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Personalizing the

HEMOPHILIA

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Management of

A C M E S U P P L E M E N T

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1Table of Contents

Table of ContentsCME Information .....................................................................................................2

Introduction .............................................................................................................6

Prophylactic Factor Replacement............................................................................12

Case-Based Learning...............................................................................................16

Personalizing Prophylaxis .......................................................................................17

Adherence ..............................................................................................................20

Managing the Level of Medication ..........................................................................23

Case-Based Learning...............................................................................................27

Emerging Therapies: Promise and Challenges .........................................................29

Conclusions ............................................................................................................31

References ..............................................................................................................32

Evaluation and Attestation Form ............................................................................78

HEMOPHILIAPersonalizing the Management of

Personalizing the Management of

HEMOPHILIA

2 CME Information

AUTHORS Salley G. Pels, MDAssistant Professor of Pediatrics(Hematology/Oncology), Yale UniversitySchool of Medicine; Associate Director, Yale Hemostasis Center

Daniel U. Rabin, PhDMedical Director, The France Foundation

Jeanne Hendrickson, MDAssociate Professor of Laboratory Medicineand of Pediatrics, Yale University School ofMedicine; Associate Director, TransfusionMedicine Service

Alfred Ian Lee, MD, PhDAssistant Professor of Medicine (Hematologyand FY15 Hematology), Yale UniversitySchool of Medicine; Firm Chief, InpatientHematology, Yale Cancer Center; Assistant Program Director, TraditionalInternal Medicine Residency Program, Yale University School of Medicine

Christopher Anthony Tormey, MDAssistant Professor of Laboratory Medicineand Lecturer in Molecular Biophysics andBiochemistry; Director, Transfusion MedicineFellowship, Yale University School ofMedicine

Caroline Irma Cromwell, MD, MSCRAssistant Professor of Medicine(Hematology), Yale University School ofMedicine

Sara Ornaghi, MSCRYale Women and Children’s Center for BloodDisorders, Department of Obstetrics,

Gynecology and Reproductive Sciences, Yale University School of Medicine

Patrick G. Gallagher, MDProfessor of Pediatrics (Neonatology), ofGenetics and of Pathology, Yale UniversitySchool of Medicine; Director, Yale Center forBlood Disorders

Gary Kupfer, MD*Professor of Pediatrics (Hematology/Oncology) and of Pathology, Yale UniversitySchool of Medicine; Clinical Program Leader,Pediatric Hematology & Oncology Program,Smilow Cancer Hospital; Section Chief,Pediatric Hematology/ Oncology; ClinicalResearch Program Leader, PediatricHematology & Oncology Program, YaleCancer Center

Michael J. Paidas, MD*Professor of Obstetrics, Gynecology, andReproductive Sciences, Yale University Schoolof Medicine; Vice Chair, Obstetrics; ProgramDirector, Maternal Fetal Medicine Fellowship;Co-Director, Yale Women and Children'sCenter for Blood Disorders; Co-Director,National Hemophilia Foundation–BaxterClinical Fellowship Program at Yale; Divisionof Maternal Fetal Medicine

*Senior Authors

AddressesYale School of Medicine333 Cedar StNew Haven, CT 06510

The France Foundation10 Vista Drive, Suite 100Old Lyme, CT 06371

CME Information

3CME Information

Corresponding AuthorDaniel U. Rabin, PhD10 Vista Drive, Suite 100Old Lyme, CT 06371 Telephone: 860.598.2235 Fax: 860.434.5390 email: [email protected]

METHOD OF PARTICIPATION/HOW TO RECEIVE CREDIT**You must go to www.YaleCME-Hemo.orgto request CME credit**

1. There are no fees for participating in and receiving credit for this activity.2. Review the activity objectives and CME information.3. Complete the CME activity. Go to www.YaleCME-Hemo.org4. Complete the posttest. A score of at least 75% is required to successfully complete this activity. The participant may take the test until successfully passed.5. Complete the CME evaluation/attestation form, which provides each participant with the opportunity to comment on how participating in the activity will affect their professional practice; the quality of the instructional process; the perception of enhanced professional effectiveness; the perception of commercial bias; and his/her views on future educational needs.6. Your CME certificate will be available for download.

PROVIDERThis activity is provided by Yale School ofMedicine in collaboration with The FranceFoundation.

TARGET AUDIENCEThis activity is intended for hematologistswho specialize in hemophilia.

STATEMENT OF NEEDHemophilia, an inherited bleeding disorder inwhich blood does not clot adequately, occursin approximately 1 in 5000 males.1 Greatprogress in hemophilia management has beenachieved over the last several decades, withself-administered treatment of clotting factorconcentrates becoming feasible in the 1970s.The threat of blood-borne illness associatedwith treatment took center stage in the 1980s.With this major safety issue addressed, thefocus in hemophilia management isincreasingly on prophylaxis with long-termsubstitution therapy of the missing clottingfactor.2

Patients with severe hemophilia A or B whoexperience recurrent joint bleeding are knownto experience progressive hemophilicarthropathy, even with on-demandreplacement of appropriate factorconcentrates.3 The frequency of bleedingepisodes and the severity of joint disease anddysfunction are closely linked.4 Thus, theapproach to hemophilia has evolved so thatnow primary prophylaxis, achieved withlong-term concentrate infusions, startingafter the first joint bleed or before the age of2, is considered an evidence-basedmanagement strategy in severe hemophilia. Italso appears to play a role in preventinginhibitor development,3 a key side effect oftreatment threatening patient health.2 The useof long-term infusions with the goal ofavoiding or delaying arthropathy is consideredsecondary prophylaxis.3


You must go to www.YaleCME-Hemo.orgto request CME credit


HEMOPHILIA

4 CME Information

EDUCATIONAL ACTIVITYLEARNING OBJECTIVESUpon completion of this course, theparticipants should be able to:• Review data on barriers to optimal prophylactic replacement of missing clotting factor• Examine data on short- and long-term ramifications of a prophylactic (vs episodic) treatment approach• List factors to be considered when formulating a personalized prophylactic approach for the individual patient• Identify aspects of new guidance that apply to a personalized prophylactic regimen• Determine how new data and agents fit into the personalized prophylactic approach in hemophilia• Formulate a management plan that anticipates, assesses, and addresses barriers to the prophylactic factor replacement approach• Summarize key factors that affect trough levels• Evaluate current data and recommendations on optimal clotting factor trough levels• Describe a detailed plan for assessing treatment adherence in a patient with hemophilia• Design a plan for supporting treatment adherence that incorporates disease education, technical training needs, relevant psychosocial factors, and utilizes tools that the patient can easily incorporate

ACCREDITATION STATEMENTYale School of Medicine is accredited by theAccreditation Council for Continuing MedicalEducation (ACCME) to provide continuingmedical education for physicians.

CREDIT DESIGNATIONPhysicians: Yale School of Medicine designatesthis enduring material for a maximum of 2AMA PRA Category 1 Credit(s)™. Physiciansshould claim only the credit commensuratewith the extent of their participation in theactivity.

Release Date: November 30, 2015Expiration Date: November 29, 2016Estimated Time to Complete Activity:2 hours

DISCLOSURESIt is the policy of Yale School of Medicine andThe France Foundation to ensure balance,independence, objectivity, and scientific rigorin all its sponsored educational activities. Allfaculty, activity planners, content reviewers,and staff involved in the development of thisactivity have disclosed any significantfinancial interest or other relationship withmanufacturer(s) of any commercialproduct(s)/device(s) and/or provider(s) ofcommercial services included in thiseducational activity. The intent of thisdisclosure is not to prevent a person with arelevant financial or other relationship fromparticipating in the activity, but rather toprovide participants with information onwhich they can base their own judgments.Yale School of Medicine and The FranceFoundation have identified and resolved anyand all conflicts of interest prior to the releaseof this activity.

Activity Staff DisclosuresThe planners, reviewers, editors, staff, CMEcommittee, or other members at Yale Schoolof Medicine who control content have norelevant financial relationships to disclose.

5CME Information

The planners, reviewers, editors, staff, CMEcommittee, or other members at The FranceFoundation who control content have norelevant financial relationships to disclose.

Faculty DisclosuresThe following faculty have indicated they haveno relationships with industry to discloserelavant to the content of this CME activity:• Salley G. Pels, MD• Daniel U. Rabin, PhD• Jeanne Hendrickson, MD• Caroline Irma Cromwell, MD, MSCR• Sara Ornaghi, MD• Patrick G. Gallagher, MD• Gary Kupfer, MD

The following faculty have indicated they haverelationships with industry to disclose relavantto the content of this CME activity:• Alfred Ian Lee, MD, PhD, has served as a consultant to Pfizer.• Christopher A. Tormey, MD, has received grant funding from the Termuo BCT Corporation. In addition, he has received honoraria for serving on the clinical advisory board of Avalon Healthcare.• Michael J. Paidas, MD has participated in an advisory board and receives research funding from CSC-Behring. He is an unpaid consultant to Novo Nordisk. He receives research funding from rEVO Biologics and Novo Nordisk.

UNAPPROVED USE DISCLOSUREYale School of Medicine and The FranceFoundation require CME faculty to disclose tothe participants when products or proceduresbeing discussed are off-label, unlabeled,experimental, and/or investigational (not FDAapproved); and any limitations on theinformation that is presented, such as datathat are preliminary or that represent ongoing

research, interim analyses, and/orunsupported opinion. Faculty in this activitymay discuss information aboutpharmaceutical agents that is outside of USFood and Drug Administration approvedlabeling. This information is intended solelyfor continuing medical education and is notintended to promote off-label use of thesemedications. If you have questions, contact themedical affairs department of themanufacturer for the most recent prescribinginformation.

COMMERCIAL SUPPORTACKNOWLEDGMENTThis activity is supported by an educationalgrant from Biogen Idec.

DISCLAIMER Yale School of Medicine and The FranceFoundation present this information foreducational purposes only. The content isprovided solely by faculty who have beenselected because of recognized expertise intheir field. Participants have the professionalresponsibility to ensure that products areprescribed and used appropriately on the basisof their own clinical judgment and acceptedstandards of care. Yale School of Medicine andThe France Foundation assume no liability forthe information herein.

CONTACT INFORMATIONIf you have questions about this educationalactivity, please contact The France Foundationat 860-434-1650 or [email protected].



HEMOPHILIA

6 Introduction

EPIDEMIOLOGYHemophilia A and hemophilia B are relatedbleeding disorders that are most commonlyinherited. When the term ‘hemophilia’ isused, it refers to factor VIII deficiency(hemophilia A) or factor IX deficiency(hemophilia B, also called ‘Christmasdisease’). The genes for factors VIII and IX arelocated on the X chromosome, and thus aregenerally inherited in an X-linked recessivemanner. As such, they affect mostly males,with females often being healthy carriers.Approximately 1 in 5,000 to 10,000 males areborn with hemophilia A, and 1 in 25,000 to30,000 males are born with hemophilia B.5,6

The incidence of hemophilia is similar for allpopulations and racial groups.7,8,9,10

Hemophilia prevalence varies widely with theeconomic status of individual countries dueto the effect of premature deaths andshortened life-expectancy in poorercountries.11

Before the introduction of pharmaceuticalclotting factor preparations, the meanlife-expectancy of patients with hemophiliawas <30 years12 and patients mostly died ofintracranial, post-operative, or other severehemorrhages.13,14,15 Since the 1960s, factor VIIIand factor IX preparations have improved thelife-expectancy of patients with hemophilia.Mortality again increased during the 1980sdue to HIV and hepatitis C infection. Clottingfactors became almost completely safe indeveloped countries since 1985 for HIV andsince 1992 for hepatitis C due to new viralinactivation technologies and theintroduction of recombinant products. Newinfectious agents and prion-related diseasesare of ongoing concern, as somemanufacturing of recombinant products uses

plasma components.16 In high-incomecountries the life expectancy of a child withhemophilia is equivalent to one without thedisease.17 Hemophilia public health programshave played a large role in this improvementin survival. This effect is most evident indeveloped countries, where patients seen inHemophilia Treatment Centers (HTC) show a60 to 70% reduction in mortality rates eventhough they comprise the most severelyaffected patients.11

Hemophilia A and B are classified into 3categories by the International Society onThrombosis and Haemostasis (ISTH): mild(>5% to <40% of normal clotting factor incirculation), moderate (1% to 5%), andsevere (<1%).6 The range of clinical severitycorrelates well with assayed factor levels.5,6

Approximately two-thirds of patients withhemophilia A and one half of individuals withhemophilia B have severe disease. Bleedingvaries with the severity of the disease. Itoccurs only in response to injury, trauma, orsurgery in patients with mild hemophilia, tointercurrent injury or surgery in moderatehemophilia, and spontaneously and at anearly age in severe hemophilia.5,18 HemophiliaA and B of comparable severity bleed withsimilar frequency.19 People with hemophilia Aor B do not bleed harder or faster than peoplewithout these disorders—they bleed longer.Some patients with severe disease may have amilder clinical course, such as cases withhemophilia B Leyden.20 or the pro-thromboticLeiden mutation of factor V.21,22 Indeed,concomitant pro-thrombotic conditions maypartially counteract the bleeding tendency ofhemophilia, resulting in fewer bleedingepisodes and a later onset of first bleeding.22

Introduction

7Introduction

CLINICAL DISEASE

Sites of BleedingBleeding is the main clinical manifestation inpatients affected by hemophilia. The majorbleeding sites in patients with severehemophilia are shown in Table 1. Hemarthrosis is by far the predominantbleeding manifestation. Joint bleeding is morecommon in lower limbs, especially at theankle.23 This pattern is different from themucosal and cutaneous bleedingcharacteristic of platelet dysfunction or vonWillebrand disease (VWD) (Table 2).

The pathogenesis of hemophilic arthropathybegins with an inflammatory infiltrate thatfollows acute joint hemorrhage. Repeatedbleeding into the joint leads to formation of atarget joint, characterized by synovialhypertrophy, articular cartilage destruction,bony changes, and a tendency towards morefrequent joint bleeding.25,26 The classic modelof hemophilic arthropathy, described almostfour decades ago, consists of five radiographicstages:27,28

• Soft tissue swelling• Subacute hemarthropathy

• Joint disorganization with hemosiderin deposition• Joint space narrowing with cartilage destruction• Marked joint destruction with severe restriction in joint movement

The extent of joint damage is directly relatedto the number of joint bleeds.25 Whilearthropathy typically becomes detectableduring school age years, joint pathologybegins much earlier with initial bleedingepisodes.

Initial PresentationNewborns with severe hemophilia maytraverse delivery and the first few months oflife without clinically significant bleedingepisodes. Early bleeding symptoms are mostoften associated with circumcision,intracranial hemorrhage (ICH), and heelsticks.29 More frequently, children with severehemophilia A or B become symptomatic afterthe newborn period but within the first twoyears of life, with a median age at diagnosis of


Bleeding Site

Joints Most common: ankle, knee, elbow Others: shoulder, wrist, hip

Muscles Most common: iliopsoas, calf, forearm

Other major bleeding sites: Mouth, throat, neck, gastrointestinal tract, genitourinary tract

Central nervous system

Frequency

70-80%

10-20%

5-10%

Less than 5%

Table 1. Bleeding Sites in Severe Hemophilia (adapted)24


HEMOPHILIA

8 Introduction

0.9 years. However, in those children carryingconcurrent pro-thrombotic risk factors (e.g.,factor V Leiden mutation), the first bleedingepisode often occurs later, at a median age of1.6 years.30

Patients with moderate hemophilia present ata median age of 22 months.31 Mild disease, inthe absence of an informative family history,may go undetected for significant periods oftime,32 since as many as one-third of patientswith mild disease have very few or nobleeding episodes.18 Forehead hematomas(‘goose-eggs’) are the characteristicpresenting in children with mild andmoderate hemophilia.33

DiagnosisThe diagnosis of hemophilia typically beginswith a careful review of the family history,particularly the maternal side. A negativefamily history is of little value in excludinghemophilia since one third of hemophiliacases are spontaneous.34 Table 2 shows theplatelet defect and clotting factor defectassociations with different bleedingsymptoms.

In patients presenting with a bleedingdiathesis of unknown etiology, three initialtests should be performed: platelet count,prothrombin time (PT), and activated partialthromboplastin time (aPTT).35 Plasma PTmeasures extrinsic and common pathways of

Bleeding Symptoms

Excessive bleedingafter minor cuts

Petechiae

Ecchymosis

Hemarthrosis,muscle hematomas

Bleeding withinvasive procedures,including surgery

Platelet Defects

Yes

Common

Generally small and superficial;may be significant dependingupon the defect or degree of

thrombocytopenia

Uncommon

Often immediate, with degree ofbleeding depending upon theseverity of the defect, rangingfrom none (e.g., mild degrees of

thrombocytopenia or mildplatelet function defect) to mild

to severe (eg, Glanzmannthromboasthenia)

Clotting Factor Deficiencies

Not usually

Uncommon

May develop large subcutaneousand soft tissue hematomas

Common in severe deficiencystates or in association withinjury in those with mild tomoderate deficiency states

May be associated either withprocedural bleeding or delayedbleeding, depending upon thetype and the severity of the

defect

Table 2. Clinical Manifestations of Bleeding Disorders

Bleeding Disorder

9Introduction

coagulation, whereas aPTT measures intrinsicand common pathways. aPTT evaluates thedegree of heparin anticoagulation and issensitive to inhibitors such as heparin and todeficiencies of all coagulation factors exceptfactors VII and XIII. It is less sensitive thanthe PT to deficiencies of the common pathway(factors X and V, prothrombin, andfibrinogen).34 A normal platelet count,normal PT, and a prolonged aPTT arecharacteristic of hemophilia A, hemophilia B,and heparin therapy.

An abnormal test occurs in individuals whohave less than approximately 30 percent ofthe mean normal activity of factor VIII or IX.However, patients with mild hemophilia Bmay have normal or near normal aPTTs. Thus,in undiagnosed mild bleeding disorders, afactor IX assay should be performed even ifthe aPTT is normal.36,37,38

Other disorders prolong the aPTT but not thePT (Table 3). They include acquired inhibitorsto factor VIII or IX, and deficiency of factorXII, prekallikrein, or HK. However, abnormalbleeding does not occur with thesedeficiencies.39 A similar pattern of laboratoryresults is seen in patients withantiphospholipid antibodies (Lupusanticoagulant), who have a tendency tothrombosis rather than bleeding. Specificassays for the factors that can produce anisolated finding of prolonged aPTT should be

performed in the order of their statisticalfrequency (factor VIII, IX, and finally XI).

Inhibitors An important complication of hemophiliatherapy is the development of antibodies,primarily IgG, that inhibit the relevantfactor.40 Inhibitors develop in approximately25% of patients with severe hemophilia A41

but less frequently with mild or moderatedisease or hemophilia B. Young age at thetime of initial replacement therapy, hightreatment intensity, and early use ofprophylaxis are characteristic of both severedeficiency and inhibitor formation.42,43

Plasma-derived and recombinant preparationsappear to be equivalent in their associationwith inhibitor development.44

Inhibitors usually decrease responsiveness tofactor concentrates and achieving hemostasisis more challenging in patients withinhibitors. They experience more bleedingcomplications, especially at musculoskeletalsites.45 An inhibitor should be suspected whenany bleeding episode is refractory to usualtherapy, particularly in patients with severehemophilia.46 Patients with factor IXinhibitors are also at risk for allergic and/oranaphylactic reactions.47 These reactions arelimited primarily to patients with genedeletions or major gene rearrangements.

Treatment of inhibitors typically requires a


Inherited

• Deficiency of factors VIII, IX, or XI

• Deficiency of factor XII, prekallikrein, � or HMW kininogen

• von Willebrand disease (variable)

Acquired

• Heparin administration

• Inhibitor of factors VIII, IX, XI, or XII

• Acquired von Willebrand disease

• Lupus anticoagulant

Table 3. Causes of a Prolonged PT and/or aPTT


HEMOPHILIA

10 Introduction

combined approach with both immuneinduction with specific factor product andby-passing agent to treat or prevent acutebleeding episodes.48 Various protocols forimmune tolerance induction (ITI) exist, andinhibitors can be treated successfully in manypatients.47,49

CLOTTING CASCADE, DISEASE SUBTYPESSevere factor VIII or factor IX deficiency leadsto bleeding because these factors playimportant roles in the coagulation pathway(Figure 1). The interaction of clotting factors,cofactors, and proteolytic enzymes is thesubject of several excellent reviews.50,51,52 Thecell-based model of coagulation refines therole of localization and cell surfaceinteractions in regulating the clottingprocess.53

Genetic Transmission and Disease SubtypesHemophilia A and B are X-linked recessivedisorders. Therefore, they occur almostexclusively in a male having one defectivecopy of the relevant gene on his Xchromosome.49 Because the affected male will transmit a normal Y chromosome to all his sons and an abnormal X chromosometo all his daughters, his sons will not beaffected and all his daughters will be carriers. Approximately one-third of patientswith hemophilia do not have a family historyof the disease and appear to have novelmutations.34

Factor VIII MutationsThe genetic defects of hemophilia Aencompass point mutations, deletions,insertions, duplications, and transpositions.55

The large size of the factor VIII gene and thepresence of ‘hot spots’ are thought to makethe gene particularly sensitive to mutation.

Approximately 40 percent of severehemophilia A is caused by a major inversionof a section of the tip of the long arm of the X chromosome, one break point of which issituated within intron 22 of the gene. Fivepercent of patients with hemophilia A havenormal protein levels of a dysfunctionalfactor VIII (“cross-reacting materialpositive”), often due to missense mutationsin the A2-domain.56

HK: high molecular weight kininogen; PK:prekallikrein; PL: phospholipid; PT: prothrombin;TH: thrombin.

Figure 1. Pro-Coagulant Complexes of theCoagulation Cascade.54

11Introduction

Factor IX MutationsHemophilia B is a heterogeneous disorderwith a wide range of factor IX plasma levelsand a variety of mutations such as completegene deletions, small insertions/deletions,and, most commonly, point mutations.57

Similar to hemophilia A, approximatelyone-third of hemophilia B cases haveantigenic levels of factor IX that are nearnormal, but they have much lower factor IXactivity levels. The clinical severity of thesecases ranges widely from mild to severe.

Hemophilia B Leyden and BrandenburgHemophilia B Leyden is a rare form ofhemophilia B caused by a mutation in thefactor IX gene promoter.58 In individuals withthe Leyden phenotype, factor IX levelsincrease following puberty, likely due to anandrogen responsive element (ARE) in thepromoter. These individuals often convertfrom a severe to a mild clinical phenotype byadulthood. Hemophilia B Brandenburg resultsfrom a GàA mutation at the -26 position thatdisrupts the ARE and results in a severeclinical phenotype that does not resolve afterpuberty.59

Bleeding in CarriersA wide range of factor VIII and factor IX levelshas been observed in normal subjects as wellas in heterozygous carriers of hemophilia A orB.60 Extreme degrees of X chromosomeinactivation (lyonization) and other geneticfactors may lead to very low clotting factorlevels in heterozygous female carriers, withassociated bleeding. Since factor levels of aknown carrier appear to be independent ofthe severity of hemophilia within the familyand vary from person to person61, clottingfactor levels should be measured in all carrierspreceding a medical or surgical interventionin order to assess their risk of bleeding.



HEMOPHILIA

12 Prophylactic Factor Replacement

PROPHYLACTIC VS EPISODICTREATMENTTraditionally, severe hemophilia was treatedafter bleeding episodes. In recent years aprophylactic approach has become thestandard of care. Prophylaxis may be primary,secondary, or tertiary.24

• Primary prophylaxis: initiation of prophylaxis before 3 years of age, prior to the second bleeding episode involving a large joint• Secondary prophylaxis: initiation of prophylaxis after 2 or more large joint bleeds prior to the onset of arthropathy• Tertiary prophylaxis: initiation after arthropathy has already occurred

In 1992 Nilsson et al published a review of upto 25 years prophylaxis in a cohort of 60Swedish boys with hemophilia A or B.62 Dueto a shortage of clotting factors in the earlyyears of the study, only the youngest patientswere treated with high doses of factor VIII orfactor IX to maintain trough levels at 1-5%(1-5 IU dL-1). The patients experienced almost

no bleeding and their joint scores remainedunchanged throughout the study. Prophylaxisdid not restore joint function or stopprogression for boys who had joint defectsbefore entering the study. A similar result wasreported in 2006 by Feldman et al who usedan escalating prophylactic dose to treat 25boys with severe hemophilia A.63 Comparedwith an historical rate of 50% development ofa target joint in 44 months, the prophylaxisgroup had a rate of 16% (4/25). Fischer et alreviewed several studies with intermediate-dose and high-dose prophylaxis and foundthat the high-dose group had less bleedingover five years (median, 0 vs 1.3 jointbleeds/y, P < 0.01) and better joint health(Haemophilia Joint Health Score > 10 of 144points in 11% vs 46% of participants),although the quality of life measures weresimilar in the two groups. Annual total costswere 66% higher for high-dose prophylaxis (P < 0.01).64

The advantage of prophylaxis over episodictreatment was confirmed in a trial byManco-Johnson et al in 2007.65 Sixty-five boysyounger than 30 months with severe

Prophylactic Factor Replacement

Variable

Joint damage (MRI)—no. (%)

Joint damage (radiography)—no. (%)

Mean joint hemorrhages(no./participant/yr)

Mean total hemorrhages(no./participant/yr)

Prophylaxis(N = 32)

2 (7)

1 (4)

0.63±1.35

3.27±6.24

Enhanced Episodic Therapy

(N = 33)

13 (45)

5 (19)

4.89±3.57

17.69±9.25

P Value

0.002

0.10

< 0.001

< 0.001

Table 4. Outcome Data in a Trial of Prophylaxis vs Enhanced Episodic Therapy with Factor VIII65

13Prophylactic Factor Replacement

hemophilia A were randomly assigned toprophylaxis (32 boys) or enhanced episodictherapy (33 boys). At age 6, 93% of those inthe prophylaxis group and 55% of those inthe episodic-therapy group had normalindex-joint structure on MRI (P = 0.006). Therelative risk of MRI-detected joint damagewith episodic therapy compared withprophylaxis was 6.1 (95% CI, 1.5 to 24.4).Table 4 shows the joint damage results of thistrial. A clinical challenge is that manypatients receive treatment only on demand oras secondary prophylaxis. Thus, orthopediccomplications remain a serious problem.

A number of additional clinical trials havedemonstrated beneficial effects on outcomes,particularly joint health, for patients whohave received prophylaxis versus on-demandtherapy starting at a young age andcontinuing through adulthood.66,67 TheOrthopedic Outcomes Study was alongitudinal study of 477 patients receivingsecondary or tertiary prophylaxis. Patients onprophylaxis had improved joint outcomes aswell as fewer missed days of school, and fewerdays hospitalized.68 Another studydemonstrated similar results in 45 childrenwith hemophilia A, with children randomizedto prophylaxis having significantly fewerhemarthrosis.66 A Cochrane Review publishedin 2011 concluded that there was strongevidence that prophylaxis was more effectivethan on-demand therapy in preserving jointfunction in children with hemophilia.69

Studies have also shown that this benefitextends to all age groups. In the Haemo-QoLstudy, adolescents on prophylaxis reportedhigher quality of life scores, particularly in theareas of academics and sports.70 In a recentstudy of 84 male patients with severehemophilia A between the age of 12 and 50,prophylaxis led to a significant decrease in thenumber of total bleeding episodes.67

The 2013 World Federation of Hemophiliaguidelines found that there is level 2(randomized trial) data supporting theposition that “Prophylaxis prevents bleedingand joint destruction and should be the goalof therapy to preserve normal musculoskeletalfunction.”24 The World Health Organization(WHO),7 World Federation of Hemophilia(WFH),24 and the National HemophiliaFoundation’s (NHF) Medical and ScientificAdvisory Council (MASAC)72 all recommendinitiation of prophylaxis where possible priorto the onset of frequent bleeding in severehemophilia to keep trough levels >1%between doses.

While the ideal prophylaxis regimen isunknown at this time, several studies haveevaluated various methods of administeringprophylaxis: tailored low-dose, escalatingregimens, or pharmacokinetic-basedregimens.73 Valentino and colleaguescompared two prophylaxis regimens versuson-demand therapy in 66 severe HemophiliaA patients ages 7-59 years. Patients werepreviously treated on-demand and wererandomized to receive standard every otherday dosing or pharmacokinetic (PK) derivedevery third day dosing. Both prophylaxisregimens were superior to the on-demandtherapy, and bleeding rates on bothprophylaxis arms were comparable. Patientson each prophylaxis regimen used the sameamount of factor and had similar healthrelated quality of life measures.74 Aretrospective chart review of 58 patientsreceiving either “traditional” Swedish(Malmo) protocol treatment or the Canadiantailored prophylaxis showed no difference inefficacy rates; the only major differencebetween the two groups was the use ofimplantable venous devices (75% versus29%).75



HEMOPHILIA

14 Prophylactic Factor Replacement

Caracao compared three models: Swedish(Malmo), Canadian, and French, andoutlined the challenges providers face whenchoosing a regimen.76 The Swedish (Malmo)model is a high-dose regimen utilizing 25-40U/kg of factor two or three times per week forhemophilia B or A, respectively, beginningbefore 3 years of age.65,77 It serves as the basisfor the NHF recommendation, starting fulldose prophylaxis after the first bleed. Thisdosing regimen often requires early placementof central lines. The Canadian and Frenchapproaches call for weekly dosing followed bystep-wise escalation. While the Canadianprotocol initiates treatment prior to the firstor second bleed, the French regimen startsafter the second bleed, raising concerns aboutwhat joint damage may have already occurred.Several studies show that early prophylaxis(prior to 3 years of age) has a clearadvantage.78,79,80 With relative equivalencedemonstrated between regimens, the optimalchoice should be determined for each patientin conversations with the patient and thefamily.

The adolescent and adult prophylaxis data arenot as robust as the pediatric data. TheSPINART trial showed significant differencesin joint and other bleeding events in adultpatients (12-50 years) who receivedprophylaxis or on-demand therapy.67 Therecommendations from NHF are therefore toconsider life-long prophylaxis for theprevention of joint bleeds and subsequentarthropathy.

BARRIERSWhile there is little expert debate that routinefactor prophylaxis starting in early childhoodreduces long term morbidity of patients withsevere hemophilia, there are a number ofpotential barriers to universal treatment,

including access to factor products and theircost, adequate venous access, and adherenceto recommended prophylaxis schedules. Asurvey of US physicians treating hemophiliafound that each of these perceived barriers ledto decreased prescription rates.81 Lack ofvenous access was reported as reducingprescription rates at least sometimes by 82%of physicians. Adherence and financialconcerns were also reported as a significantbarrier by 87% and 71% of physiciansrespectively. Patient surveys have yieldedsimilar results. Difficult venous access andthe time required for dosing were the mostcommonly cited reasons for incompletecompliance. Fewer patients and familiesreported cost of therapy as a barrier.82

While prophylaxis is feasible in countrieswhere there is widespread access to factorproducts, only 54% of all patients with severehemophilia A have access to on-demandtherapy and only 37% receive regularprophylaxis.83 Although access to product isnot a widespread issue in the US, it is clearthat the high cost of hemophilia care stemsfrom expensive factor products, with thehighest costs incurred by those on prophylaxisregimens or with inhibitors.84 Studies of factorcosts and healthcare use by patients withhemophilia have found that 72-80% ofhealthcare expenditures are for factorconcentrates and that the average cost ofhemophilia care in the US in 2008 was$142,987 and $155,136 for Medicaid andprivate insurance, respectively.85,86 These costsplace a great burden on patients and payersalike, but routine prophylaxis bringssignificant benefits related to quality of life,productivity, and complications (reducedjoint disease and hospitalization).

Administering intravenous factor replacement

15Prophylactic Factor Replacement

several times per week starting at a young ageis a difficult task, and many families andproviders opt for central venous access devices(CVADs). A survey of 62 HTCs in the USrevealed that 90.3% of centers use CVADs intheir young patients, with 19 centers usingCVADs for 100% of patients on prophylaxis,while only 7 centers are not using them atall.87 CVADs have potential complications,including infection, thrombosis and devicefailure. A large meta-analysis of CVADs inhemophilia patients found that the incidenceof infection was only 0.66 per 1000 CVADdays, however infection was reported as themost common reason for device removal at69.9%. Thrombosis was cited in only 4.1% ofcases where patients required central lineremoval.88 Because of these potentialcomplications, implanted devices are typicallylimited to early childhood with transition toperipheral infusions by the second decade oflife. Self-infusion is challenging and requiresfamily and patient education by the HTC andnursing staff.

Medication adherence requires availability ofproduct, venous access, and a willing patient.Unfortunately, one third of patients with allseverities of hemophilia A and B from theUnited States reported depressive symptoms,with 18% reporting moderate to severesymptoms of depression.89 Seventy-six percentof those patients with depression reportedfunctional impairment secondary to their

depressive symptoms, which significantlyimpacts self-care. Multidisciplinarypatient-centered care teams are essential toaddress this condition as well as chronic painand other illnesses of the aging population,including cardiovascular disease, urologicalproblems, and cancer.90,91

CLINICAL PEARLS• Hemophilia A and B are classified as mild (>5% to <40% of normal clotting factor in circulation), moderate (1% to 5%), and severe (<1%) • The most common sites of bleeding are joints (70-80%), muscle (10-20%), and digestive tract (5-10%)• A normal platelet count, normal PT, and a prolonged aPTT are characteristic of hemophilia A, hemophilia B, and heparin therapy• Inhibitor antibodies develop in 25% of patients with hemophilia A and can decrease the efficacy of therapy• The median age of presentation is ~1 year, frequently associated with circumcision, ICH, and heel sticks• Approximately one third of patients present without a family history of hemophilia• Prophylaxis is superior to episodic therapy; multiple protocols are available



HEMOPHILIA

16 Case-Based Learning

Case-Based LearningEB is a 2-year-old boy with severe hemophilia A. He has been on prophylaxis since age 14months, when he was started on 50 U/kg once weekly per the Canadian protocol. His troughlevel of factor VIII today is <1%. He has never been positive for an inhibitor; however there is afamily history of inhibitors in a maternal uncle. He has mild bruising, but has not had anyjoint bleeds since starting prophylaxis. He is in clinic today for his weekly infusion andeducation with his parents. They are anxious and not yet able to independently performinfusions at home. They have heard about central line placement and are wondering if itwould be appropriate for EB.

Which option would you recommend and why? A. Place a central lineB. Modify his dosing regimenC. Wait until he has a joint bleed and then modify his dosing regimen

_____________________________________________________________________________________

_____________________________________________________________________________________

If his trough level today were 2% how would your decision change?

_____________________________________________________________________________________

_____________________________________________________________________________________

Answer these questions at: www.YaleCME-Hemo.org

17Personalizing Prophylaxis

“Personalized prophylaxis” has emerged asone of the most important and challengingmandates in the care of hemophilia patients.While there is a clear benefit of earlyprophylaxis initiation in severe hemophilia,how to treat the individual patient is oftenunclear. Many studies of prophylaxis reportonly a weak correlation between coagulationfactor levels and prevention of bleeding,92 andthere is marked heterogeneity among patientsin onset and progression of arthropathy.68,80,93

A successful plan takes into account medicalissues such as individual bleeding patterns,musculoskeletal health, physical activity, bodymass, age, and inhibitors, while beingsensitive to patient and parental concernsregarding costs, the discomfort of frequentvenipuncture and possible central venouscatheter placement, and time commitments.

MUSCULOSKELETAL ASSESSMENTSeveral studies have demonstratedabnormalities in gait, lower extremity musclestrength and size, and joint mobility inchildren and adolescents with severehemophilia.94,95 Such differences may be seenat a very early age, prior to radiographicarthropathy and even before differences inphysical examination scores, suggesting thatearly adaptation occurs from the time of thefirst joint bleeds.

Musculoskeletal health in hemophilia may beevaluated using a number of differentassessment tools. The World Federation ofHaemophilia Physical Examination score(Gilbert score)96 was one of the first scoringsystems but was subsequently shown to be lesssensitive than other physical examinationtools, including the Colorado Physical

Examination and Child PE scores.97 TheStockholm scoring system advocated by theEuropean Paediatric Network for Haemophiliaexpanded upon the Gilbert score by includingassessments of gait and pain.98 In 2001 theInternational Prophylaxis Study Group (IPSG)was formed with the goal of synthesizing allthe different functional scoring systems,culminating in the Hemophilia Joint HealthScore (HJHS), which takes into account allthe features of the original Gilbert score plusduration of swelling, joint flexion andextension, strength, and gait.99,100 The HJHS iscomprehensive and effective in monitoringjoint changes in response to prophylaxis buthas not yet been validated in very youngchildren, adults, or patients with severe jointdisease. Radiographic scoring systems ofarthropathy have also been developed basedon X-ray (Pettersson score)101 or magneticresonance imaging.102

PHYSICAL ACTIVITYWhile older literature advised physical activityrestriction in hemophilia patients, manyinvestigators now encourage selectiveparticipation in sports, physical exertion, andfitness programs.103 Children, adolescents,and young adult hemophilia patients onprophylaxis who play high-impact sports donot appear to have a higher risk of bleedingthan those involved exclusively in low-impactsports.104 Studies of the dynamics ofsports-related bleeding in hemophilia patientson prophylaxis reveal that a 1% increase infactor levels via prophylaxis decreases thebleeding risk by 2%, bleeding risk increasestransiently with escalating vigor of physicalactivity, and most bleeds occur within anhour after activity.105


Personalizing Prophylaxis


HEMOPHILIA

18 Personalizing Prophylaxis

SPECIAL CONSIDERATIONSBody WeightPatients with hemophilia are obese oroverweight at least as often as the generalpopulation. A greater body mass index (BMI)in hemophilia patients leads to limitations injoint range-of-motion and worsenedarthropathy,106 particularly involving thehip.107 While obesity itself does not causeincreased bleeding, abnormalities infibrinolysis have been described in obesepatients with hemophilia and may underliesome of this pathology.108 Guidelines do notexist for factor replacement in obese patients,although some pharmacokinetic data suggeststhat dosing by ideal rather than actual bodyweight in obese patients may be adequate,109

perhaps due to decreased vascularity ofadipose tissue compared to muscle.110

While overweight patients may be overtreated, underweight patients are frequentlyundertreated. Henrard and colleaguesobserved factor VIII recoveries of 1.6, 2.14,and 2.70 IU dL-1/IU kg-1 in patients withhemophilia A who were underweight, average,and obese, respectively.111 Individualizedtherapy should be based on PK measurementsrather than body weight.

OsteopeniaPatients with severe hemophilia A have higherrates of osteopenia in the lower lumbar spineand femoral neck.112 This appears to beindependent of body size113 and may be due toabnormalities in osteoblast function andincreased osteocalcin levels.114

COAGULATION FACTORMEASUREMENTMeasurement of factor levels and individualPK are important for personalized

prophylaxis. Standard prophylaxis regimensare designed to maintain a trough level offactor above 1%, converting severehemophilia to moderate hemophilia. Patientsare monitored upon initiation of prophylaxisto ensure adequate exposure and to detectinhibitors. Recommendations from the UKgroup include monitoring of trough levels atclinic visits, considering PK studies if apatient’s trough level is at <1% in the absenceof an inhibitor, and optimizing dosingregimen if bleeding is uncontrolled.115

Elements that negatively affect factor levelsinclude younger age, weight (obese orunderweight), infection, comorbidities, andphysical activity level. Additionally, there issome debate regarding the ideal trough level.

Collins et al studied a cohort of 99 patientswith severe hemophilia A.116 Compared topatients who had no bleeds, patients whoexperienced at least 1 bleed spent more thantwice the amount of time with a factor VIIIlevel <1%. In a study of 82 patients withstandard prophylaxis in Sweden, there was aweak but significant relationship betweentime below 1% factor VIII or factor IX leveland incidence of joint bleeding. However,there were some patients with trough levels<1% who did not bleed and others >3% whodid bleed.117 Patients with milder phenotypesmay also possess pro-thrombotic traits suchas Factor V Leiden which in some waycompensate.117,118,119

GUIDELINESThere are no strict guidelines forpersonalization of prophylaxis. While NHF,WFH, WHO, and the UK Haemophilia CentreDoctor’s Organization recommend initiationof prophylaxis prior to the onset of significantbleeding and provide a general outline ofinfusions to maintain a factor trough level

19Personalizing Prophylaxis

>1%, this may be optimized for the individualpatient’s bleeding symptoms, activity level andlifestyle.24,71,72,115 Full prophylaxis shouldconsist of either three times a week or everyother day dosing in hemophilia A and 2-3times weekly in hemophilia B, using theminimum dose necessary to avoid significantbreakthrough bleeding. Venous access devicesare an important aid for treating youngchildren. New longer half-life products shouldreduce the dosing burden on patients.

CLINICAL PEARLS• Multiple personal, medical, and lifestyle issues impact personalized prophylaxis, presenting the health care provider with frequent challenges• Selective physical activity should be part of the management plan• There is increasing evidence that dosing should be based on ideal body weight• Individual PK measurement should be performed to optimize dosing• Guidelines provide general recommendations, but therapy should be individualized



HEMOPHILIA

20 Adherence

Medication adherence in patients withhemophilia is critical. In order to realize thefull potential of scientific advances andprevent complications, barriers to prophylaxismust be identified and addressed. Patientswith chronic illnesses often do not takemedications as prescribed. In hemophilia thiscan have devastating consequences. Themanagement paradigm has shifted away fromthe concept of the “non-compliant patient,”and today’s models involve the patient, theirenvironment, and the care team. Adherenceto prophylaxis has been associated with areduced risk of intracranial hemorrhage.120

Patients on prophylaxis also report less painand improved quality of life.121 (Table 5).Non adherence often leads to poor jointoutcomes, more missed days of school orwork, and a poorer quality of life.

Lack of disease-specific education has beenidentified as a major barrier to prophylaxis(Table 5). Education should cover the disease

itself, as well as the clinical impact ofprophylaxis. In a UK study of 65 patients,adherence to a prophylaxis regimen wascorrelated with belief in the need fortreatment and belief in the efficacy oftreatment.122 Some patients on prophylaxiswho have not experienced severe symptomsare not aware of the natural course of theirdisease.123 But knowledge does not ensureadherence; in a Scandinavian study of 108patients, 41% acknowledged noncompliancewith their prophylaxis regimen despite a highdegree of knowledge of their disease.124 Across sectional telephone survey queried 38patients with hemophilia who were advised tobegin prophylaxis. Lack of initiation ofprophylaxis was generally found to be due tocost or disbelief regarding effectiveness.125

Adherence also decreases with age.81,123 Forparents of young children with hemophilia,child resistance can be a barrier to regularprophylaxis.126 The average age at which a

Adherence

Benefits

Decreased frequency of bleeding episodes

Improved joint function/prevention ofhemarthropathy

Improved school attendance

Decreased emergency roomvisits/hospitalizations

Improved academic performance

Improved quality of life

Decreased pain

Barriers

Lack of awareness of consequences ofnon-adherence

Lack of education

Fear of injection

Lack of child cooperation

Cost

Inconvenience

Travel/Center hours

Table 5. Benefits and Barriers to Adherence

21Adherence

young person with hemophilia begins to takeover his own care with self-infusions is 11.6years.124 The adolescent experiencing chronicillness may become less compliant withtreatment as he transitions to adulthood. Upto 60% of patients will report a trial ofdiscontinuation of prophylaxis as youngadults.127 These patients often cite inadequatetime/scheduling difficulties, as well as a lackof understanding of the importance ofprophylaxis in prevention of both short andlong term disability.128 While historicallythese actions have been attributed to teenage“angst,” research has clearly identified otherdevelopmental factors. A study by Colver etal129 describes the changes to the brain thatoccur between the ages of 11 and 25. There isan initial increase then a decrease in greymatter, with synaptic proliferation in thepre-frontal area of the brain. This region isassociated with emotional regulation anddecision making. These brain changes areassociated with impulsive and risky behavior,highly valuing peer interactions, andirrational decision making.130 In the contextof chronic illness, this can lead to increasedchallenges to comprehensive care. Theinconvenience and time required forprophylaxis has been noted in multiplesurveys as a hindrance to adherence.124,125

Factors associated with high rates ofadherence include longer time spent at HTCvisits and a good relationship with thephysician and the hemophilia nurse.123

Assessment of adherence should occur atevery patient visit, although historicallyphysicians often do not assess adherence.131

Patients should receive age-appropriateinformation on the risks and consequences of non-adherence.

Self-reported logs, questionnaires,documentation of number of joint bleeds orhospitalizations, and evaluation of pharmacy

records can be used to assess adherence.Evaluation has moved away from sole relianceon patient self-report to more complex,objective, and validated methods.132 Anexample of this is a novel assessment knownas the VERITAS-Pro (Validated HemophiliaRegimen Treatment AdherenceScale-Prophylaxis).105 VERITAS-Pro is a tenminute 24 question tool that can accuratelyassess a patient’s adherence rate and can alsoidentify areas needing improvement. While itis gaining use in clinical studies, this validatedmeasure of adherence is not frequently usedin the HTC setting. Smart-phone andcomputer-based applications can help patientskeep a precise log of infusions and bleeds.133

Some of these accept information such aspain medications and activity levels and someweb-based logs can be accessed by the HTC.Other aids to adherence include electronicdiary, internet dialogue page, remindertelephone calls, and home visits.

Other supportive measures should be offeredto the patient (Table 6). In one study


• Assess adherence at every visit

• Use objective tools–infusion logs, VERITAS-Pro

• Educate patient and family – Use age-appropriate educational tools: CDs, DVDs, peer mentoring

• Individualize treatment plans for lifestyle and activity level

• Engage HTC for close follow-up and support

• Plan transition of care, identify at-risk patients

• Identify financial barriers

Table 6. Strategies to Improve Adherence


HEMOPHILIA

22 Adherence

frequent specialty pharmacy educator contactwith patients with hemophilia B significantlydecreased the annualized bleeding rate.134

A high rate of compliance is often found in clinical trials.65 Patients are selectedaccording to strict inclusion criteria andreceive a high level of HTC contact,education, communication, and follow up.The challenge for the health care provider asthe point of contact is how to translate theselessons from clinical trials into daily clinicalpractice. In addition to providing support thatencourages adherence the HTC staff can alsohelp the patient address financial barriers.

Another approach derives from recentadvances in therapy. Patients believe that afactor supplement with longer half-life willlead to improved quality of life, and patientadherence may improve with moreconvenient prophylaxis.124,135

CLINICAL PEARLS• Prophylaxis is a lifelong commitment• Physical, social, emotional, and financial barriers must be continuously addressed throughout the patient’s journey• Knowledge of disease and awareness of the importance of prophylaxis are key modifiable barriers to prophylaxis adherence• Adolescence is a unique time during which special strategies may be needed to keep the patient engaged in their care• Prophylaxis must continue to be individualized• The comprehensive hemophilia treatment center is integral to supporting these processes

23Managing the Level of Medication

MEDICATION TROUGHSFactor VIII deficiency is classified as severe (< 1 IU dL-1, < 1% of normal), moderate (1-5 IU dL-1, 1-5% of normal) and mild (5-40 IU dL-1, 5-40% of normal).24 Den Uijlet al136 reviewed historical data from a cohortof 377 patients with hemophilia A. Theyobserved that the patients with factor VIII lessthan 1 IU dL-1 at any measurement sufferedapproximately 6 joint bleeds per year whilepatients with more than 12 IU dL-1 had none(Figure 2).

Pharmacokinetics is a crucial determinant ofdrug exposure and efficacy. After initialdosing and distribution, levels of plasmafactor VIII are approximated by exponentialdecay. When the drug concentration is at thelowest point, the trough value, patients aremost susceptible to bleeding. While 1 IU dL-1

is generally accepted as a minimum thresholdtherapeutic goal some patients bleed with

trough levels ≥ 3 IU dL-1 and some do notbleed below 1 IU dL-1;137 a higher level mightbe needed to prevent all joint bleeds.138

Multiple factors such as individual variationin PK, adherence, inhibitors, suboptimaldosing, and irregular dosing schedules caninfluence how long a patient remains abovethe bleeding threshold. Figure 3 illustrateshow the half-life of factor VIII in differentadults influences how rapidly they reach the 1 IU dL-1 threshold following an infusion of30 IU kg-1.

Time below threshold has clinicalconsequences. Each additional hour per weekbelow threshold is calculated to increase theannual bleed rate by 2.2% for children and1.4% for adults (Figure 4).116 While a detailedPK profile is laborious, an individual patient’sfactor VIII PK can be estimated with datafrom two or three blood samples.140


Managing the Level of Medication

Figure 2. Annual number of joint bleeds according to factor VIII activity.136 The lowestrecorded value for each patient was used for this analysis.


HEMOPHILIA

24 Managing the Level of Medication

Figure 3. Effect of half-life on factor VIII level following a bolus infusion. The short half-lifeand long half-life lines represent the 5th and 95th percentiles of the normal half-life in a 70 kgman. An individual with a short half-life crosses the 1 IU dL-1 threshold 59 hours sooner thanone with a long half-life.139

Figure 4. The calculated probability of having no bleeds per year versus time per week spentwith a factor VIII level less than 1 IU dL-1.116 Open circles (o) and asterisks (*) representhemarthroses in patients aged 1–6 years and 10–65 years, respectively.

25Managing the Level of Medication

Figure 5 shows how the dosing scheduleimpacts trough levels. The upper panelillustrates the gap in factor VIII on Sunday. Inthe bottom panel an increased dose is givenon Friday to keep the patient above thresholduntil Monday. A more cost-effective approachis to give a small dose on Sunday or to usesmall daily doses. The large therapeuticadvantage conferred by the elevated troughwith daily dosing must be balanced in clinicalpractice by considerations of inconvenience,injection site reactions, adherence, andvariable pharmacokinetics that could result inunsafe elevations in levels of factor VIII.Collins et al141 estimated the impact ofnonadherence on the time below 1 IU dL-1.Fully adherent adults on a Monday/Wednesday/Friday schedule of 30 IU kg-1 are

below the threshold for approximately 10hours during the week, while those with an80% adherence rate on the same dosingschedule would be below the threshold forapproximately 16.5 hours. This translates intoa sizeable increase in annual bleed rate andcan be especially risky for patients who arephysically active on Sundays.

Another way to view the impact of PK anddosing on factor VIII infusion dosage is tocalculate the dose required to maintain atrough level above 1-1.5 IU dL-1. Table 7presents the dose of factor VIII per infusionrequired to maintain this level in a 70 kg manfor daily, alternate day, and every third daydosing. The estimations are given for short,median, and long half-lives.


Figure 5. Model of factor VIII levels with Monday, Wednesday, Friday dosing. The upperpanel depicts a patient whose factor VIII reaches 1 IU dL-1 after 48 hours. Factor VIII isbelow 1 IU dL-1 on Sunday. The lower panel shows one method to sustain factor VIII abovethreshold: giving a fourfold dose on Friday.140

Plas

ma

Fact

or V

III


HEMOPHILIA

26 Managing the Level of Medication

The standard of prophylaxis for hemophilia Bis to dose twice weekly to maintain troughlevels of factor IX above 1 IU dL-1. There arefew outcomes data to support this choice andthe number is derived from experience withfactor VII.142 Two preparations of factor IX areavailable: plasma-derived factor IX (pdfactorIX) and recombinant factor IX (rFIX). Theyare similar in structure and function143 buthave different PK properties. rFIX has a higherclearance rate and shorter half-life thanpdfactor IX144 so rFIX requires a higher dosethan pdfactor IX with careful monitoring.Estimates for the increase in dose range from25%24 to 100%.144

Bleeding episodes in spite of prophylaxisadherence and measured levels suggest thepossibility of additional causes of bleeding.Given the high incidence of von Willebranddisease and assorted platelet disorders, suchpatients should undergo a workup thatincludes a VWD panel and a plateletaggregation assay. Patients should be regularlycautioned against the use of aspirin and otherdrugs with anticoagulation effects.

PATIENT DIFFERENCESThe maintenance of trough levels greater than1% depends upon several key patient variablesincluding age and weight. There are severalstudies which have demonstrated reducedclearance of factor VIII, increased recovery,and increased terminal half-life with increasesin age.145,146 On the other hand, the terminalhalf-life of factor IX does not change withage.147 A patient’s PK cannot be predicted bydemographic information, and PKmeasurements should be a part of anyindividualized dosing regimen.

Half-life

Short: 7.5 h (5th percentile of normalrange)

Median: 10.4 h

Long: 16.5 h (95th percentile of normalrange)

DailyDosing

240

120

50

Alternate DayDosing

2420

700

200

Every ThirdDay Dosing

22410*

3570

600

Table 7. Dose of factor VIII (IU) per infusion required to maintain trough level of 1–1.5 IU dL-1 in a 70 kg man, depending on dose schedule and half-life

*The high dose required with every third day dosing for patients with a short factor VIIIhalf-life is unrealistic and potentially harmful.139

27Case-Based Learning

Case-Based LearningMr. H is 37-years-old. He is in relatively good health and is able to lead a healthy lifestyledespite severe hemophilia A. He comes to clinic today for his annual comprehensive visit andto discuss his current prophylaxis regimen. He has 1-2 joint bleeds per year. Unfortunately, hehas recently developed a target joint in his right knee.

He had a bleed after tripping on a rock when he was camping several months ago and he didnot have his supplies with him. He had infused the prior day, but after the event was unable toinfuse until the following day and did so daily for the remainder of that week. Since then, hehas had several more bleeding episodes with and without minor trauma.

He works as an accountant and is not physically active during the week. He and his wife enjoyhiking and other activities on the weekends and he is not sure that his current infusionschedule of M-W-F is optimal. He rarely misses doses and has never had trouble with venousaccess.

Does Mr. H have adequate factor VIII on the weekend when he typically engages in physicalactivity?

_____________________________________________________________________________________

_____________________________________________________________________________________

Would you change his medication, his schedule, or both? Why?

_____________________________________________________________________________________

_____________________________________________________________________________________

How would you monitor his factor levels after changing his schedule?

_____________________________________________________________________________________

_____________________________________________________________________________________

Answer these questions at: www.YaleCME-Hemo.org



HEMOPHILIA

28 Case-Based Learning

CLINICAL PEARLS• Prophylaxis should be used for patients with hemophilia to maintain a milder level of disease• A trough level greater than 1 IU dL-1 is the therapeutic standard for factor VIII but there is individual variation in patients’ bleeding at this level• PK measurements should be considered for individualizing therapy• Long-acting analogs of rFVIII and rFIX enable increased dosing intervals, higher interval trough levels, and equivalent prophylaxis compared to standard shorter acting factors. Clinical trials reveal no short term increase in the incidence of inhibitors

29Emerging Therapies: Promise and Challenges

CLINICAL AND PATIENT BENEFITSOF FACTORS WITH PROLONGEDHALF-LIVESOne significant promise of emergingtherapies is their extended half-lives andassociated ease of use. Modified forms ofcoagulation factors VIII and IX increase theinterval between dosages for prophylaxistherapy and may be useful for patients withnew-onset bleeds. Such factors are predictedto markedly enhance quality of life measuresfor hemophilia patients, particularly whenissues such as ease-of-use, complexity ofdosing, maximum protection from bleeding,and increased ability to participate in physicalactivities are taken into consideration.Greater efficacy and maintenance ofhemostasis should result from products withincreased in vivo stability and extended

half-lives.148 Table 8 lists some of theapproaches to extending factor in vivostability.

REDUCED-IMMUNOGENICITYCOAGULATION FACTORCONCENTRATESNew recombinant factor VIII products shouldbe minimally immunogenic, have coagulationfactor function, and bear a low infection risk.One new product, turoctocog alfa(NovoEight®),149 is a truncated factor VIIImolecule containing 21 amino acids of theß-domain. Site specific enzymaticglycoPEGylation of the ß-domain extends thehalf-life but thrombin cleavage in vivoremoves the PEGylated peptide, resulting in aproduct that is similar to native factor VIII.150

Recently completed Guardian™ studies in


Emerging Therapies: Promise andChallenges

Factor VIII

BAY 94-9027

Turoctocog (NovoEight®)

1.4-1.5X

Efraloctocog (Eloctate™)

Factor IX

Nonacog

Fc fusion

CSL654

Modification

PEGylated rBDD

PEGylated rBDD

PEGylated rFL

rBDD-Fc fusion

PEGylated

Fc fusion

Albumin fusion

Increase in Clinical t1/2

1.5X

1.6X

1.4-1.5X

1.5-1.7X

5X

2.5X

5X

Table 8. New and emerging clotting factors with extended half-lives (adapted from148)BDD: B-domain deletion, FL: full length


HEMOPHILIA

30 Emerging Therapies: Promise and Challenges

adult and pediatric populations have shownturoctocog alfa to be effective and potentiallyless immunogenic than other recombinantproducts.151,152 A single chain rFVIII expressedin human embryonic kidney cells (human-clrhFVIII) is also in clinical development.153

Posttranslational modification in human cellsmay decrease the generation of inhibitors.ACE910 is a bispecific antibody thatrecognizes factors IXa and X and mimics thecofactor function of factor VIII. Early clinicalresults suggest that this molecule may beeffective for patients with hemophilia A withand without factor VIII inhibitors.154-155

A similar set of objectives exist for new factorIX products. Alprolix®156 is an FDA-approvedrecombinant factor IX IgG Fc fusion productthat has a terminal half-life of 82 hours, anincrease of 2.5-fold over rFIX,148 and has a low rate of inhibitor formation. Recombinantfactor IX expressed in human hepatomaHuH-7 cells is also in development.157

CHALLENGES OF EMERGINGTHERAPIES: SCIENTIFICOBSTACLES AND PRACTICALCONSIDERATIONSWhen considering the biology andpathophysiology of hemophilia disorders, newtherapies face several challenges, including:• A low-risk profile, including both infectious and non-infectious complications• Inherent biological limitations (e.g., extending the half-life of factor VIII beyond that of von Willebrand factor)• Maintenance of coagulation function without augmented immunogenicity• Pushing the boundaries with “curative” therapies (e.g., FVIII gene therapy)158

In addition to these biological obstacles, thereare other challenges. One of the mostsignificant questions is the optimal time totransition a patient from an older factorconcentrate to a new therapy. Someconsiderations include: 1) poor adherence toolder therapies due to complex administrationtechniques or schedules; 2) lifestylelimitations of an older therapy; and 3) adesire of a newly-diagnosed patient to use alow-risk/low antigenicity product. Costs mayalso be a significant concern for somepatients and the economics of new and oldtherapies must be considered.

Finally, the emergence of novel hemophiliatherapeutics will also have an impact onprescribing practices. Clinicians mustcarefully consider not only the safety andefficacy of novel therapies but also how thenew regimens will impact adherence. Onetool recommended by Witkop et al is apatient-provider agreement to enhancecommunication, adherence, and assessmentof adherence.159 Such a document sets clearguidelines and goals for patients. Withadequate preparation and mindfulness ofpotential pitfalls, clinicians should be able tosmoothly transition to prescribing novelfactor concentrates.

31Conclusion

ConclusionsHemophilia A and B are X-linked recessivebleeding disorders that typically affect males.Patients present most frequently in earlychildhood with bleeding after minor surgeryor with intracranial hemorrhages. Dependingon the level of clotting factor, hemophilia iscategorized as mild, moderate, or severe. Theseverity of bleeding depends on the paucity ofclotting factor and therapeuticsupplementation is aimed at decreasing theseverity of factor deficiency and hence theseverity of clinical disease.

The most serious chronic problem ofhemophilia is arthropathy subsequent to jointbleeding. The extent of joint damage is relatedto the number of bleeding events. This has ledto a therapeutic strategy of prophylaxis ratherthan episodic treatment. Initiation andaggressiveness of prophylaxis varies amongdifferent countries and different practitioners.The dose and timing of prophylacticsupplementation depend on factors such aspatient tolerance of infusion, age, physicalactivity, adherence, and treatment cost. TheNHF, WFH, WHO and the UK HaemophiliaCentre Doctor’s Organization supportprophylaxis and maintaining factor troughlevels > 1% but the details of the treatmentplan are ultimately decided by the health careprovider, patient, and family. HemophiliaTreatment Centers can be invaluableresources that provide experience andmultidisciplinary support. The HTC can offerexpert guidance and support for barriers suchas education, design and transition of care,

and medical problems such as inhibitoryantibodies to exogenous factor preparations.A key practice in personalizing therapy ismeasuring a patient’s PK pattern. Though acomplete PK workup is quite involved, simplified protocols can be very useful inindividualizing care.

Adherence plays a crucial role in maintainingthe balance between using the minimaleffective dose and keeping the trough valuesabove 1%. Routine assessment, patient tools,family involvement, individualized treatmentplans, an HTC approach, and addressingfinancial barriers should all be incorporated,with the recognition that a patient may havemultiple barriers to adherence. New andemerging factor VIII and factor IXpharmaceuticals with longer half-lives and/orreduced immunogenicity could have a hugeimpact on patient lifestyle, help protectagainst low trough levels, and potentiallyimprove adherence.



HEMOPHILIA

32 References

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