIIComputing,USA;
4DepartmentforCoagulationDisorders,UniversityHospital,Malmo€,Sweden;
5LouisianaCenterforBleedingandClottingDisorders,TulaneUniversitySchoolof
Multivariateanalysisoftheoccurrenceofintracranialhemorrhageamong Medicine,USA;and6SainteJustinePediatric/AdultComprehensiveCareHemostasis
adulthemophiliacsinJapan andInhibitorCenter,Montreal,Canada
MASASHITAKI,1SHINOBUTATSUNAMI,2JUNICHIMIMAYA,3
MIEKOAKITA,4YUTAKA NISHINA,5JUGOHANAI,6 Introduction and Objectives: With the advances in treatment of the last 30years,
KATSUMIOHIRA7andAKIRA SHIRAHATA8 people with hemophilia are living longer and experiencing health and lifestyle
1DepartmentofPediatrics,St.MariannaUniversitySchoolofMedicineYokohama challengesassociatedwithnormalaging.However,ashighlightedbymanyhealthcare
CitySeibuHospital,Yokohama,Japan;2UnitofMedicalStatistics,St.Marianna providers(HCPs)throughpublicationsandpresentations,thereareveryfewresources
UniversitySchoolofMedicine,Kawasaki,Japan;3AtamiPublicHealthandWelfare availableonthesetopicsforHCPswhotreatandmanagethecareofolderadults
Center,Atami,Japan;4DepartmentofPediatrics,St.MariannaUniversitySchoolof withhemophilia.Toaddressthisneed,wecreatedanonlineresourcetosupportthis
Medicine,Kawasaki,Japan;5NishinaandFukadoLawOffice,Tokyo,Japan; growingpartofthehemophiliacommunity.
6MedicalCareandHumanRightsNetwork,Osaka,Japan;7SocialWelfare MaterialsandMethods:In2011,aninternational,multidisciplinaryeditorialboard
CorporationHabatakiWelfareProject,Tokyo,Japan;and8KitakyushuYahata wasestablishedtodeveloptheAboveAndBeyondHemophiliaprogramwiththegoal
ofprovidinginformationandresourcestobetterunderstandandaddressthephysical
HigashiHospital,Kitakyushu,Japan
andsocialchallengesofagingwithhemophilia.Controlledexclusivelybytheeditorial
Objectives: The Research Committee for the National Surveillance of Coagulation board and sponsored by Bayer HealthCare, AboveAndBeyondHemophilia.net is
Disorders in Japan collected information on intracranial hemorrhage in the annual specificallydesignedtofacilitateHCPs’dialoguewiththeirolderpatientsontopics
surveillanceperformedin2012.Wesummarizetheresultsoftheanalyses. relatedtoaging.
MaterialsandMethods:WeuseddatacollecteduptotheendofMay2012.Atotal Results:Sincelaunchingthewebsitein2012,theboardhasguidedthecreationof
of 749 institutions throughout Japan participated in the research. History of nearly 40 articles on topics ranging from common medical issues associated with
intracranialhemorrhagewasanalyzedbymultivariatelogisticregressionanalysisusing aging such as cardiovascular disease, joint issues and sexual health, to the
thefollowingcovariates:patients´age,diseasetypeandseverity,presenceofinhibitors psychosocialimpactofaging.AlsoavailablefordownloadistheTalkingAboutAging
against FVIII or IX, and regular replacement therapy. The following medical booklet, which HCPs can offer to their older adult patient to help them be more
complicationswere also taken into account: diabetes,hypertension, hyperlipidemia, proactiveinpreparingforandmanagingdoctorvisits.
andHIVinfection,aswellasinformationoncriticalliverdisease. To date, AboveAndBeyondHemophilia.net has seen more than 2,000 visitors.
Results:Weextracteddataon1909patientswhowereover20yearsofageatthe Additional booklets and content are in development. Plans for the content to be
end of May 2012. This included 44% of the entire number of hemophiliacs over localized in different countries are underway. Both the brochure and website have
20years of age at that time in Japan. The subjects comprised 1581 patients with alreadybeenintroducedtoolderadultswithhemophiliaattheVanCreveldClinicin
hemophiliaA(977severe,290moderate,and314mild)and328withhemophiliaB The Netherlands. The content has been well-received, many considering it to be
(180 severe, 77 moderate, and 71 mild). Among the covariates, the presence of empoweringandhelpfulinadvocatingforthemselvesonhealthmattersbeyond,but
inhibitor, and hypertension were identified as statisticallysignificant variables (OR: potentiallyimpactedby,theirbleedingdisorder.Therearealsoplanstotranslatethe
5.7, 95%CI: 1.9–16.5, p<0.01; and OR: 2.9, 95%CI: 1.4–6.1, p<0.01, brochureintoDutch.
respectively). Although statistical significance was not clearly recognized, a higher Conclusion:AboveAndBeyondHemophilia.netisafirst-of-its-kindresourcetoinform
frequencyofintracranialhemorrhagewasfoundinpatientswithseverehemophilia andsupportHCPsintheirworkwiththisgrowingandchallengingsegmentofthe
comparedtopatientswithmoderateandmildhemophilia. hemophiliacommunity.
Conclusion: A history of adult intracranial hemorrhage was associated with the
presenceofhypertensionaswellasthepresenceofinhibitor,butnotwiththeother
covariates. With the increasing age of the Japanese hemophiliac population,
continuingresearchshouldincludethemonitoringoflifestyle-relateddiseases.
©2014TheAuthors Haemophilia(2014),20(Suppl.3),1--186
Haemophilia©2014JohnWiley&SonsLtd
6 AGEING
AcutecoronarysyndromeinapatientwithhemophiliaA Disclosure: The project itself is supported by Bayer, however none of the authors
MIKA MORI,1CHIAINAGAE,1 TOMOKOASHIKAGA,2 directlyorindirectlyissponsoredbyBayeroranyotherpharmaceuticalcompany.
ATSUKIYAMASITA,1DAIKEINO,1RYOOYAMA,1
MIZUHOMORIMOTO,1AKITOSHIKINOSHITA1and
MASASHITAKI2
1St.mariannaUniversity,Kanagawa,Japan;and2YokohamaCitySeibuHospital, Pointprevalenceestimatesofcomorbiditiesamongpeoplewith
Kanagawa,Japan hemophiliausingalargecommercialinsurancedatabase
CHRISTOPHERWALSH,1 ANISSACYANIUK,2
Case:A64-year-oldmalehemophiliapatient(residualfactorVIIIlevel0.19IUml-1) DAVIDL.COOPER,3DESIREE HALL,2DAVIDUNGAR,4
presented to the emergency department with chest pain at rest. The patient had CHIOMA SMITH3andTAMIWISNIEWSKI3
hypercholesterolaemiaandhyperuricaemia.Theechocardiographicfindings(signsof 1MountSinaiHospital,NewYork,NewYork,USA;2OptumInsightLifeSciences,
myocardial ischaemia of the anterior and septal walls) prompted coronary Horsham,PA,USA;3NovoNordiskInc.,Plainsboro,NJ,USA;and4Formerlyof
angiography (CAG) to be performed. Subsequently, primary percutaneouscoronary NovoNordiskInc.,Plainsboro,NJ,USA
intervention(PCI)wasperformedandtheanteriordescendingbranchofthecoronary
arterywasstented.A3000IUFVIIIboluswasinfused,aimingtoachieveaclotting IntroductionandObjectives:Today,peoplewithhemophilia(PWH)havenearnormal
factor level of 1.0IU ml-1 during the intervention. In addition, a loading dose of lifeexpectancy.Thereislittleunderstandingoftheprevalenceofcomorbiditiesamong
5000IUunfractionatedheparin(UFH)wasgivenbeforePCI,followedbycontinuous agingPWHascomparedtothegeneralpopulation(GenP).Thepurposeofthisstudy
infusionfor48h.Duringheparintreatment,2000IUFVIIIwereinfusedthreetimes is to describe differences in point prevalence estimates of chronic comorbidities in
dailyaimingtoachieveaclottingfactorlevelof0.80IUml-1,andthedoseswerethen PWHversusGenP.
tapered.DualantiplatelettherapywasstartedafterPCI.Onday16,electivePCIof MaterialsandMethods:UsingClinformaticsDataMart,aproductofOptumInsight
the right coronary artery was performed. Before PCI, 3000IU FVIII and 7000IU LifeSciences,afactor-treatedhemophiliacohortwasdevelopedusingdatafromJan.
UFHwereinfused.Duringthe48hperiodafterPCI,2000IUVIIIwereinfusedtwice 2009–Sept.2011.Includedpatientsweremale,hadhemophiliaA/Bdiagnosis(ICD-9
daily. The patient was not treated with heparin after the intervention. Dual 286.0-1),≥1orderforfactor,1yearofcontinuouseligibility,and≥2claimsper
antiplatelet therapy and once-a-week FVIII prophylaxis were continued. No comorbidity.Propensityscoresforage,geography,ethnicity,insurance,andprimary
complicationsoccurred,andFVIIIinhibitorsdidnotdevelop. carevisitmatchedPWHwithGenP.GenPfulfilledthesameinclusioncriteriaexcept
Discussion:Aginghemophiliapatientsareincreasingandbeingconfrontedwithage- forhemophiliarequirements.FifteencommoncomorbiditiesweredefinedviaICD-9
relateddiseases,suchasischaemicheartdisease(IHD).However,therearenowidely codes,thenbyrelatedprescription.Aftermatching,chi-square/Fisher’sexacttestsand
acceptedrecommendationsonhowtotreatIHDinhemophiliapatients.Itisnecessary oddsratios(OR)with95%confidenceintervals(CI)werecalculated.
toprovideindependentguidelinespromptly.Inaddition,primarypreventivecarefor Results:Atotalof818PWHand40,900GenPwereidentified.MeanageofPWH
IHDisalsoimportantinhemophiliapatients. was 23.6years; GenP was 23.7. When only diagnosis codes for the comorbidities
were included, eight comorbidities were significantly different (see table). When a
prescription for the comorbidity was also required, no significant differences were
noted.
Theelderlyhemophiliapopulation:ANordicpatientorganization
perspective
ZYGMUNTGRUSZKA,1TRONDLANGVIK,2 BENNY(cid:2)ASBERG1
andSTEINERIKWESTLI2 Table.
1SwedishHemophiliaSociety,Sundbyberg,Sweden;and2NorwegianHemophilia PWH GenP
Society,Nesoddtangen,Norway Comorbidity Estimate(%) Estimate(%) OR(95%CI)
Background:ThesituationfortheageinghemophiliapopulationinScandinaviahas
frequentlybeendiscussedwhenevertheNordicSocietiesgettogether.Thereisalack AtrialFib. 0.2 0.0 9.1(3.1-26.6)
of knowledge how ageing affects elderly PWH; among the PWH themselves, their Cirrhosis 1.0 0.0 23.8(10.2-55.2)
relatives, as well as within the medical health care system, social services and Hemorr. 0.1 0.0 9.1(2.0-41.2)
institutions.Inordertoaddresstheseissues,athreeyearprojectwascreatedin2011
Cerebrovascular
bytheSwedishandNorwegianHemophiliaSocietieswithsupportfromBayerAB.
Aim of the project: To identify the needs of elderly PWH in the Swedish and Disease
Norwegianhemophiliasocietiesandtocommunicatetheseneedstomembers,tothe Hep.C 8.4 0.1 163.7(101.6-263.9)
medicalprofessionandtosocialservices. Hypertension 1.3 0.9 1.5(1.0-2.2)
Methods:Yearlygatheringsofelderlymembersinbothcountriesserveasreference
andworkgroups.Asteeringgroup ineachcountrytakes theproject forwardand Osteoarthritis 3.7 0.5 8.3(5.6-12.3)
communicatesresultsbetweenthetwosocieties.ThemedicalneedsofelderlyPWH Osteoporosis 0.2 0.0 250.5(12.0-5221.1)
are also subject to cooperation with the Nordic Hemophilia Care via an Advisory RenalDisease 1.2 0.2 5.1(2.6-9.7)
Board.TheAdvisoryBoardwill,whenneeded,serveasmedicalback-upandhave
accesstoresultsfromtheproject.Results
Sofar,theprojecthasresultedinthecreationofthefollowingmaterialavailablefor
downloadfromthehomepagesofthehemophiliasocieties:ashortpamphletWhatis
important to know about elderly PWH to hand over in contacts with medical Conclusion: Small sample sizes and resulting wide CIs make inferences for some
professionalsandsocialservices;checkliststobeusedinmeetingswithdoctors,social comorbiditydifficult.Wehypothesizeourcohortreflectsmoderate/severePWHdueto
servicescounselorsandphysiotherapistsattheHemophiliaCenters;checkliststobe therequirementforfactorprescriptionandarthritis.DatasupportsthatPWHpatients
used in contacts with the local health care, home service, social services, are at risk for hypertension and renal disease. Cirrhosis due to Hepatitis C was
physiotherapisst,occupationaltherapistsandretirementhomes;APatientSelf-Record increased in PWH. There was no significant increase in atherosclerotic disease or
tobeusedbyPWHandtheirrelativesincontactwithlocalandacutehealthcare cancer in PWH.Despite the limitationsof this study, we believe the medicalrisks
facilities.Ongoingworkalsoincludes:checklistsonpainmanagement,mentalhealth identified suggest that PWH be monitored prospectively. Expanded data collection
issues,travellingandworkingoverage50;identifyingandattendingtotheneedsof throughintegratedsystemscanallowbetterunderstandingofthispopulation’sneeds.
therelativesofelderlyPWH.
Haemophilia(2014),20(Suppl.3),1--186 ©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd
CARRIERS AND PRENATAL ISSUES 7
03-CARRIERS AND PRENATAL ISSUES
ValidationoftheSelf-BAT(Self-administeredBleedingAssessmentTool) Interviewee Issues
inhemophiliacarriers:preliminaryresults
JANE YOUNG,1 JULIEGRABELL,1ANGIETUTTLE,1 A Notificationofhereditaryissuestodaughterwithlittle
MEGHANDEFOREST,2 DAVIDGOOD,1,3NATALIA RYDZ,4,2 knowledgeofhemophilia
JOHNNYMAHLANGU,5WILMA HOPMAN1,3and
PAULAJAMES1,3 B Lackofgeneticissuesofhemophiliawithinfamilies
1QueensUniversity,Kingston,Ontario,Canada;2UniversityofCalgary,Calgary, C NegativeimpactofHIVondaughter’slifestyleregarding
Alberta,Canada;3KingstonGeneralHospital,Kingston,Ontario,Canada;4Foothills marriageandgivingabirth
Hospital,Calgary,Alberta,Canada;and5TheNationalHealthLaboratoryService D Avarietyofconflictsinthefamily
NHLS,UniversityofWitwatersrand,Johannesburg,SouthAfrica
E Noreadinessforacceptinghemophilia
Introduction and Objectives: Approximately 30% of carriers of hemophilia (HC)
manifest low FVIII or FIX levels and can have abnormal bleeding symptoms.
Currently,thereisnostandardizedtoolfortheassessmentofbleedingsymptomsin
HC.TheSelf-administeredBleedingAssessmentTool(Self-BAT)wasdevelopedfrom
the expert-administered International Society on Thrombosis and Haemostasis Lifeevents,supporttakingexperiencesandhealthreadiness;psychosocial
BleedingAssessmentTool(ISTH-BAT)andoptimizedbystudyingindividualsknown difficultiesamonghemophiliccarriersinJapan(Apilot)
tohaveType1vonWillebranddisease(VWD)andhealthycontrols.Ourobjectives TOSHIYA KUCHII,1AKIKOKAKINUMA,1KAYOINOUE,2
forthisstudyaretoensureahighdegreeofconsistencybetweentheSelf-BATand YUKIKOSEKI3andKATSUMIOHIRA1
ISTH-BATbleedingscores(BS)inHCandtovalidatetheSelf-BATasascreeningtool 1SocialWelfareCorporationHabatakiWelfareProject,Hatataki,Japan;2Graduate
foridentifyingHCwithlowFVIIIorFIXlevels. SchoolofHumanitiesandSciences,OchanomizuUniversity,Ochanomizu,Japan;and
Patients, Materials and Methods: This is a multi-centre, international, prospective 3FacultyofEducation,SaitamaUniversity,Saitama,Japan
studywithparticipationfromQueen’sUniversityinKingston,Canada,theUniversity
ofCalgaryinCalgary,Canada,andtheUniversityofWitwatersrandinJohannesburg, Background:Carriersofhemophiliastillhaveavarietyofpsychosocialdifficultiesas
SouthAfrica.EligiblesubjectswerefemalecarriersofhemophiliaAorB,>18years wellasinsufficientsocialsupportresources(Kakinuma,WFH,2012).
of age. Subjects were excluded if they had another potential cause of bleeding. Objectives:Thepurposeofthisstudywastoexamineexplanatoryempiricalmodels
Followinginformedconsent,subjectswereadministeredtheISTH-BATandtheSelf- amongJapanesecarriersofhemophiliainvolvingdifficultiesingettingsocialsupport,
BATinrandomorderatleasttwoweeksapart.Atthefirstvisit,abloodsamplewas as well as to develop a social support readiness scale including elements such as
obtainedforcoagulationfactortesting,FVIIIorFIXgenotypingandABO. knowledgeabouthemophilia,supportexperienceandpotentialsocialsupportneeds,
Results: To date, 15 HC have been enrolled in Kingston. Of the 15, 11 have asapilotstudy.
completedbothBATsand9havehadtheirrelevantfactorleveldetermined.Datacan Methods: A self-administered questionnaire was administered to 30 hemophilic
befoundinTable1.PreliminaryanalysisshowsthattheBSsfromtheISTH-BATand carrierscomprisedofobligatecarriers(n=21,70.0%)andpossiblecarriers(n=9,
Self-BAT are highly correlated, with an Intraclass Correlation Coefficient of 0.87. 30.0%)thathadbeenrecruitedbythesnowballapproach.Thefollowingvariables
Additionally,apositive orabnormalSelf-BATBS (≥ 5) hasa sensitivity of100%, werecollected:maritalstatus,childbirthexperience,age(20-39,n=7,23.3%),(40-
specificityof50%,apositivepredictivevalueof0.75andanegativepredictivevalue 59,n=7,23.3%),(60+,n=16,53.4%).Theoriginalscalesweredeveloped,which
of1.0fortheidentificationofthosewithlowcoagulationfactorlevels. wereknowledgeabouthemophilia(6items,rangescore6-30,Cronbach’sa=0.906),
Conclusion:PreliminaryanalysisofourdatasuggeststhattheSelf-BATisahighly experienced social support (8 items, range score 8-40, Cronbach’s a=0.837), and
effectivetooltoincorporateintotheclinicalassessmentofHCs.TheSelf-BATallows social support needs (8 items, range score 8-40, Cronbach’s a=0.842). Multiple
the identification of HC who will benefit from treatment strategies aimed at regressionswereconductedtoestimatetherelationshipsamongvariablesorscales.
controllingbleedingsymptomsandwillfacilitateimprovementsinthemanagementof Results:We obtainedresults asfollows: 1)Age-adjustedsocial supportneeds were
thesepatientsoverall. strongly explained by the experience of childbirth. 2) The effect of childbirth
experiencewasdiminishedbytheadditionofknowledgefactor.3)Astrongeffectof
experienced social support was found, and the effect of knowledge factor was
Table1. decreased in the full model. 4) In the full model, the explanatory model was
improved.
HemophiliaA HemophiliaB
(n=10) (n=1) DiscussionandConclusions:Theeffectofknowledgeandsocialsupportexperience
were found to be mediators. Practical values of good readiness experiences were
Age(years) 46 29 suggested when applying a diverse of social support resources to carriers of
Mean(range) (27–64) hemophilia. Based on our study, we need to develop a planning program and
multidisciplinary support for carriers of hemophilia in Japan, focusing on health
FactorLevel(IU/mL) 0.47 0.75 literacy,diseaseprevention,andgeneticcounselingaswellasemergingsocialsupport
Mean(range) (0.17-0.95)(n=9) resourcesandnetworks.
Self-BATBleedingScore 10 4
Mean(range) (1–21)
ISTH-BATBleedingScore 9 3 TheuseofBclIRestrictionFragmentLengthPolymorphismfor
Mean(range) (1–18) hemophiliaAcarrierdetectioninSudanesefamilies
RAYANN.YOUSIFELSHEIKH
InstituteofEndemicDiseases,UniversityofKhartoum,Khartoum,Sudan
IntroductionandObjectives:HemophiliaAisthemostcommonX-linkedinherited
bleedingdisordercausedbyadeficiencyintheactivityofcoagulationfactorVIII,with
anincidenceof1in5000malebirths.Theaimofthisstudywastoinvestigatethe
HowweaddresssupportneedsandhereditaryissuesinJapanese usefulness of BclI restriction fragment length polymorphism (RFLP) in the linkage
hemophiliccarriers?Narrativecasestudybasedonsemi-structured analysis for carrier detection in Sudanese families, in order to formulate an
interviews(apilot) informativeandaccuratecarrierdiagnosis.
AKIKOKAKINUMA,1TOSHIYAKUCHII,1 KAYOINOUE,2 Materials and Methods: The study included 20 families with at least one subject
YUKIKO SEKI3andKATSUMIOHIRA1 affected with hemophilia A, and 30 unrelated normal females as a control group.
1SocialWelfareCorporationHabatakiWelfareProject,Hatataki,Japan;2Graduate Polymerasechainreaction(PCR)andrestrictionenzymeanalysiswereusedtostudy
SchoolofHumanitiesandSciences,OchanomizuUniversity,Ochanomizu,Japan;and thepolymorphisminBclI.
3FacultyofEducation,SaitamaUniversity,Saitama,Japan Results:TheincidenceofBclI(+)allelewas78%,39.5%and33%inpatients,female
Background: As with other genetic disorders, hemophilia can considerably affect relatives and the control group, respectively. Expected heterozygosity for BclI was
interpersonalrelationshipsanddisruptpatients’familylife.Thesituationisevenmore 0.48infemalerelativescomparedwith0.46inthefemalecontrolgroup.However,
complicatedduetocasesofHIVcontaminationintheearly1980s.Ourprojecthas observedheterozygositywasfoundtobe0.54infemalerelatives,comparedwith0.66
been dedicated to helping both Japanese HIV victims, and their families since our in the control group. The defective X chromosome was identified in 13/20 (65%)
establishmentin1997.Wehavepreviouslypresentedourstudy,addressinghowto mothers,hencethismarkeralonewasfoundtobeinformativein65%ofthestudied
effectivelysupportpatients(Kakinumaetal,2012WFHcongressinParis). families.
Objectives: Our goal is to identify the social support needs and strategies of Conclusion:ThisstudydemonstratedthatthePCR-basedanalysisoftheBclIRFLP
hemophiliccarriersinJapan,thoughathoroughanalysisoftheirhealthhistory. wasusefulinthecarrierdetectionofhemophiliaAintheSudanesepopulation.
Methods: Semi-structured interviews were conducted among women with carrier
statusorwomenwithafamilyhistoryofhemophilia.Oursurveywasconductedin
accordance with qualitative research protocols. An analysis of each case was
comprehensivelyinvestigatedbyresearchers,focusingonobjectivefacts.
Results:Issuesthatwereidentifiedareasfollows:
DiscussionandConclusions:Inaseriesoffiveinterviewswithfamilymembers,we
obtainedthesefindings.1)Lackofinformationsharingamongfamilymembers.2)
Imperfect relationships between family members and a daughter who may be a
carrier.3)Hesitantattitudebyfamilymemberstowardspeoplewithhemophilia.Our
studiessuggestthatcomprehensivegeneticcounselingisnecessaryforcarriers.
©2014TheAuthors Haemophilia(2014),20(Suppl.3),1--186
Haemophilia©2014JohnWiley&SonsLtd
8 CARRIERS AND PRENATAL ISSUES
Non-invasiveprenataldiagnosisforearlydetectionoffetalsexin testingisnotalwaysavailableandclinicianssometimesrelyonwomen’s’FIXlevelsto
X-linkeddisorders determine carrier status. Over the last decade, our clinic implemented a policy of
SILVIALINARI,1CLAUDIAGIACHINI,2 genetictestingonallpatientswithhemophiliaanddeterminedtheirmothers’carrier
FRANCESCAGERUNDINO,2 CHIARAPESCUCCI,2 status.Recently,wehavealsobeenobtainingbaselineFVIII/FIXlevelsonallcarrier
SABRINA FRUSCONI,2FIAMMETTASBERNINI,2 mothers regardless of whether they demonstrate clinical bleeding. We present the
ENRICO PERITI,3ELISABETTAPELO,2 MASSIMO MORFINI1 results of our evaluation of our HB mothers. Currently, 74 boys with HB are
andFRANCESCATORRICELLI2 registeredinourgeneticsdatabase.Theseboyshave65mothers(somemothershave
1AgencyforHaemophilia;and2DiagnosticGeneticUnitand3PrenatalDiagnosis ≥1affectedson).Ofthese65mothers,42(64.5%)areobligatecarriers.Additionally,
Unit,UniversityHospitalofFlorence,Italy 15mothers(23%;allwithanegativefamilyhistoryofhemophilia)wereproventobe
carriersbygenetictesting.In7mothers(11%),genetictestingwasneverperformed,
IntroductionandObjectives:Thedeterminationoffetalsexisindicatedforcarriersof as these mothers were not available for testing (deceased; child adopted or family
X-linkedgeneticconditions(suchashemophiliaAandB)andforthosepatientsat moved before mother tested). Only 1/65 mothers (1.5%) was proven not to be a
riskofconditionsassociatedwithambiguousdevelopmentoftheexternalgenitalia. carrier;hersoncarriedaninsertionmutationatn20458(exonF)causingaframeshift
Thisistraditionallyperformedbyinvasivetestingafterthe11thweekofgestation, atcodon160.In29carrierswherebothgeneticresultsandFIXlevelswereavailable,
usingeitherchorionicvillussamplingoramniocentesis.Thediscoveryofcell-freefetal themother’smedianFIXlevelwas68%(IQR:51-74%;min/max,29/122%).Only7/
DNA(cffDNA)inmaternalplasmahasopenedupnewpossibilitiesfornoninvasive 29mothers(24%)hadFIXlevels <50%.FIXlevels werenotstatisticallydifferent
proceduresinprenataldiagnosis(NIPD),withnoriskoffetalloss. (p=0.79)betweenmothersofboyswithsevereHB(n=12;median:70%,IQR:55-
Materials and Methods: The aim of the study is to optimize and validate a 82),moderateHB(n=12;median:62%,IQR:50-72;)andmildHB(n=5;median:
noninvasiveprocedureforsexdeterminationonalargecohort(n=2000)ofpregnant 61%, IQR: 52-68). FIX levels were not statistically different (p=0.94) between
womenatdifferentgestationalperiods(8–11weeks).Themolecularmethodconsists mothers carrying missense mutations (n=22; median: 65%; IQR: 52-73%) vs.
ofamultiplexqRT-PCRtargetingYchromosome-specificsequences(SRYandDYS14 motherscarryingothermutations(n=7;median:69%;IQR:48-83%).Inconclusion,
genes).Sinceafemalefetusispredictedbyanullresult(absenceofYchromosome- ourdataindicatethatwhenaboyisdiagnosedwithHBthelikelihoodofhismother
specificsequencesamplification),whichcouldindicatetheabsenceofcffDNAorthe beingacarrierisbetween88%(57/65)and98%(64/65).Furthermore,mostcarrier
failure of the test, the simultaneous analysis of a fetal-specific DNA marker as an mothershavebaselineFIXlevelsthatare>50%,provingthatFIXlevelsareunreliable
internalcontrolisrequiredtoconfirmthepresenceofcffDNA,inordertoavoidfalse atpredictingcarrierstatusinmothersofboyswithhemophilia.
negative results. The set-up of fetal-specific (epigenetic) marker analysis – i.e.
sequencesthataredifferentiallymethylatedinmaternalbloodcellsandfetalplacenta
–representsthesecondaimofthisstudy.Real-timePCRresultswerecomparedwith
QF-PCR/karyotype results and/or with follow up data to establish the sensitivity/ CharacteristicsofhemophiliacarriersinclinicandtestinginNational
specificityofthemethods,andthereforewhetherthistestcouldbesuitableforroutine InstituteofHematologyandBloodTransfusion,Hanoi,Vietnam
clinicalsettings. NGUYENHOANGHA, NGUYENTHINU, NGUYENTHIMAIand
Results:Atotalof1300maternalplasmasampleshavebeencollectedandthefirstsetof NGUYENANHTRI
250 samples have been analyzed. At present, postnatal sex identification or fetal NationalInstituteofHematologyandBloodTransfusion,Hanoi,Vietnam
karyotyperesultswereavailablefor148samples,showinga100%concordancebetween
resultsobtainedbyRT-PCRandfollow-updata.Sensitivityandspecificityoftheassay IntroductionandObjectives:Carriersofhemophiliaexperiencesymptomssimilarto
areboth100%.Inthisstudy,5/148samplesbelongedtocarriersofhemophilia. thoseseeninmenwithmildhemophilia.Theyarepronetobruisingundertheskin,
Conclusions:Onthebasisofourpreliminarydata,weconcludethatnoninvasivefetal menorrhagia,prolongedbleedingafterinjury,surgeryorafterchildbirth.
sexdeterminationishighlyreliableanditcouldbeusedasanearlytesttoestablish Methods:Wehaveimplementedastudyinvolving72womenwhowerecarriersof
whetherinvasiveprenataldiagnosisneedstobeperformedonafetusatriskofX- hemophilia,including64carriersofhemophiliaAand8carriersofhemophiliaB.
linkeddisorders. Results: Average age was 35.2(cid:1)9.8, (12-58years old). Results included the
following: abnormal bleeding symptoms (31.9 %); prolonged bleeding after injury,
intervention(39.1%),menorrhagia(26.1%);othersymptomssuchaspurpura,gum
bleeding.Therewerenocaseswithmusculoskeletalbleeding.Resultsshowed29.2%
Atotalmanagementsystemofcarrierdiagnosisforhemophiliausing ofcarriershadprolongedAPTT(rAPTTfrom1.25–1.5).TheaveragefactorVIII
geneanalysis:resultsof24individualsin15Japanesefamilieswith levelofhemophiliaAcarrierswas51.68(cid:1)20.31,andtheaveragefactorIXlevelof
hemophilia hemophiliaBcarrierswas55.13(cid:1)18.0.
KAGEHIRO AMANO,1,2TAKESHIHAGIWARA,2 Conclusions: Hemophilia carriers with prolonged APTT have a bleeding risk 3.57
TAKASHISUZUKI,2HIROSHIINABA2 and timeshigherthanthosewithoutprolongedAPTT.Hemophiliacarriershavingfactor
KATSUYUKIFUKUTAKE1,2 VIII/IX≤40%incomparisonwithoneshavingfactorVIII/IX>40%willhavea
1DepartmentofMolecularGeneticsofCoagulationDisorders;and2Departmentof riskofmenorrhagia5.65timeshigherandariskofprolongedbleedingafterinjury
LaboratoryMedicine,TokyoMedicalUniversity,Tokyo,Japan 5.7timeshigher.
Introduction:HemophiliaAandBarehereditaryX-linkedbleedingdisorderscaused
by gene mutations in coagulation factor VIII (FVIII) or IX (FIX) resulting in an
absence or reduced activity of FVIII or FIX. Confirmation of the carrier status of Thrombingenerationcapacityandbleedingphenotypeincarriersof
womeninfamilieswithahistoryofhemophiliaisvaluableforthesesubjectsandtheir hemophiliaA
relatives. Until recently, carrier diagnosis has been performed by standard pedigree FARIBABAGHAEI,1MARGARETAHELLGREN,2
analysis and conventional clotting factor assays. However, because factor activity ERIK BERNTORP,3 MARGARETA HOLMSTRO€M4and
varies by X-lyonization and daily variance etc., the subjects on whom carrier ANNAOLSSON1
diagnoseswasdoneusingabloodcoagulationtesthavenotbeenpreciselyidentified. 1CoagulationCentre,DepartmentofMedicine/HematologyandCoagulation
Objectives Disorders,SahlgrenskaUniversityHospital,Gothenburg,Sweden;2Departmentof
Weaimedtoapplygeneanalysistocarrierdiagnosisforhemophiliaandtodevelopa ObstetricsandGynaecology,SahlgrenskaAcademy,UniversityofGothenburg,
precisecarrierdiagnosissysteminhemophiliaclinics,undertheapprovaloftheethics Sweden;3DepartmentofHematologyandCoagulationDisorders,Sk(cid:3)aneUniversity
committeeonmedicalresearch,TokyoMedicalUniversity. Hospital,Malmo€,Sweden;and4CoagulationUnit,HematologyCentre,Karolinska
Methods:Atotalmanagementsystemfrominformedconsentthroughthereportingof UniversityHospital,Stockholm,Sweden
results was generated. Purified PCR templates from genomic DNA were directly
sequenced.AnalysisofLongPCRwasusedtodetectinversion. IntroductionandObjectives:HemophiliaisanX-linkedrecessivegeneticdisorderand
Results:Twentyfemaleswhobelongedto13familieswithahistoryofhemophiliaA femaleswhoinheritthegenemutationareknownascarriersofdisease.Studieshave
and 4 females who belonged to 2 families with a history of hemophilia B were suggestedanincreasedbleedingtendencyinsomecarriers,evenwhenclottingfactor
analyzedforcarrierdetectionbygeneanalysis.OneobligatecarrierofhemophiliaA levelsarewithinthelowernormalrange.Thus,thefactorlevelsmightnotbeagood
was included in the subjects. Seventeen females were diagnosed as carriers and 3 predictorofbleedingtendency.PreviousstudieshaveshowntheabilityofTGassay
femaleswerediagnosedasnon-carriersinfamilieswithhemophiliaA.Inversionof (TGA) to identify a milder bleeding phenotype among certain patients with
intron 22 in the heterozygous state were identified in 7 females. Six missense hemophilia. In this study, we aimed to investigate the association between TGA
mutations,3deletions,and1nonsensemutationwereidentifiedintheheterozygous outcomes and bleeding phenotype as well as clotting factor levels in carriers of
state.Threefemaleswerediagnosedascarriersin2familieswithhemophiliaBand hemophiliaA.
identifiedmissensemutationsintheheterozygousstate.Resultsforafemalefroma MaterialsandMethods:CarriersofsevereandmoderatehemophiliaA,registeredat
familywithahistoryofhemophiliaBfamilyhavenotyetbeenconducted. thethreehemophiliacentresinSweden,wereeligibletoparticipateinthestudy.Each
Conclusions: The prenatal diagnosisof hemophiliais not performed in Japan. The femalecarriersuggestedafemalefriend(withnobleedinginherownmedicalhistory
carrier diagnosis is important to ensure the safety of carriers and babies during or family history) as a control to evaluate bleeding tendency according to a
delivery.Ourcarrierdiagnosissystemwillplayanimportantroleinenhancingthe standardisedbleedingassessmenttool.VenousbloodforcoagulationanalysesandTG
qualityoflifeinpatients,carriersandrelativeswithhemophilia. wascollectedandanalysedonlyforcarriers.TGAwasperformedusingthecalibrated
automatedthrombinmethod(CAT)onPPP(plateletpoorplasma).
Results: The type of data which will be submitted later on are based on TGA
outcomesonthecarriersandcorrelationswithbleedingtendencygivenasbleeding
FactorIXlevelsinanunselectedpopulationofmothersofHaemophilia score(BS),aswellasassociationsbetweenTGAandcoagulationfactorlevels.The
Bpatients upcominganalysiswillbeperformedonfinalresults.Ourintensionistosubmitthe
MATTIARIZZI,1VANESSABOUSKILL,2 CINDY WAKEFIELD,2 finalupdateddata,includingresultsandconclusions,beforeMarch1,2014.
ANN MARIE STAIN,2CECILIAMANUEL1and
MANUEL CARCAO1
1DepartmentofPaediatrics,DivisionofHaematology/Oncology;and2Departmentof
Nursing,TheHospitalforSickChildren,UniversityofToronto,Toronto,Canada
FactorIX(FIX)levelsshowconsiderablevariabilityincarriersofhemophiliaB(HB).
Genetictestingistheonlyreliabletooltodeterminecarrierstatus.However,genetic
Haemophilia(2014),20(Suppl.3),1--186 ©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd
CARRIERS AND PRENATAL ISSUES 9
Influenceofpsychologicalandsocialfactorsonhealth-relatedqualityof ProfileofsuspectedwomencarriersforHaemophilia-Ainanew
lifeincarriersofhemophilia hemophiliacentre
CORNELIAWERMESandMARIOVONDEPKAPRONDZINSKI SHRUTIKATE,1SUNITAAGGARWAL,2,3ALPANASAXENA3and
WerlhofInstitute,Hanover,Germany NARESH GUPTA2,4
1TataMemorialHospital,Mumbai,India;2MaulanaAzadMedicalCollege,New
Introduction and Objectives: Hemophilia is a severe inherited x-linked bleeding Delhi,India;3LokNayakHospital,NewDelhi,India;and4HaemophiliaCentre,Lok
disorder. About 50 per cent of female carriers have reduced factor levels and are NayakHospital,NewDelhi,India
suffering from bleeding episodes themselves. In addition, emotional and social
problemscouldhaveanimpactontheQualityofLife(QoL)ofcarriers. IntroductionandObjectives:HemophiliaAisX-linked,recessive,inheritedbleeding
Materialsandmethods:Carrierswereaskedaboutseveralissues,includingbleeding disorder,withresultantdeficiencyofprocoagulantfactorVIII.Womenarethecarriers
history,familyplanning,andtheirsociallifeusingananonymousquestionnaire.QoL of this disease, and can be classified as obligate or possible carriers. Clinical,
hasbeenmeasuredbythestandardizedshortversionoftheWHO-QoL-100-test(bref- haemostatic and genetic profiles of suspected women carriers from families of
test), including the results of a normalfemale population, which served as control haemophilia patients attending our hemophilia centre in New Delhi, India were
group. The test consists of 26 items and 5 domains including physical, emotional, studied.
social,environmental,andglobalaspectsofQoL.AhigherscoremeansahigherQoL MaterialsandMethods:Amongst25familiesofhemophiliacpatientsattendingour
withamaximumof100. hemophilia centre, 61 suspected women carriers were identified and subjected to
Results:Inthismulticentrestudy318carrierswithamedianageof27yearswere pedigreeanalysis,andhematologicalinvestigationsincludingprothrombintime(PT),
enrolled.Ofthose,80%werecarriersforhemophiliaA,and70%carriedthesevere activated partial thromboplastin time (A PTT) and Factor VIIIc assay. Molecular
form. We recorded that 78.3% lived in partnerships, and 87.7% had at least one geneticanalysisbylinkageanalysisusingmarkerbcl1forIntron18wasdonein31
child.TheoverallQoLwascomparabletothenormalpopulation.Onlytheemotional suspectedcarriers.
domainshowedslightlyreducedvalues(70.24versus72.49).Wefoundthat72%of Results:Amongstthetotalsuspectedcarriers,therewere47(77%)possiblecarriers
carriersweresufferingfrombleedslikeMenorrhagia,hematomas,andepistaxisand and14(23%)obligatecarriers.Nobleedinghistorywasrecordedin57(93.45%).
had a lower QoL. Anxiety occurred in 77%. QoL was reduced (Emotional 69.08 Hemoglobinwasnormalin24outof61suspectedcarriers(39.4%),mild(Hb10-12)
versus75.34;p<0.004;Social70.09versus79.78;p<0.0001;Global70.82versus andmoderately severe(Hb 7-10) anemia were found in 33 (54.1%) in 4 (6.55%)
76.41;p<0.046).Feelingofguiltin47.8%reducedQoL(Emotional66.93versus cases respectively. Abnormal APTT was seen in 6/61 (10%) of suspected carriers.
74.38, Social 68.24 versus 76.49; p<0.0001; Environment 72.00 versus 76.01; MeanfactorVIIIclevelinthesesuspectedcarrierswas25.47(cid:1)16.3%.Eightyseven
p<0.013). Conflicts in the family (42.5%) lead to reduced QoL (Physical 78.06 percent(53/61)ofcarriershadabnormallylowfactorVIIIclevelandonly8/61had
versus82.66;Emotional66.37versus73.79;Social66.29versus77.07;Environment normallevels.MeanfactorVIIIlevelamongstsuspectedwomencarrierswithpositive
71.11 versus 75.94; Global 68.14versus 75.54; p<0.008). Feelingsof depression, familyhistory(inheritedcase)wassignificantlylowerat22.6%(cid:1)8.8%comparedto
andreducedcommunicationabouthemophiliaalsohadanegativeinfluenceonQoL. 26.9%(cid:1)19.1%forwithoutpositivefamilyhistory(sporadiccase),pvalue=0.04.Out
Conclusion:Comparingcarrierswhoareworriedabouttheirstatusorthehemophilia of25 families, ten families (10 confirmedpatients and 31suspected carriers) were
intheirfamilies,thosewithfeelingsofguiltoranxiety,carrierswithconflictsinthe selectedformoleculargeneticprofilingbyRFLPlinkageanalysisusingBCL1(Intron
family,orthosewithproblemsintheirsocialenvironmentsuffersignificantlymore 18)andHINDIII(Intron19)markerswhichgavenon-informativeresults.
often from a reduced QoL in contrast to carriers who have not these feelings or Conclusions:Whereasthemalepatientswithhemophiliaareaffectedclinically,the
problems. asymptomaticfemaleswithasinglemutatedgenearethecarriersofdisease.Evena
clinicalandbasichematologicalevaluationofthesuspectedwomencarrierscanbe
informativepriortothemoleculargeneticanalysistoassessthecarrierstatus.
©2014TheAuthors Haemophilia(2014),20(Suppl.3),1--186
Haemophilia©2014JohnWiley&SonsLtd
10 CLINICAL ASPECTS
04-CLINICAL ASPECTS
Thrombingenerationassayinhemophilicpatientswithorwithout Non-musculoskeletalsurgeryinpatientswithhemophilia:Asinglecentre
inhibitorundergoingorthopedicsurgery experience
MARIAELISAMANCUSO,VEENACHANTARANGKUL, AUROVISWABANDYA,1ABRAHAMSUNDER SINGH,1
MARIGRAZIA CLERICI,MARIAROSARIA FASULO, ABYABRAHAM,1ABHIJEETP. GANAPULE,1BIJUGEORGE,1
LIDIAPADOVAN,ERICASCALAMBRINO,FLORAPEYVANDI, VIKRAMMATHEWS,1M.J.PAUL2andALOKSRIVASTAVA1
ARMANDO TRIPODIandELENASANTAGOSTINO Departmentsof1Haematology,and2EndocrinologySurgery,ChristianMedical
AngeloBianchiBonomiHemophiliaandThrombosisCenter,FondazioneIRCCSCa’ College,Vellore,India
GrandaOspedaleMaggiorePoliclinico,Milan,Italy
Introductionand Objectives: Thereis limited data in the literature describing non-
Introduction and Objectives: Laboratory monitoring of patients with hemophilia musculoskeletalsurgeryinpatientswithhemophilia.Thereishardlyanydatafrom
undergoing surgery is limited to the measurement of factor VIII (FVIII) levels. No developingcountries.Herewedescribeourdataonnon-musculoskeletalsurgeryin
routinecoagulationmonitoringisavailableforinhibitor(INH)patientstreatedwith patientswithhemophilia.
by-passing agents (BPA). The aims of this study were to assess if TGA is able to MaterialsandMethods:Datawasreviewedfromthemedicalrecordsofallpatients
provideinformationonglobalcoagulationactivationafterFVIIItherapyinnon-INH withhemophilia(bothAandB)whowereseenforsurgeryfornon-musculoskeletal
patientsandifinINHpatientsitisrelatedtothehemostaticandclinicalresponseto indicationsbetween2002andAugust2013.Patientswithinhibitorswereexcluded.
BPA. Forsurgicalhemostasis,wefollowedalowerdoseclottingfactorconcentrate(CFC)
Materials and Methods: TGA was assessed in platelet-rich (PRP) and platelet-poor infusionprotocolaspreviouslyreported(Srivastavaetal,Haemophilia1998;4;799–
(PPP)plasmawiththeadditionofcorntrypsininhibitor(CTI)in17patientswith 801).
severehemophiliaA(9withhigh-respondinginhibitors)aged5-59years(median:39) Results:Atotalof52patientswereincludedinthisanalysis:38withhemophiliaA
undergoingorthopedicsurgery.FourparametersoftheTGAcurve wereevaluated: (severe-28,moderate-5andmild-5)and14withhemophiliaB(severe-9;moderate-3,
lagtime, endogenous thrombin potential (ETP), peak and time-to-peak. TGA was mild-2).Thesurgeriesincludedherniarepair(12),fasciotomyandwounddebridement
assessedoncedailyprior,and30minutesafter,druginjection(FVIIIorBPA)starting (5), hydrocelectomy (5), circumcision, appendectomy, nephrectomy (3 each),
fromthepre-operativebolusandfor4post-operativedays.Hemostatictreatmentto percutaneous nephrostomy, pyloroplasty, stent for stricture urethra (2 each), atrial
coversurgicalprocedureswasestablishedirrespectiveofTGAmeasurements.Innon- septal defect (ASD) closure (1), skin grafting (4), thyroidectomy (2), nasal
INHpatientsFVIIIlevelsweremeasuredonthesamebloodsamples. polypectomy, parotidectomy, bilateral phaeochromocytoma excision, carpal tunnel,
Results:Inthegroupof8non-INHpatientsTGAvaluesincreasedafterthefirstFVIII anoplasty,colostomy(1each),Themedianageofthepatientswas30years(range:3–
infusion, however during the post-operative period (FVIII trough levels >50IU/dL) 65).Themedianpre-procedurefactorlevelafterloadingdosewas89%(range:54–
TGAwasscarcelysensitivetothesignificantvariationobservedinFVIIIlevelsprior 218).Themediantroughfactorlevelsondays1,3,5and7were36%(range:15-83);
(median: 74%) and after daily infusions (median: 155%; p<0.001); a correlation 35% (range: 6 – 121); 29% (range: 6–74) and 16% (3–36%), respectively. The
betweenTGAandFVIIIlevelswasobservedonlyforETPandpeakinPPP+CTI.In median total dose of CFC used was 243IU/kg (range: 122 – 658). The median
thegroupof9INHpatientsTGAincreasedafterBPAinjectionhoweverTGAdidnot duration of factor support was 8days (range: 4–16). Seven (13%) patients had
reveal differentresponses related to the type of BPA (rFVIIa/aPCC), the doseused complicationspost-surgery:(infectionandbleeding-2,haematoma-2(however,didnot
and/ortheoccurrenceofbleedingcomplications(n=5).Moreover,alackofresponse requirere-exploration),resuturing-1(slippedligature),inhibitorformation-1,expired-
of the TGA curve was observed during the post-operative period irrespective of 1(diverticulitiswithintestinalperforationandintra-abdominalabscess)).Only8%of
treatmentregimenmodificationsinallINHpatients. thesewereclinicallysignificant.
Conclusion: Our results indicate that TGA is not a suitable tool to monitor Conclusion: Major surgery in patients with hemophilia presenting with non-
hemostatic response during surgery in hemophiliacs: in non-INH patients TGA is musculoskeletal indication is feasible with lower doses of CFC when resources are
moderately sensitive to FVIII levels variations and does not provide additional limited,andnomajorcomplicationswereseeninover90%ofpatients.
information on coagulation activation during replacement therapy and in INH
patientsTGAisnotabletopredicteitherthehemostaticresponsetodifferenttypeof
BPAand/ordosesusednortheriskofbleedingcomplications.
Across-sectionalstudyofcomorbiditiesandhypertensioninpatientswith
hemophiliaAandBinEurope:InterimresultsfromtheH3study
P(cid:2)ALANDRE HOLME,1 CHRISTOPHECOMBESCURE,2
Cognitivedisorderinadultpatientswithhemophilia:AclinicalandMRI ERIK BERNTORP3andCAMPBELLTAIT4
study 1DeptofHematology,OsloUniversityHospital,Rikshospitalet,Oslo,Norway;
EZIOZANON,1 RENZO MANARA,2 BARBARABRANDOLIN,1 2UniversityofGenevaandUniversityHospitalsofGeneva,Geneva,Switzerland;
RODICAMARDARI,3SANDRAROSINI,4DANIELAMAPELLI5 3CenterforThrombosisandhemostasis,Sk(cid:3)aneUniversityHospital,LundUniversity,
andPIEROAMODIO6 Malmø,Sweden;and4Departmentofhematology,RoalInfirmary,Glasgow,UK
HaemophiliaCenterandDepartmentsof1Cardiac,Thoracic,andVascularSciences,
3Neuroradiology,DepartmentofNeurosciences;4CIRMANMEC;5General Introduction and Objectives: Retrospective studies suggest hypertension is more
Psychology;6Medicine,DIMED,UniversityofPadua,Italy;2Neuroradiology, prevalentamongpeoplewithhemophilia(PWH)comparedtothegeneralpopulation.
Hematuria and consequential renal disease are also common among PWH. Renal
DepartmentofMedicineandSurgery,UniversityofSalerno,Italy
disease is associated with hypertension in the general population. The ADVANCE
Introduction: Studies about the cognitive features of adult with hemophilia are Working Group, representing 20 hemophilia centres in 10 European countries,
lacking, despite some data showing low performance at school in children with conducted a cross-sectional epidemiological study (Hematuria and Hypertension in
hemophilia. Hemophilia;H3)toidentifyfactorsassociatedwithhypertensioninPWH.
Objectives: To describe the neuropsychological profile in adult patients with Materials and Methods: Each centre collected demographic and medical data at a
hemophiliaandassessitsrelationshipusingbrainimaging,toseverityofhemophilia singletime-pointperpatientinaround40consecutivelyrecruitedPWH,over40years
anditstreatment. of age. Descriptive analyses of the data were performed using basic summary
MaterialsandMethods:Afterobtaininginformedconsent,49adults(42(cid:1)15years) statistics. Hematuria-specific information was summarized in a severity index.
with hemophilia (31 severe, 18 mild), without inhibitors were enrolled. Patients Associationsbetweensuspectedfactorsanddiagnosisofhypertensionweretestedin
underwent: i) a psychometric battery comprising 13 tests; ii) brain Magnetic univariate analyses. Multivariate logistic regression modeling was conducted to
ResonanceImaging(MRI). identifyindependentpredictorsofhypertension.Thepredictiveperformanceofmodels
Results: Impaired overall cognitive performance was found in hemophilic patients wasassessedbyROCcurveanalysis.
(meanZscoreofthetests=-018(cid:1)0.07,73%ofthepatientshadalteredperformance Results: We enrolled 509 patients (median age 52years, range 35-98) with
on at least one test), which included a neuropsychological profile pointing to hemophiliaA(n=448,88%)orhemophiliaB(n=61,12%).Hemophiliawassevere
prefrontal functional impairment. Only a non-significant trend for more severe in 291 patients (58%), moderate in 55 (11%) and mild in 158 (31%), and 224
cognitive impairment in patients with severe hemophilia on-demand treatment was patients (44%) had hypertension. In multivariate analyses, age and BMI were
detectable. MRI findings, available in 44 patients, showed remarkable brain significantlyandindependentlyassociatedwiththeriskofhypertension(ORreached
abnormalities.Atrendtowardmorecerebralmicrobleeds(CmBs)wasfoundinsevere 10.7, p<0.001 in elderly patients and 11.5, p<0.001 in patients with BMI>30).
hemophiliatreatedon-demand;howeveracorrelationbetweenCmBsandagemight Patientswithahistoryofcoronaryheartdisease(5.6%,28/498)anddiabetes(48/506,
have biased the results. CmBs were found to be correlated with the reduction of 9.8%) were more at risk of hypertension (OR 3.3 p=0.04 and 2.8 p=0.02
overall psychometric performance (r=0.39 p<0.05) and the number of respectively).Asignificantassociationbetweencreatinineandhypertensionwasalso
cardiovascularriskfactors(r=0.33p<0.05). found(p=0.04).TheAUCforthismodelwas0.80.Inasecondmodel,hypertension
Conclusion: Minor cognitive impairment and high prevalence of minor brain riskincreasedsignificantlywithhematuriaindex(OR1.2perpoint,p=0.03)andin
abnormalitiesinMRIstudiesaredetectablein adultswithhemophilia;CmBswere patientswithafamilyhistoryofhypertension(OR3.6,p<0.001);theAUCforthis
foundtoberelatedtocognitiveimpairment,thusprovidingcuesforfurtherstudieson modelwas0.82.
braindamageinpatientswithhemophilia. Conclusion:H3representsthelargestcohortofolderpatientswithhemophiliawhere
systematicallycollected informationon hypertension andcomorbidities isavailable.
Established risk factors for hypertension were confirmed; further variables (e.g.
hematuria)seemtohaveanindependentinfluenceandneedtobefurtherinvestigated.
Haemophilia(2014),20(Suppl.3),1--186 ©2014TheAuthors
Haemophilia©2014JohnWiley&SonsLtd