Current and Future Issues in Hemophilia Care

178 Pages·2011·12.583 MB·English

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Current and Future Issues in Hemophilia Care
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Current and Future
Issues in
Hemophilia Care
EDITEDBY
EME´ RITO-CARLOS RODRI´GUEZ-MERCHA´ N MD, PHD
ConsultantOrthopedicSurgeon
DepartmentofOrthopedicSurgeryandHemophiliaUnit
LaPazUniversityHospital;
AssociateProfessorofOrthopaedicSurgery
SchoolofMedicine
AutonomousUniversity
Madrid,Spain
LEONARD A. VALENTINO MD
ProfessorofPediatrics,InternalMedicine,
Immunology/MicrobiologyandBiochemistry
Director,HemophiliaandThrombophiliaCenter
RushUniversityMedicalCenter
Chicago,IL,USA
A John Wiley & Sons, Ltd., Publication
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LibraryofCongressCataloging-in-PublicationData
Currentandfutureissuesinhemophiliacare/editedbyEme´rito-CarlosRodr´ıguez-Mercha´n,LeonardA.
Valentino.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN-13:978-0-470-67057-6(hardcover:alk.paper)
ISBN-10:0-470-67057-6(hardcover:alk.paper)
1.Hemophilia.I.Rodr´ıguez-Mercha´n,E.C.II.Valentino,LeonardA.
[DNLM:1.HemophiliaA–prevention&control. 2.HemophiliaA–therapy. 3.BloodCoagulation
Factors. WH325]
RC642.C872011
616.1(cid:2)572–dc22
2011007517
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
Thisbookispublishedinthefollowingelectronicformats:ePDF9781119979371;
WileyOnlineLibrary9781119979401;ePub9781119979388;Mobi9781119979395
(cid:3)
Setin9.25/12ptMinionbyAptaraR Inc.,NewDelhi,India
1 2011
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Contents
ListofContributors,vii 10 ManagingtheMaturePersonwithHemophilia,44
SavitaRangarajanandThynnThynnYee
Preface,xi
11 QualityofLifeinHemophilia,49
EduardoRemor
Part1: Introduction
Part3: Inhibitors
1 HistoryofHemophilia,3
CarolineCromwellandLouisM.Aledort 12 ImmunologyofInhibitorDevelopment,55
BirgitM.Reipert,ChristophJ.Hofbauer,
2 HemophiliaCareintheModernWorld,6
KatharinaN.Steinitz,Hans-PeterSchwarz,
ChristineA.Lee
andFrankM.Horling
3 ComprehensiveCareModelinHemophilia,10
13 EpidemiologyofInhibitors,60
PrasadMathew
JohannaG.vanderBom
14 EarlyTolerizationtoMinimizeInhibitorsinPUPswith
Part2: GeneralTopics
HemophiliaA,68
Gu¨nterAuerswaldandKarinKurnik
4 WhenShouldWeSwitchfromOn-Demandto
15 PredictionofInhibitorsinSevereHemophilia,74
ProphylaxisRegimen?,17
H.MarijkevandenBergandKathelijnFischer
Jos´eA.Aznar,AndresMoret,LydiaAbad-Franch,
AnaR.Cid,SaturninoHaya,andFelipeQuerol 16 GeneticBasisforInhibitorDevelopment,79
JohannesOldenburgandAnnaPavlova
5 ProphylaxisinChildren,21
MarilynJ.Manco-Johnson 17 Non-GeneticRiskFactorsforInhibitorDevelopment,84
LisaN.BoggioandMindyL.Simpson
6 ProphylaxisinAdultswithHemophilia,27
VictorJim´enez-Yuste,Em´erito-CarlosRodr´ıguez-Mercha´n,
Part4: InhibitorTreatment
Maria-TeresaAlvarez-Roma´n,andMo´nicaMart´ın-Salces
7 TheEconomicsofProphylaxis:DoesProphylaxiswith
18 ImmuneToleranceInductionPrograms,91
ClottingFactorRepresentValueforMoney?,30
JanBlatnyandPrasadMathew
AlecMiners
19 ProphylaxisinHemophiliaAPatientswithInhibitors,97
8 TheTransitionofCarefortheYoungAdultHemophilia
LeonardA.ValentinoandGuyYoung
Patient,35
PiaPetrini 20 TreatmentofBleedinginFVIIIInhibitorPatients,102
PaulL.F.GiangrandeandJeromeTeitel
9 PerinatalClinicalCareandMolecularDiagnosisin
Hemophilia,39 21 DiscordancyofBypassingTherapy,107
CarmenAltisentandFranciscoVidal JanAstermark
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Contents
Part5: JointHealthandDisease Part6: NewDevelopments
22 ExperimentalStudiesonHemarthrosis,Synovitisand 27 NewTechnologiesforthePharmacokineticImprovement
Arthropathy,113 ofCoagulationFactorProteins,141
LeonardA.ValentinoandNarineHakobyan LeonardA.Valentino
23 AssessmentofJointInvolvementinHemophilia,117 28 CurrentandFutureApproachestoGeneTherapyin
ErikBerntorp PatientswithHemophilia,146
Maria-TeresaAlvarez-Roma´n,MonicaMart´ın-Salces,
24 ImagingoftheHemophilicJoint,121
VictorJim´enez-Yuste,andEm´erito-Carlos
CarmenMartin-Herva´sandEm´erito-Carlos
Rodr´ıguez-Mercha´n
Rodr´ıguez-Mercha´n
29 NewDevelopmentsinHemophilicArthropathy,150
25 InitialandAdvancedStagesofHemophilicArthropathy,
Em´erito-CarlosRodr´ıguez-Mercha´nandLeonardA.
andOtherMusculo-SkeletalProblems:TheRoleof
Valentino
OrthopedicSurgery,127
Em´erito-CarlosRodr´ıguez-Mercha´n,VictorJimenez-Yuste, 30 PhysiotherapyEvaluationandInterventionintheAcute
andNicholasJ.Goddard Hemarthrosis:ChallengingtheParadigm,156
NichanZourikianandAngelaL.Forsyth
26 PerioperativeThromboprophylaxisforPersons
withHemophiliaUndergoingOrthopedic 31 LaboratoryAssaystoPredictResponsetoBypassing
Surgery,133 Agents,162
GerardDolan,DonnaM.DiMichele,andEm´erito-Carlos BennySørensenandClaudeNegrier
Rodr´ıguez-Mercha´n
32 Combination/SequentialUseofBypassingAgents,167
AlessandroGringeri
Index,171
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Contributors
LydiaAbad-FranchMD ErikBerntorpMD,PhD GerardDolanMBChB,FRCP,
SpecialistinFamilyMedicine ProfessorofHemophilia FRCPath
HemostasisandThrombosisUnit LundUniversity; ConsultantHaematologist
LaFeUniversityHospital Malmo¨CentreforThrombosisandHaemostasis NottinghamUniversityHospitals
Valencia,Spain Ska˚neUniversityHospital Nottingham,UK
Malmo¨,Sweden
LouisM.AledortMD KathelijnFischerMD,PhD
TheMaryWeinfeldProfessorofClinicalResearch JanBlatnyMD,PhD PediatricHematologistandClinical
inHemophilia ConsultantHematologist Epidemiologist
MountSinaiSchoolofMedicine DepartmentofPediatricHematology VanCreveldkliniek,DepartmentofHematology,
NewYork,NY,USA CenterforThrombosisandHemostasis andJuliusCenterforHealthSciences
Children’sUniversityHospitalBrno andPrimaryCare
CarmenAltisentMD Brno,CzechRepublic UniversityMedicalCenterUtrecht
Unitatd’Hemof´ılia Utrecht,TheNetherlands
HospitalUniversitariValld’Hebron LisaN.BoggioMS,MD
Barcelona,Spain AssistantProfessorofMedicineandPediatrics AngelaL.ForsythPT,DPT
DivisionofHematologyandOncology Physiotherapist
Maria-TeresaAlvarez-Roma´nMD RushUniversityMedicalCenter PennHemophiliaandThrombosisProgram
ConsultantHematologist Chicago,IL,USA HospitaloftheUniversityofPennsylvania
HemostasisandThrombosisUnit Philadelphia,PA,USA
LaPazUniversityHospital AnaR.CidMD
Madrid,Spain Hematologist PaulL.F.GiangrandeBSc,MD,FRCP,
HemostasisandThrombosisUnit
FRCPath,FRCPCH
JanAstermarkMD,PhD LaFeUniversityHospital ConsultantHaematologistandDirector
Valencia,Spain
AssociateProfessor OxfordHaemophiliaandThrombosisCentre
LundUniversity; ChurchillHospital
Malmo¨CentreforThrombosisandHaemostasis CarolineCromwellMD Oxford,UK
Ska˚neUniversityHospital AssistantProfessorofMedicine
Malmo¨,Sweden DivisionofHematology/Oncology NicholasJ.GoddardMBFRCS
MountSinaiSchoolofMedicine
ConsultantOrthopaedicSurgeon
Gu¨nterAuerswaldMD NewYork,NY,USA DepartmentofOrthopaedicSurgery
KlinikumBremen-Mitte RoyalFreeHospital
Ambulanzfu¨rThromboseund DonnaM.DiMicheleMD London,UK
Ha¨mostasesto¨rungen,Prof.-HessKinderklinik WeillCornellMedicalCollege;
Bremen,Germany DeputyDirector AlessandroGringeriMD,MSc
DivisionofBloodDiseasesandResources
DepartmentofMedicineandMedicalSpecialities
Jose´ A.AznarMD NationalHeart,LungandBloodInstitute FondazioneIRCCSCa`Granda–Ospedale
NewYork,NY,USA
HeadofHemostasisandThrombosisUnit MaggiorePoliclinicoandUniversityofMilan
DepartmentofHematologyandHemotherapy Milan,Italy
LaFeUniversityHospital
Valencia,Spain
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Contributors
NarineHakobyanPhD CarmenMartı´n-Herva´sMD,PhD SavitaRangarajanFRCP,FRCPath
AssistantProfessor ConsultantRadiologist ConsultantHematologist
RushHemophiliaandThrombophiliaCenter; DepartmentofMusculo-SkeletalRadiology ComprehensiveCareCentreforHaemophilia
DepartmentofPediatrics LaPazUniversityHospital; HaemostasisandThrombosis
RushChildren’sHospitalandRushUniversity AssociateProfessorofRadiology BasingstokeandNorthHampshireNHS
MedicalCenter SchoolofMedicine FoundationTrust
Chicago,IL,USA AutonomousUniversity Basingstoke,UK
Madrid,Spain
SaturninoHayaMD BirgitM.ReipertPhD
Hematologist PrasadMathewMB,BS,DCH,FAAP AssociateProfessor
HemostasisandThrombosisUnit ProfessorofPediatrics DirectorR&D
DepartmentofHematologyandHemotherapy Director,TedR.MontoyaHemophiliaProgram DepartmentofImmunology
LaFeUniversityHospital andPediatricHemostasis TABioTherapeutics
Valencia,Spain UniversityofNewMexico BaxterInnovationGmbH
Albuquerque,NM,USA Vienna,Austria
ChristophJ.HofbauerDipl.-Ing.(FH)
DepartmentofImmunology AlecMinersBSc(Hons),MSc,PhD EduardoRemorPhD
TABioTherapeutics LecturerinHealthEconomics AssociateProfessor
BaxterInnovationGmbH FacultyofPublicHealthandPolicy DepartmentofPsychobiologyandHealth
Vienna,Austria LondonSchoolofHygieneandTropicalMedicine FacultyofPsychology
London,UK AutonomousUniversity
FrankM.HorlingPhD Madrid,Spain
ManagerImmunotoxicology Andre´sMoretMS
DepartmentofImmunology HemostasisandThrombosisUnit Eme´rito-Carlos
TABioTherapeutics LaFeUniversityHospital Rodrı´guez-Mercha´nMD,PhD
BaxterInnovationGmbH Valencia,Spain ConsultantOrthopedicSurgeon
Vienna,Austria DepartmentofOrthopedicSurgeryand
ClaudeNegrier,MD,PhD HemophiliaUnit
VictorJime´nez-YusteMD,PhD Professor LaPazUniversityHospital;
ConsultantHematologist HematologyDivision AssociateProfessorofOrthopaedicSurgery
DepartmentofHematologyandHemostasisUnit EdouardHerriotUniversityHospital SchoolofMedicine
LaPazUniversityHospital; Lyon,France AutonomousUniversity
AssociateProfessorofHematology Madrid,Spain
SchoolofMedicine JohannesOldenburgMD,PhD
AutonomousUniversity ProfessorandDirector Hans-PeterSchwarzMD,PhD
Madrid,Spain InstituteofExperimentalHematologyand Professor
TransfusionMedicine VicePresidentandHeadTABioTherapeutics
KarinKurnikMD HaemophiliaCenterBonn BaxterInnovationGmbH
KlinikumBremen-Mitte UniversityClinicBonn Vienna,Austria
Ambulanzfu¨rThromboseund Bonn,Germany
Ha¨mostasesto¨rungen,Prof.-HessKinderklinik MindyL.SimpsonMD
Bremen,Germany AnnaPavlovaMD,PhD ClinicalInstructorofPediatrics
SeniorLecturer PediatricHematology/Oncology
ChristineA.LeeMA,MD,DSc,FRCP, InstituteofExperimentalHematologyand RushUniversityMedicalCenter
FRCPath,FRCOGadeundem TransfusionMedicine Chicago,IL,USA
EmeritusProfessorofHaemophilia HaemophiliaCenterBonn
UniversityofLondon UniversityClinicBonn BennySørensenMD,PhD
London,UK Bonn,Germany DirectorofHRUandAssociateProfessor
AarhusUniversity,Denmark;
MarilynJ.Manco-JohnsonMD PiaPetriniMD HaemostasisResearchUnit
Director,HemophiliaandThrombosisCenter; AssociateProfessor CentreforHaemophiliaandThrombosis
ProfessorofPediatrics DepartmentofPediatrics Guy’sandStThomas’NHSFoundationTrust
UniversityofColoradoDenver CoagulationUnit London,UK
Aurora,CO,USA KarolinskaUniversityHospital
Stockholm,Sweden KatharinaN.SteinitzMagRerNat
Mo´nicaMartı´n-SalcesMD DepartmentofImmunology
ConsultantHematologist FelipeQuerolMD,PhD,PT TABioTherapeutics
HemostasisandThrombosisUnit ProfessorofPhysiotherapy BaxterInnovationGmbH
LaPazUniversityHospital HemostasisandThrombosisUnit Vienna,Austria
Madrid,Spain LaFeUniversityHospital
Valencia,Spain
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Contributors
JeromeTeitelMD FranciscoVidalPhD GuyYoungMD
Professor,UniversityofToronto UnitatdeDiagno`sticiTera`piaMolecular PediatricHematologyandOncology
DivisionofHematologyandOncology BancdeSangiTeixits UCLAHealthSystem
StMichael’sHospital Barcelona,Spain LosAngeles,CA,USA
Toronto,ON,Canada
ThynnThynnYeeMD,FRCP NichanZourikianBSc,PT
H.MarijkevandenBergMD,PhD ConsultantHematologist Physiotherapist
PediatricHematologist KatharineDormandyHaemophiliaCentreand Sainte-JustinePediatric/AdultComprehensive
MeanderHospital,Amersfoort; ThrombosisUnit HemostasisCenterandQuebecReferenceCenter
DepartmentofChemistryandHaematology RoyalFreeHospital forCoagulationInhibitors
UniversityMedicalCenterUtrecht London,UK Sainte-JustineUniversityHospitalCenter
Utrecht,TheNetherlands Montreal,QC,Canada
LeonardA.ValentinoMD
JohannaGvanderBomMD,PhD ProfessorofPediatrics,InternalMedicine,
AssociateProfessorofClinicalEpidemiology Immunology/MicrobiologyandBiochemistry
DepartmentofClinicalEpidemiologyandJonJ Director,HemophiliaandThrombophiliaCenter
vanRoodCenterforClinicalTransfusionMedicine RushUniversityMedicalCenter
LeidenUniversityMedicalCenter Chicago,IL,USA
Leiden,TheNetherlands
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Preface
Anytextonhemophiliamustacknowledgetherootsofthedis- associatedco-morbidities.Finallytheissuesofinheritedbleeding
ease.Hemophiliaisanancientbleedingdisorder,firstdescribed disordersinwomenarediscussed.Mathewcontinuesinthissec-
in the 2nd century AD. Little attention was paid to this disease tiontointroducethecomprehensivecaremodelbutalsodraws
untiltheearly1900’swhenitwasdeterminedthatQueenVictoria attentiontothenecessitiesoffundinginordertosustainthepin-
passedthegenedowntoseveralofherdaughters,whocarriedthe nacleofcarethatshouldbethegoalofallnationsandprovidersof
diseaseintoseveraloftheroyalfamiliesofEurope.Assuch,the hemophiliacareinordertoreducemorbidityandmortalityand
careofhemophiliahasevolvedfromthetimeofAlexei,thesonof increasequalityoflife.
AlexandraandNicholas,CzarofImperialRussia,tothecurrent Thenextsectiondelvesintothedaytodaymanagementissues
comprehensive model of care which has resulted in substantial thatcaregiversfacewithourpatients.Thisbeginswithadiscus-
decreasesinmorbidityandmortalityandanimprovementinthe sionofprophylaxisinchildrenbyManco-Johnsonandmovesto
qualityoflifeofpatientswithhemophilia.Manymilestonesmark a review by Aznar and colleagues of the issues around chang-
thecourseoftimeforthediseasebutfewsoimportantasthedis- ing from an on-demand regimen to prophylaxis. This is espe-
coveryofcryoprecipitateinthe1960’swhichleadtodevelopment ciallyimportantincountrieswithlimitedresources.Minersdeals
ofadvancedproductstotreathemophiliaincludingrecombinant with the economics of prophylaxis in the next chapter address-
factorproductsessentiallydevoidoftheriskoftransmissionofin- ingthequestion,“Doesprophylaxiswithclottingfactorrepresent
fectiousdiseases.Theseadvancementslaidthefoundationforthe valueformoney?”Hisconclusion,althoughnotsurprising,offers
developmentoftreatmentregimensdesignedtopreventbleeding somewhatofamandatetothebleedingdisorderscommunityand
andthecomplicationsofbleeding.Prophylaxis,initiatedinyoung specifically to the manufacturers of clotting factor, to find ways
children, now has the potential to deliver patients into adoles- toreducethehighcostoftheselife-andjoint-savingbiologicals.
cence and adult life with normal joints, having nearly identical Jime´nez-Yusteandcolleaguesaddressthedifficulttopicofprophy-
qualityoflifeoftheirunaffectedpeers.Thistreatmentcomesata laxisforadultpatients.Althoughmanyproviderstreatingthese
price.Theeconomicvalueofprophylaxisinhemophiliaremains patientsfeeltheremaybesomebenefit,thecost-effectivenessre-
amatterofdebate,especiallyincountrieswithlimitedresources mainstobeprovenandrepresentsabarriertobeovercome.As
availableforhealthcare.Adherencetoprophylaxisandthetran- eachofushasdone(somebetterthanothersIsuspect),wehave
sitiontoindependenceremainsamajorconcernforprovidersof transitionedfromchildhoodtoadulthood.Thistaskisparticularly
care. Management of patients at the ends of the age spectrum problematicforpatientswithhemophiliaastheyfacenumerous
hasattractedconsiderableattention.Keytooptimalperinatalcare obstacles, which, as Petrini discusses in the next chapter, “can
andgeneticcounselingforcarriersofhemophiliaisanaccurate haveasignificantlynegativeeffectonmorbidityandmortalityin
moleculardiagnosisandappropriatemanagementofdeliveryto youngadults.”Theutilityandeffectivenessofprogramstospecif-
ahealthystarttolifeofaboywithhemophilia. icallyassistyoungpeoplewithhemophiliaduringthisvulnerable
Thistextattemptstoaddressthecurrentandfutureissuespa- timeawaitevaluationandmoreimportantly,validation.Asacon-
tientsaffectedwiththediseaseaswellasthenurses,doctorsand genital disease, hemophilia begins in neonates, not all of which
othercaregiverstreatingthesepatientsmustfaceinordertopro- aresymptomatic.However,sub-optimalcareatthisfragiletime
videoptimalcare.InthefirstthreechaptersCromwellandAledort canresultinalifetimeofchallengesfortheboywithhemophilia.
reviewthehistoryofhemophilia,anappropriatestartingplacefor AltisentandVidalreviewsthemanagementofpregnantwomen
anybooksuchasthis.NextLeediscussesthecareofhemophilia whoarecarriersofhemophiliaandappropriatemoleculardiag-
in the modern world focusing on the worldwide improvements nosis.Finally,thissectionendswithadiscussionbyRangarajan
in diagnosis and care and the new problems of ageing with its andYeeonmanagingthematurepersonwithhemophilia.This
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Preface
population brings many new challenges to hemophilia clinics with bypassing agents and the factors which may play a role in
acrosstheglobeincludinginsuringlinksbetweenhemophiliacare these divergent responses. When bleeding is poorly controlled,
providersandthoseintheareasofgeriatrics,oncology,cardiol- such as that which occurs in patients with inhibitors, the joint
ogy and primary care in order to provide a comprehensive and isthemainfocusofmorbidity.ValentinoandHakobyandiscuss
coordinatedapproachtocare. theexperimentalstudieswhichshedlightonthepathobiologyof
ThedevelopmentofalloantibodiesagainstfactorVIIIorfac- blood-inducedjointdisease.Berntorpthenprovidesareviewof
torIXwhichinhibitthefunctionofinfusedclottingfactoristhe theinstrumentsavailablefortheassessmentofjointfunctionand
mostcommon,serious complicationthatmustbefacedbythis Mart´ın-Herva´s and Rodr´ıguez-Mercha´n discuss imaging of the
population.Inhibitordevelopmentisonlyrecentlybeginningto jointstobetterquantifynotonlythedamagewhichoccursafter
be understood. Reipert and her colleagues, leading researchers bleedingbutalsotoprovideobjectivetoolstoassesstheimpact
in this area, provide the reader with a state of the art review of ofnewtreatmentmodalitiesdesignedtoreducedmusculoskeletal
theimmunologyofinhibitorformation.VanderBom,inthenext morbidityincludingsurgicalinterventionsthatarediscussedby
chapter,discussestheepidemiologyofinhibitorformationinclud- Rodr´ıguez-Mercha´nandcolleaguesinthenextchapter.Thrombo-
ingtheevidencebehindamultitudeofputativeriskfactorsand sisisamajorconcerninpatientsundergoingorthopedicsurgery
explainsaframeworkforinterpretationofpublicationsdescribing andthromboprophyalxisinthispopulationisreviewedbyDolan
ratesofinhibitordevelopmentincludingpotential confounding andcolleaguesnext.Finallythissectionofinhibitormanagement
variables.ThenovelapproachofAuerswaldandKurniktoprevent, concludeswithastimulating(andlikelyprovocative)chapteron
oratleastreduce,thelikelihoodofinhibitordevelopmentispre- physiotherapy by Zourikian and Forsyth which focuses on the
sentedinthenextchapter.Thisprovocative(andasyetunproven) physiotherapy evaluation and intervention opportunities avail-
approachinvolvesadministrationofsmalldosesofclottingfactor ableduringtheacutebleedingepisode.
topatientsintheabsenceof“dangersignals”andwillbenotonly The next section explores the new modalities that are on the
afrequenttopicfordiscussionatfuturemeetingsbutwillalsobe horizonincludingareviewofthenewtechnologiesinpre-clinical
moreimportantly,thefocusofseveralnationalandinternational and clinical development for improvement in the pharmacoki-
clinicaltrials.Next,VanderBergandFischerpresentprovocative neticprofileofcoagulationfactorsbyValentinoandadiscussion
dataontheirmodeltopredictinhibitor formation inaspecific ongenetherapybyAlvarez-Roma´nandcolleagues.Thenewde-
patient.Ifvalidated,thismodelcouldchangethemanagementde- velopmentsinhemophilicarthropathy,includinganassessment
cisionsandthetreatmentparadigmsused,especiallyinveryyoung ofthecostsrelatedtotheoccurrenceofhemophilicarthropathy
children with severe hemophilia. As noted previously, inhibitor andmanagementofarthropathyinelderlypatients,aresumma-
developmentiscomplexandOldenburgandPavlovadiscussthe rizedbyRodr´ıguez-Mercha´nandValentino.Inthenextchapter,
geneticbasisforinhibitorformationfollowedbyadiscussionof SorensenandNegrierprovidearationalfortheuseofanindivid-
thenon-geneticriskfactorsbyBoggioandSimpson. ualized“theranostic”approachutilizinggloballaboratoryassays
Thenextsectionfocusesonthedifficultareaofmanagement totailorchoicesaroundthemostsuitablebypassingagentaswell
ofpatientswithinhibitorstofactorVIIIorfactorIX.Optimally, astoguideselectionofeffectivedosagesofbypassingagents.The
immunetoleranceshouldbeundertakeninanattempttoeradi- lastchapterinthissectionbyGringeriaddressestheuseofcom-
catetheinhibitorandreturnthepatienttohispriornon-inhibitor bination sequential therapy with bypassing agents, which have
stateallowingtheuseoffactorVIIIorIXasreplacementtherapy. a synergistic effect in vitro and in vivo. Although this approach
BlatnyandMathewfirstdiscussimmunetoleranceprogramsde- seemsefficaciousinchildrenandinadults,caremustbetakenas
signedtoachievethisgoalfocusingontheimportantquestions adverseeventsarepossibleandthismodalityshouldbeconsidered
includingwhichregimentouse,whentoinitiateandabortim- asalvagetreatmentduetoitspotentialrisks.
munetolerancetherapy,whichproducttouseandhowtoidentify Finally, the management of the patient with hemophilia has
theidealpatientforimmunetoleranceaswellasdiscussingthe as its goal the optimization of quality of life. Remor discusses
issues around venous access and the control of bleeding. This thetoolsandinstrumentsavailabletoestimatequalityoflifeand
is followed by the review by Valentino and Young on the use addresses the links of quality of life with health and well-being
ofprophylaxisininhibitorpatientsandthenthepresentationof as well as the merits of the various disease-specific measures of
treatment guidelines by Giangrande and Teitel. Despite what is qualityoflife.
consideredoptimaltreatmentofbleeding,asmanyas20–30%of
hemorrhagesmaynotrespondtobypassingtherapy.Astermark Eme´rito-CarlosRodriguez-Mercha´n
discussesthediscordancyobservedinthetreatmentofbleeding andLeonardA.Valentino
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