Advances in Care of Children With Hemophilia

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Pediatric Thrombosis and Hemostasis: Maureen Andrew Memorial Issue, Part 2; Editor in Chief, Eberhard F. Mammen, M.D.; Guest Editors,Lesley Mitchell, M.Sc., and Shigenori Suzuki, M.D. Seminars in Thrombosis and Hemostasis, volume 29, number 6, 2003. Address forcorrespondence: Marilyn J. Manco-Johnson, M.D., Mountain States Regional Hemophilia and Thrombosis Center, P.O. Box 6507, Mail Stop F-416, Aurora, CO 800450507. E-mail: [email protected]. 1Professor of Pediatrics; Director, 2Mountain States RegionalHemophilia and Thrombosis Center, University of Colorado Health Sciences Center and The Childrens Hospital, Denver, Colorado;3Orthopedic Hospital, Los Angeles, California. Copyright 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY10001, USA. Tel: +1(212) 584-4662. 0094-6176,p;2003,29,06,585,594,ftx,en;sth00923x.

Advances in Care of Children with HemophiliaMarilyn J. Manco-Johnson, M.D.,1,2 Brenda Riske, M.S., M.B.A., M.P.A.,2 andCarol K. Kasper, M.D.3

ABSTRACT

Care for children with severe hemophilia has moved from pediatric hospital wardsand rehabilitation services to the home, school, and community. Advances in hemophiliaare due largely to the development of specialized hemophilia treatment centers, whichcreated a system of comprehensive care and focused healthcare efforts on prevention andeducation. Parallel advances in coagulation resulted in identification of clotting factorsVIII and IX, elucidation of the protein molecular and biochemical structures and func-tions, sequencing of their respective genes and transfer of the human genes for productionof proteins by recombinant technology, and development of gene therapy. The tragedy ofthe human immunodeficiency virus and hepatitis C raised awareness in patients as well ashealthcare providers of the vulnerability of blood products to viral contamination andspurred progress in science leading to viral inactivation of purified proteins. Concomi-tantly, physicians treating bleeding episodes in the clinic investigated pharmacokineticsand pharmacoeconomics of various strategies of clotting factor replacement. The obser-vation that trough factor levels as low as 1 to 2% were adequate to prevent most bleedingepisodes led to current prophylactic regimens that allow boys to participate fully in schooland community activities while factor concentrate is infused at home on a regular sched-ule. Currently, children with hemophilia look forward to a normal life expectancy and ex-cellent health-related quality of life. Physician and community partnerships through re-search and advocacy societies have accelerated clinical advancements as well as extensionof treatment to developing countries. The future of hemophilia promises a cure with genetherapy. Given the past accomplishments in hemophilia, a long-term solution to replace-ment of the genetically deficient protein lies on the horizon.

KEYWORDS: Hemophilia, treatment, factor concentrates, blood products, bleeding

Objectives: On completion of this article, the reader should be able to (1) list the main contributions that led to improved life ex-pectancy of patients with hemophilia and (2) state which accomplishments led to a reduction of joint bleedings in hemophiliacs.Accreditation: Tufts University School of Medicine (TUSM) is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians. TUSM takes responsibility for the content, quality, and scientific in-tegrity of this CME activity.Credit: TUSM designates this educational activity for a maximum of 1 Category 1 credit toward the AMA Physicians RecognitionAward. Each physician should claim only those credits that he/she actually spent in the educational activity.

586 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 29, NUMBER 6 2003

a large number of proteins involved in coagulation ledto development of the International Committee for theNomenclature of Blood Clotting Factors, which was laterrenamed The International Committee for Haemostasisand Thrombosis, now The International Society forThrombosis and Haemostasis (ISTH), including theScientific Standardization Committees.

Rapid advances in the field of coagulation pro-gressed from the identification, isolation, and biochemi-cal characterization of factors VIII and IX8,9 to identifi-cation and sequencing of their respective genes10,11;understanding coagulation protein structure, function,and interactions at the molecular level12,13; and develop-ment of dynamic integrated theoretic models of throm-bin generation and regulation.13 Functional assays of fac-tors VIII and IX allowed prediction of bleeding risk andprovided the rationale for structured treatment protocolsto manage acute bleeding events and prevent surgicalbleeding. New laboratory techniques to assess globalthrombin generation potential helped to explain clinicaldifferences among hemophilia patients and allow fortherapies tailored to individual hemostatic potential.13

DEVELOPMENT OF SPECIALIZEDCENTERS FOR HEMOPHILIACOMPREHENSIVE CAREIn 1958, in an attempt to organize experience and ser-vices for persons with hemophilia, Biggs and Macfarlane14reviewed records of 187 hemophilia patients who received

The care of children with hemophilia has im-proved immensely over the last 40 years, from an era inwhich children with hemophilia rarely were expected tosurvive beyond the first decade to the present state inwhich babies currently born with severe hemophilia canbe expected to have a normal life span, participate fullyin school and the workplace, and receive treatment inthe home with minimal disruption to personal and fam-ily life. Hope for a significant modification of hemo-philia through gene therapy still looms as a promise, al-though lasting gene transfer has yet to be demonstratedin humans with hemophilia. The tremendous evolutionin prognosis of severe hemophilia from a chronic crip-pling and often fatal condition to one for which parentscan anticipate a fairly normal quality of life occurredthrough parallel improvements in several aspects of he-mophilia care over the last four decades. A few advancesoriginated in dramatic scientific discoveries, but the ma-jority resulted from basic and practical incremental im-provements in care contributed by a large number ofdedicated hemophilia treaters world-wide. This paperreviews the major achievements.

ELUCIDATION OF BASIC MECHANISMSOF COAGULATIONThe hemophilias are X-linked genetic bleeding disor-ders caused by deficiencies of coagulation factor VIII(FVIII) and factor IX (FIX). The history of early med-ical progress in understanding and treating hemophiliawas published in a classic review by Rosemary Biggs in1967.1 In 1937, Carroll Birch2 chronicled the clinicalcourse in 98 living patients with hemophilia and reviewedrecords of other family members. Table 1 lists the causeof death in 113 persons with hemophilia reported byBirch2 and serves as a stark testimony to the fatal natureof trivial lacerations, epistaxis, circumcision, and toothextraction prior to factor replacement therapy. Macfar-lane realized in the 1930s that treatment of hemophiliawould not be achieved until the physiology of normalclotting and hemostasis were determined. In 1934, Mac-farlane and Barnett reported that only transfusion ofwhole blood, and not any local therapies, showed effi-cacy in cessation of hemophilic bleeding.3 Macfarlane4hypothesized in his seminal 1938 article that a clottingfactor necessary to activate prothrombin was missing inpersons with hemophilia, and identification of this fac-tor would be necessary to understand and ultimately treathemorrhage in persons with hemophilia. Until 1952, itwas believed that tissue-derived thromboplastin directlyactivated prothrombin. In 1953, this group discovered aplasma thromboplastin activity formed in normalblood and defective in the plasma of persons with hemo-philia.5,6 They went on to develop coagulation assaysthat differentiated plasmas deficient in FVIII from thosedeficient in FIX, and the stage was set for the develop-ment of specific therapies.7 The subsequent discovery of

Table 1 Cause of Death for 113 Patients with Hemophilia2

Cause of Death Number

Operations 25Circumcision 15Tooth extraction 6Vaccination 1Lanced hematomas 2Tonsillectomy 1

Trivial injuries 23(cut lip, bitten tongue, injuries to forehead, finger, scalp, etc.)

Internal bleeding 21Central nervous system bleeding 7Birth trauma and umbilical bleeding 7Epistaxis 6Lung hemorrhage 5Haematuria 4Throat bleeding 3Intestinal bleeding 3Gastric bleeding 3Cutting first tooth 1Fracture of leg 1Miscellaneous 4

Data from Birch.2 AQ10

CHILDREN WITH HEMOPHILIA/MANCO-JOHNSON ET AL 587

specialized services at Oxford. Observations of these 187patients led to several sentinel findings regarding the nat-ural history of hemophilia, including the classification ofhemophilia severity based on levels, with mild symptomsobserved in most patients with more than 5% of FVIIIand very mild disease noted in many hemophilia B pa-tients with 1% or more FIX. In addition, it was noted thathemophilia A patients with 1 or 2% FVIII activity ex-hibited far fewer bleeding episodes in comparison withpatients who had no detectable FVIII. Macfarlane andBiggs14 noted that it required far higher levels of factoractivity to prevent surgical bleeding than to prevent spon-taneous hemorrhages, an observation that laid the ground-work for rational design of factor replacement recom-mendations and suggested a role for prophylaxis. Withexperience, the Oxford group developed standardizedapproaches to various types of bleeding in hemophiliapatients. At this time local hospitals often cared for he-mophilia patients with routine hemorrhages and referredonly the most difficult cases to Oxford. Biggs and Mac-farlane14 described the case of a young man with pro-tracted complications following surgery for trauma whosecare consumed the time of 9 physicians, 5 of whom spentmost of their time with him during a 3-month hospital-ization, in addition to constant services of nurses, physio-therapists, and laboratory personnel. Biggs and Mac-farlane15 suggested that treatment of this patient in aspecialized center such as Oxford would have consumeda small part of one hematologists time with fewer com-plications and a better outcome. In addition, they stressedcollaboration among hematologists, surgeons, physio-therapists, and laboratory personnel was key to improvedclinical outcomes. Thus, the rationale was presented forthe development of specialized centers to deliver hemo-philia comprehensive care. The same year Carol Kasperet al16 reported the first US multidisciplinary center serv-ing more than 500 patients with hemophilia. The con-cept of hemophilia comprehensive care spread and 10years later, reports were published on the benefits of or-ganized comprehensive care clinics for hemophilia fromItaly, the United Kingdom, France, the United States,and Asia.1721

In 1975, the US Congress appropriated moneyfor the creation of a national network of HemophiliaDiagnostic and Treatment Centers by Section 1131 ofthe Public Health Service Act.22 The first centers wereestablished the next year. The system was expanded grad-ually to the current 135 federally funded hemophilia treat-ment centers. Similar national programs were developedin Canada and several European countries. The initialcharge to the treatment centers was to establish and main-tain high-quality reference coagulation laboratories withvalidated assays to identify accurately persons with thehemophilias and other congenital bleeding disorders.Comprehensive clinic programs staffed by a team of spe-cialists were developed to provide comprehensive evalu-ation and generate an integrated treatment plan.20 The

central figure in the hemophilia treatment center wasthe nurse coordinator, who was responsible to provideeducation about hemophilia to the patient, the family,teachers, employers, and healthcare providers in the com-munity.23 In addition to nurse coordinators, the originalmultidisciplinary hemophilia center teams included hema-tologists, pediatricians, internists, geneticists, dentists,physical therapists, orthopedic surgeons, social workers,and psychiatrists to deal with the protean issues sur-rounding hemophilia.1,16,20 Hemophilia care advancedsignificantly when all patient calls were funneled to onenurse specialist who expedited clinic visits for bleed as-sessment, facilitated prompt outpatient factor replace-ment therapy, and ultimately taught and monitored homeinfusion therapy. The majority of persons with severehemophilia rapidly enrolled in the US federal hemophiliasystem and within 5 years of their inception, Smith,Levine, and others were able to document that com-prehensive hemophilia treatment centers dramatically re-duced cost, hospitalizations, and absenteeism from workand school.24,25 By 1984, the World Federation ofHemophilia determined international standards for he-mophilia centers.26 More recently, the US Centers forDisease Control and Prevention (CDC) funded a sur-veillance project and confirmed reduced mortality andmorbidity for persons with hemophilia who access fed-erally funded hemophilia treatment centers.27 The roleplayed by the hemophilia comprehensive care centers inthe improvement in hemophilia outcome cannot beoverstated.

PARENTAL AND SELF-INFUSION OFFACTOR CONCENTRATE IN THE HOMEEarly observations linked prompt treatment with faster,more effective control of hemorrhage. Shortly after cry-oprecipitate became available, families requested supportto institute replacement therapy in the home. A homeprogram including 14 patients with FVIII deficiency wasreported from Michael Reese Hospital in Chicago in1970.28 Home therapy was quickly adopted in countrieswith access to replacement therapies.2931 Of interest,hemophilia patients using self-treatment at home werenoted to use a higher FVIII dose, based on perceived ef-ficacy.31 International recommendations endorsing hometherapy were published in 1979.32 Home therapy avoidstime delay and expense associated with emergency roomvisits, allows treatment in a comfortable environment,and continues as a keystone in hemophilia therapy. In2001, the US CDC Surveillance Project reported thathome therapy and hemophilia comprehensive care cen-ters were each independently associated with a reducedrate of hospitalization for bleeding episodes.33

The goal of home therapy for young childrenwith hemophilia is to facilitate prevention or early treat-ment of bleeding events in hopes of preventing targetjoint disease. Venous access is often problematic in chil-


dren below the age of 4 or 5 years. Placement of in-dwelling central venous access devices (CVADs) hasmade primary prophylaxis available to many children wholive far away from treatment centers. CVADs carry po-tential morbidities of infection, mechanical malfunction,and large vessel thrombosis. Short-term observations ofsingle centers (median, 30 months) yielded low infec-tion rates of 0.14 and 0.19 per 1000 catheter days incontrast to a national US nursing survey that found in-fection in 45% of 568 CVADs.3436 Infection within theport is more common than systemic bacteremia.37 Allstudies have found a higher rate of infection in CVADsused to induce immune tolerance of inhibitors.38 Symp-tomatic thromboses appear to be rare.39 Despite com-plications, CVADs have greatly increased therapeuticoptions for very young children with hemophilia whiledecreasing cost and stress.

DEVELOPMENT OF SAFE, EFFECTIVEREPLACEMENT PROTEINSThe development of safe, effective coagulation proteinsfor replacement therapy has been paramount in the ad-vancement of hemophilia care. The history of plasmaproduct safety has been reviewed recently.40 The trans-mission of viral pathogens to children with hemophiliathrough blood products caused untold pain and suffer-ing in the hemophilia community and substantially de-layed implementation of preventive strategies includingprophylaxis and immune tolerance (see the following sec-tions). However, remarkable advances came even fromthe tragedy of human immunodeficiency virus (HIV) inthe form of basic scientific discoveries in virology andimmunology as well as application of the hemophiliacomprehensive care system to creation of comprehensivepediatric HIV programs. Emerging knowledge regard-ing hepatitis transmission through blood products stim-ulated the development of rational approaches to prospec-tive safety studies of new products through the ISTHSubcommittee for factors VIII and IX.41

Early attempts to develop concentrates of anti-hemophilic globulin from animal and human plasmaswere initiated in the United Kingdom, France, and Swe-den. However, the 1965 description by Judith GrahamPool et al42,43 of a FVIII concentrate made using cryo-precipitation in a procedure easily adaptable to most bloodbanks led to immediate large-scale clinical application ofFVIII replacement therapy to hemophilia A. Concen-tration of FIX in prothrombin complex concentrates wasdescribed the same year.44 Routine treatment of jointand muscle bleeds became widespread shortly thereafter.However, the emergence of viral transmission throughblood products, in the form on hepatitis B as well asnon-A, non-B hepatitis was recognized soon after wide-spread application of human plasma products for infu-sion.45,46 It was observed that the risk of hepatitis wasgreater with the use of pooled in comparison to single-

donor products.46 The US National Institutes of Healthconvened a consensus conference to discuss the preva-lence and potential consequences of non-A, non-B hep-atitis in 1975.47 Hepatitis C was later identified as theoffending viral agent in most transfusion-associated hep-atitis, and most hemophilia patients who had been ex-posed to blood products manifested positive serologicevidence of hepatitis C infection.48 Heat treatment offactor concentrates was the first effective viral attenuationprocedure, inactivating several logs of lipid-encapsulatedviruses, including human immunodeficiency virus (HIV)and hepatitis B and C.49 Isolation of FVIII by affinitychromatography employing monoclonal antibodies pro-vided the next significant advancement in blood productpurity and safety in 1989.50 Hepatitis A and ParvovirusB19, lacking a lipid capsule, were more difficult to inac-tivate using heat and solvent detergent.51,52 The appli-cation of several procedures including donor screeningand donor unit testing for viral antibody, antigen, andnucleic acids, in addition to improved viral inactivation,have increased the safety of products derived from humanblood.53,54 Still, fears of emerging infections such as WestNile virus (which has been determined to be transmissi-ble through blood transfusions) and variant Creutzfeldt-Jacob disease (which has not been determined to be trans-missible through blood transfusions) continue to exertpressure for the development of alternative treatmentproducts to human blood-derived proteins.55,56

The FVIII gene was first sequenced in 1984.8 Fac-tor VIII produced in cell culture by recombinant tech-nology was first applied to human trials in 1989.57 Twofull-length recombinant FVIII molecules are availablecommercially with excellent performance for clinical ef-ficacy and safety.57 More recently, a -domain-deletedFVIII (BDD FVIII) has allowed more efficient yieldfrom tissue culture systems and has contributed to anincreased availability of FVIII.58 BDD FVIII is clini-cally comparable to the full-length recombinant mole-cule.58,59 However, assay of BDD FVIII by clotting ac-tivity yields results approximately 50% compared withthe full-length molecule; this phenomenon is related tothe phospholipids in the assay.60 Using a chromogenicassay, function of BDD FVIII and the native moleculeare comparable. There is one recombinant FIX mole-cule.61 Recombinant FIX lacks phosphorylation at serine158, has decreased tyrosine sulfation, and has a variablydecreased peak plasma concentration following injection(known as plasma recovery) as compared with plasma-derived FIX.61 Still, the hazards of emerging infectiousrisks, such as prions, that could contaminate plasma orrecombinant clotting proteins has driven a demand forrecombinant proteins completely devoid of human pro-teins.62 Currently, third-generation recombinant FVIIImolecules are being developed with no human proteinseither in the cell culture or in final stabilization of thelyophilized recombinant protein. To date, tens of mil-lion units of recombinant FVIII and IX have been in-


fused worldwide with no evidence of HIV or hepatitisC transmission.53,57 Recombinant clotting factor con-centrates have increased the world supply of hemophiliatreatment products and, owing to their excellent safetyprofile, have fostered more liberal application of preven-tive treatment protocols for young children and recon-structive surgeries for adults. To date, however, recom-binant FVIII molecules have not fulfilled physician andpatient expectations of unlimited factor quantity at aprice affordable for widespread use in many countries.

DEVELOPMENT OF OTHER THERAPIESIn addition to specific factor concentrates, the develop-ment of a small number of other therapies has con-tributed enormous benefit for prevention or treatmentof bleeding episodes in persons with hemophilia. Theefficacy of the fibrinolytic inhibitor epsilon-aminocaproicacid in dental extractions was first reported from theCardeza Foundation in Philadelphia in 1964.63 Epsilon-aminocaproic acid is still a mainstay for adjuvant ther-apy of mucus membrane bleeding including mouth andgum bleeding and menorrhagia. A controlled trial of thefibrinolytic inhibitor tranexamic acid was reported in1973.64 Tranexamic acid causes less gastrointestinal dis-tress as compared with epsilon-aminocaproic acid and isequally effective. 1-Deamino-8-D-arginine vasopressin(DDAVP), a synthetic vasopressin, was found to increaseplasma levels of FVIII and von Willebrand factor in pa-tients with mild hemophilia A and von Willebrand dis-ease.65 This nonblood-product therapy can be used foreither prevention or treatment of bleeding in individualswith an adequate response. Seizures secondary to hypo-natremia have been reported, especially in infants; ac-cordingly, DDAVP is not recommended for childrenyounger than the age of 2 years.66 Activated recombi-nant FVII (rFVIIa) was first successfully employed tocontrol hemostasis in a hemophilia patient with inhibitoryantibodies in 1991.67 rFVIIa has been demonstrated tobypass factors VIII and IX in the activation of FX onthe platelet surface in the absence of tissue factor, and inaddition, may aid tissue factor-mediated generation ofactivated FX.68 rFVIIa has become a first-line therapyfor bleeding in children with inhibitors.69 Finally, a localhemostatic agent concocted from a combination of pro-teins including fibrinogen, thrombin, FXIII, and apro-tinin was developed in Israel as a topical agent to pro-mote hemostasis.70 Fibrin glue is particularly useful inoral bleeding.

PROPHYLAXISThe most costly and prevalent complication in personswith severe hemophilia is progressive degenerative arthri-tis following recurrent episodes of hemorrhage into joints.Hemophilic arthropathy results in debilitating chronicpain, decreased range of motion of joints, and functional

impairment. Prophylaxis in hemophilia refers to a treat-ment strategy of infusing factor concentrate preven-tively, prior to the onset of bleeding. Prophylaxis usinglyophilized plasma was first given to halt intractablebleeding events by John Johnson at Howard Universityin 1942.71 Limitations in the quantity and safety of fac-tor concentrate limited preventive therapy for at leasttwo decades. During the 1960s, early reports of prophy-laxis were published from Sweden, Canada, the UnitedStates, and The Netherlands.7275 Clinical trials to de-termine optimal dose and dose frequency were con-ducted in the late 1960s and early 1970s primarily inpatients with a long history of joint hemorrhage.7379 Asingle case study of Shanbrom and Thelin74 reportedthe response of 100% FVIII correction given daily, fivetimes a week, three times a week, and weekly, andshowed a minimal effective dose of 50 U/kg givenweekly. The US National Institutes of Health publishedpharmacokinetic data on FVIII prophylaxis and relatedclinical cessation of bleeding events to a trough FVIIIlevel of 2%, achieved giving 60% correction every 36hours.76 Incremental effects of increasing prophylacticdosing were shown by Kasper et al77 and demonstratedoptimal efficacy using daily dosing with 50% reductionof bleed frequency using 250 U of FVIII per day and75% reduction with 500 U/day. The effect of higherdoses was limited to 3 or 4 days. A double-blind, placebo-controlled crossover trial performed by Aronstam et al78in children with hemophilia given 25% FVIII correctiononce weekly showed reduced frequency of bleeding by15% overall, with most of the effect in the first 3 days.The same authors showed that 30% correction twice aweek was superior to 15%, with most of the effect in thefirst 48 hours.79 Although availability and safety of fac-tor concentrates limited broad application of prophylaxisto children, Inga Marie Nilsson80 continued to pioneerregular infusions of FVIII to prevent joint bleeding inyoung Swedish children with hemophilia. In observa-tional studies, Nilsson et al81 were able to demonstratephysical and radiologic evidence of improved joint out-come in children treated with early prophylactic regi-mens. Initiation of prophylaxis after the onset of jointchanges was determined to improve physical functioningand pain, but did not reverse or halt progressive arthriticchanges.82 However, the cost and effort of factor infu-sion three to four times weekly is enormous and long-term compliance is a significant issue.83 Less intensivepreventive strategies had not been well-studied inyoung children with healthy joints.

Currently, there is an ongoing US prospective,randomized clinical trial of every other day prophylaxisversus an intensified episode-based therapy in 65 youngchildren < 2.5 years of age with FVIII 2% that willcompare joint outcome using very sensitive magneticresonance imaging (MRI) and a physical evaluation toolspecifically developed for young children.84 The USprophylaxis study will be completed in 2005. A recently


completed single-arm trial of escalating prophylaxis inyoung children has been conducted in Canada and willbe analyzed shortly.84 The rationale of dose-escalationin prophylaxis is to decrease the cost of factor and limitthe need for CVADs by treating children with less fre-quent infusions of factor replacement based on clinicallyevident bleeding rate. There is no doubt that preventionof bleeding episodes, overall, conveys a better outcomefor hemophilic arthropathy as well as life-threateningbleeding events, such as intracranial hemorrhage. Like-wise, the widespread use of CVADs has fostered earlierhome therapy and more effective treatment of acutebleeding events in addition to prophylactic infusions.Clinical trials such as the US and Canadian studies de-scribed will refine prophylaxis and determine optimaldose, dose frequency, and age of initiation to achieve thebest outcome with the least morbidity and cost.

IMMUNE TOLERANCEOne of the most significant morbidities of hemophiliatherapy is the development of inhibitors.85 Inhibitors areimmunoglobulin G (IgG) antibodies (most frequentlysubclass IgG4) that bind to specific FVIII epitopes, pri-marily active sites in the A2 and C2 regions of the mol-ecule.86,87 Inhibitory antibodies cause irreversible inac-tivation of FVIII, limiting the usefulness of replacementfactor therapy. Inhibitor titer is determined in theBethesda assay in which serial dilutions of patient plasmaare incubated with an equal volume of pooled normalplasma for 2 hours at 37C.88 The titer is defined as theplasma dilution that inactivates 50% of the FVIII innormal plasma and expressed in Bethesda units (BU).High-titer inhibitors are variously defined as those higherthan 5 or 10 BU. Inhibitor formation always follows ex-posure to exogenous FVIII. In prospective studies ofyoung children given recombinant FVIII, the incidenceof inhibitors was approximately 30%, with half being hightiter; the median time to development of an inhibitorwas 9 exposure days to recombinant FVIII, with mostinhibitors presenting within 50 exposure days.57

The predisposition to inhibitor formation is de-termined partly by the nature of the gene mutation andpartly by the immune constitution of the patient.8993The risk of inhibitor development is increased in pa-tients with large deletions, the intron 22 inversion, andnonsense mutations, and decreased in patients with mis-sense mutations and small deletions. In addition, theimmune response elicited by FVIII is a mixed Th1 andTh2 response. Inhibitor formation may be modulatedby blockade of costimulatory molecules important inoptimal T-cell activation.93

Persons with inhibitors cannot be treated optimallyfor bleeding events. As a consequence, they suffer moresevere and extensive hemophilic arthropathies, recurrentintracranial hemorrhages, and other bleeding complica-tions. The cost of care is significantly increased and

quality of life is markedly diminished.94 Nilsson95,96 re-ported regimens using a combination of factor and cy-toxan to suppress the inhibitory response to FIX andFVIII in 1973 and 1974, respectively. After many mod-ifications of the original therapy, Nilsson et al97 publishedthe Malm regimen for immune tolerance induction em-ploying FVIII exposure (100 U/kg/day) with monthlycourses of cytoxan and intravenous immune globulin(IVIG) in 1988. A German immune tolerance regimendubbed the Bonn protocol, first reported in 1976, em-ployed higher doses of FVIII (100 U/kg bid) withoutimmunosuppressive therapy and showed similar efficacy.98A Dutch adaptation was shown to achieve tolerance withas little FVIII as 50 U/kg three times weekly.99 A recentretrospective review of immune tolerance suggests thatup to 90% of young children with high-titer inhibitorscan achieve tolerance.100 Doses of 100 U/kg/day orhigher, and initiation within a year of inhibitor onset,predicted successful tolerance induction. However, thereare many unanswered questions including the optimaldose schedule, treatment product, and window of thera-peutic efficacy following diagnosis of an inhibitor. Cur-rently, an international study is ongoing to determinerelative benefits and costs of high-dose versus low-doseimmune tolerance.101

ORTHOPEDIC INTERVENTIONS FORJOINT DISEASEDespite the greater availability of safe, effective factorconcentrate for treatment and prevention of acute bleed-ing episodes, persons with severe hemophilia continueto develop synovitis and arthropathy.102 Local therapiestargeted to the affected joint are indicated for childrenwith mild hemophilia, children in whom most bleedingevents are localized to one joint, and in areas of the worldwhere prophylaxis is not available or affordable. Intra-articular injections of P32, termed radiosynoviorthesis,were first applied to persons with rheumatoid arthritis.103P32 radiosynoviorthesis has been applied to children andadolescents with hemophilia. Radiosynoviorthesis in chil-dren, particularly with early synovitis, is effective inlong-term reduction in bleeding rate.104 The procedureis effective, well tolerated even by children as young as4 or 5 years, inexpensive, and appears to be safe.104,105Radiosynoviorthesis should not be considered an equalalternative to prophylaxis in children with recurrent he-morrhages into multiple joints. However, radiosynovior-thesis has been so successful that it is being recom-mended as a first approach to local therapy of hemophilicarthropathy in many hemophilia centers.

Synovitis has also been treated with surgical re-moval of synovium. Early synovectomies were performedin open joint procedures. Open surgical synovectomy iseffective in decreasing the rate of joint hemorrhage,106but is expensive, requires protracted physical therapyand factor replacement, and is accompanied by a high


rate of decreased joint range of motion and functionalgait abnormalities. Arthroscopic synovectomy appearsto have less damaging effects on range of motion andgait.107 Arthroscopic synovectomy is limited technicallyby the small size of the joint in young children, particu-larly the elbow and the ankle; results are dependent onthe skill and experience of the surgeon.

EXPANDING HEMOPHILIA CARE TODEVELOPING COUNTRIESDuring the last decade extensive work has been per-formed by the World Federation of Hemophilia to de-velop hemophilia programs for children throughout theworld.108 Success has been achieved by twinning pro-grams that link personnel from established hemophiliacenters with interested physicians and other healthcarepersonnel in developing countries, in addition to link-ages with national healthcare initiatives to organize basichealthcare elements required for comprehensive hemo-philia care.108 Despite the obstacle created by the highcost of safe replacement factor concentrates, remarkableprogress has been made in several countries throughoutthe world in development of safer national blood sup-plies, and the extension of safe, manufactured factor con-centrates to more countries.109111 The greatest achieve-ment may be that, through the efforts of the WorldFederation of Hemophilia, hemophilia healthcare per-sonnel throughout the world have embraced the princi-ple that we must work globally, and not just locally, forimprovement in hemophilia care and outcomes.

FORMING COLLABORATIONS FORRESEARCH AND THE ADVANCEMENT OF CAREAs demonstrated in this article, many if not most seminalobservations regarding the nature and therapy of hemo-philia were made long ago. However, the development ofevidence-based medicine was hampered by small num-bers of patients at any one treatment center. The last dec-ade has seen progress in the development of clinical trialsbrought about by increased collaborations through newlydeveloped organizations such as the Hemophilia andThrombosis Research Society, an embrace of hemophiliaresearch through established organizations such as theInternational Society for Thrombosis and Haemostasis,and economic support through government funding.Through these combined efforts national and multina-tional randomized clinical trials on prophylaxis, immunetolerance, and novel therapies have been developed.

GENE THERAPY FOR HEMOPHILIANo discussion of advances in care of children with hemo-philia could be complete without inclusion of milestonesin the development of gene therapy. The five gene ther-

apy trials that have enrolled subjects with hemophiliahave been reviewed recently.112 Exciting progress has beenmade. Long-term expression of the transgene producthas been demonstrated in dogs and safety of gene ther-apy has been demonstrated in human adults. To date,however, gene therapy is not a therapeutic option forchildren with hemophilia. Children with other disordershave experienced adverse outcomes following gene ther-apy. An adolescent with a metabolic liver disease devel-oped liver failure following receipt of a hepatic-directedadenoviral vector and two children have developed leu-kemia following gene therapy for severe combined im-munodeficiency. Despite these setbacks, enthusiasm forthe cure of hemophilia persists and will ultimately beachieved.

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