Advances in Care of Children with Hemophilia

Advances in Care of Children
with Hemophilia
Marilyn J. Manco-Johnson, M.D.,1,2 Brenda Riske, M.S., M.B.A., M.P.A.,2 and
Carol K. Kasper, M.D.3
ABSTRACT
Care for children with severe hemophilia has moved from pediatric hospital wards
and rehabilitation services to the home, school, and community. Advances in hemophilia
are due largely to the development of specialized hemophilia treatment centers, which
created a system of comprehensive care and focused healthcare efforts on prevention and
education. Parallel advances in coagulation resulted in identification of clotting factors
VIII 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 production
of proteins by recombinant technology, and development of gene therapy. The tragedy of
the human immunodeficiency virus and hepatitis C raised awareness in patients as well as
healthcare providers of the vulnerability of blood products to viral contamination and
spurred progress in science leading to viral inactivation of purified proteins. Concomi-
tantly, physicians treating bleeding episodes in the clinic investigated pharmacokinetics
and 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 bleeding
episodes led to current prophylactic regimens that allow boys to participate fully in school
and 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 extension
of treatment to developing countries. The future of hemophilia promises a cure with gene
therapy. 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 Recognition
Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
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 for
correspondence: Marilyn J. Manco-Johnson, M.D., Mountain States Regional Hemophilia and Thrombosis Center, P.O. Box 6507, Mail Stop F-
416, Aurora, CO 80045–0507. E-mail: marilyn.manco-johnson@uchsc.edu. 1Professor of Pediatrics; Director, 2Mountain States Regional
Hemophilia and Thrombosis Center, University of Colorado Health Sciences Center and The Children’s Hospital, Denver, Colorado;
3Orthopedic Hospital, Los Angeles, California. Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662. 0094-6176,p;2003,29,06,585,594,ftx,en;sth00923x.
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 29, NUMBER 6 2003
The care of children with hemophilia has im- Table 1 Cause of Death for 113 Patients
proved immensely over the last 40 years, from an era in
with Hemophilia2
which children with hemophilia rarely were expected to
Cause of Death
Number
survive beyond the first decade to the present state in
Operations
25
which babies currently born with severe hemophilia can
Circumcision
15
be expected to have a normal life span, participate fully
Tooth extraction
6
in school and the workplace, and receive treatment in
Vaccination
1
the home with minimal disruption to personal and fam-
Lanced hematomas
2
ily life. Hope for a significant modification of hemo-
Tonsillectomy
1
philia through gene therapy still looms as a promise, al-
Trivial injuries
23
though lasting gene transfer has yet to be demonstrated
(cut lip, bitten tongue, injuries to forehead,
in humans with hemophilia. The tremendous evolution
finger, scalp, etc.)
in prognosis of severe hemophilia from a chronic crip-
Internal bleeding
21
pling and often fatal condition to one for which parents
Central nervous system bleeding
7
can anticipate a fairly normal quality of life occurred
Birth trauma and umbilical bleeding
7
through parallel improvements in several aspects of he-
Epistaxis
6
mophilia care over the last four decades. A few advances
Lung hemorrhage
5
originated in dramatic scientific discoveries, but the ma-
Haematuria
4
jority resulted from basic and practical incremental im-
Throat bleeding
3
provements in care contributed by a large number of
Intestinal bleeding
3
dedicated hemophilia treaters world-wide. This paper
Gastric bleeding
3
reviews the major achievements.
Cutting first tooth
1
Fracture of leg
1
Miscellaneous
4
ELUCIDATION OF BASIC MECHANISMS
OF COAGULATION
Data from Birch.2
AQ10
The hemophilias are X-linked genetic bleeding disor-
ders caused by deficiencies of coagulation factor VIII
a large number of proteins involved in coagulation led
(FVIII) and factor IX (FIX). The history of early med-
to development of the International Committee for the
ical progress in understanding and treating hemophilia
Nomenclature of Blood Clotting Factors, which was later
was published in a classic review by Rosemary Biggs in
renamed The International Committee for Haemostasis
1967.1 In 1937, Carroll Birch2 chronicled the clinical
and Thrombosis, now The International Society for
course in 98 living patients with hemophilia and reviewed
Thrombosis and Haemostasis (ISTH), including the
records of other family members. Table 1 lists the cause
Scientific Standardization Committees.
of death in 113 persons with hemophilia reported by
Rapid advances in the field of coagulation pro-
Birch2 and serves as a stark testimony to the fatal nature
gressed from the identification, isolation, and biochemi-
of trivial lacerations, epistaxis, circumcision, and tooth
cal characterization of factors VIII and IX8,9 to identifi-
extraction prior to factor replacement therapy. Macfar-
cation and sequencing of their respective genes10,11;
lane realized in the 1930s that treatment of hemophilia
understanding coagulation protein structure, function,
would not be achieved until the physiology of normal
and interactions at the molecular level12,13; and develop-
clotting and hemostasis were determined. In 1934, Mac-
ment of dynamic integrated theoretic models of throm-
farlane and Barnett reported that only transfusion of
bin generation and regulation.13 Functional assays of fac-
whole blood, and not any local therapies, showed effi-
tors VIII and IX allowed prediction of bleeding risk and
cacy in cessation of hemophilic bleeding.3 Macfarlane4
provided the rationale for structured treatment protocols
hypothesized in his seminal 1938 article that a clotting
to manage acute bleeding events and prevent surgical
factor necessary to activate prothrombin was missing in
bleeding. New laboratory techniques to assess global
persons with hemophilia, and identification of this fac-
thrombin generation potential helped to explain clinical
tor would be necessary to understand and ultimately treat
differences among hemophilia patients and allow for
hemorrhage in persons with hemophilia. Until 1952, it
therapies tailored to individual hemostatic potential.13
was believed that tissue-derived thromboplastin directly
activated prothrombin. In 1953, this group discovered a
“plasma thromboplastin” activity formed in normal
DEVELOPMENT OF SPECIALIZED
blood and defective in the plasma of persons with hemo-
CENTERS FOR HEMOPHILIA
philia.5,6 They went on to develop coagulation assays
COMPREHENSIVE CARE
that differentiated plasmas deficient in FVIII from those
In 1958, in an attempt to organize experience and ser-
deficient in FIX, and the stage was set for the develop-
vices for persons with hemophilia, Biggs and Macfarlane14
ment of specific therapies.7 The subsequent discovery of
reviewed records of 187 hemophilia patients who received

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CHILDREN WITH HEMOPHILIA/MANCO-JOHNSON ET AL
587
specialized services at Oxford. Observations of these 187
central figure in the hemophilia treatment center was
patients led to several sentinel findings regarding the nat-
the nurse coordinator, who was responsible to provide
ural history of hemophilia, including the classification of
education about hemophilia to the patient, the family,
hemophilia severity based on levels, with mild symptoms
teachers, employers, and healthcare providers in the com-
observed in most patients with more than 5% of FVIII
munity.23 In addition to nurse coordinators, the original
and very mild disease noted in many hemophilia B pa-
multidisciplinary hemophilia center teams included hema-
tients with 1% or more FIX. In addition, it was noted that
tologists, pediatricians, internists, geneticists, dentists,
hemophilia A patients with 1 or 2% FVIII activity ex-
physical therapists, orthopedic surgeons, social workers,
hibited far fewer bleeding episodes in comparison with
and psychiatrists to deal with the protean issues sur-
patients who had no detectable FVIII. Macfarlane and
rounding hemophilia.1,16,20 Hemophilia care advanced
Biggs14 noted that it required far higher levels of factor
significantly when all patient calls were funneled to one
activity to prevent surgical bleeding than to prevent spon-
nurse specialist who expedited clinic visits for bleed as-
taneous hemorrhages, an observation that laid the ground-
sessment, facilitated prompt outpatient factor replace-
work for rational design of factor replacement recom-
ment therapy, and ultimately taught and monitored home
mendations and suggested a role for prophylaxis. With
infusion therapy. The majority of persons with severe
experience, the Oxford group developed standardized
hemophilia rapidly enrolled in the US federal hemophilia
approaches to various types of bleeding in hemophilia
system and within 5 years of their inception, Smith,
patients. At this time local hospitals often cared for he-
Levine, and others were able to document that com-
mophilia patients with routine hemorrhages and referred
prehensive hemophilia treatment centers dramatically re-
only the most difficult cases to Oxford. Biggs and Mac-
duced cost, hospitalizations, and absenteeism from work
farlane14 described the case of a young man with pro-
and school.24,25 By 1984, the World Federation of
tracted complications following surgery for trauma whose
Hemophilia determined international standards for he-
care consumed the time of 9 physicians, 5 of whom spent
mophilia centers.26 More recently, the US Centers for
most of their time with him during a 3-month hospital-
Disease Control and Prevention (CDC) funded a sur-
ization, in addition to constant services of nurses, physio-
veillance project and confirmed reduced mortality and
therapists, and laboratory personnel. Biggs and Mac-
morbidity for persons with hemophilia who access fed-
farlane15 suggested that treatment of this patient in a
erally funded hemophilia treatment centers.27 The role
specialized center such as Oxford would have consumed
played by the hemophilia comprehensive care centers in
a small part of one hematologist’s time with fewer com-
the improvement in hemophilia outcome cannot be
plications and a better outcome. In addition, they stressed
overstated.
collaboration among hematologists, surgeons, physio-
therapists, and laboratory personnel was key to improved
clinical outcomes. Thus, the rationale was presented for
PARENTAL AND SELF-INFUSION OF
the development of specialized centers to deliver hemo-
FACTOR CONCENTRATE IN THE HOME
philia comprehensive care. The same year Carol Kasper
Early observations linked prompt treatment with faster,
et al16 reported the first US multidisciplinary center serv-
more effective control of hemorrhage. Shortly after cry-
ing more than 500 patients with hemophilia. The con-
oprecipitate became available, families requested support
cept of hemophilia comprehensive care spread and 10
to institute replacement therapy in the home. A home
years later, reports were published on the benefits of or-
program including 14 patients with FVIII deficiency was
ganized comprehensive care clinics for hemophilia from
reported from Michael Reese Hospital in Chicago in
Italy, the United Kingdom, France, the United States,
1970.28 Home therapy was quickly adopted in countries
and Asia.17–21
with access to replacement therapies.29–31 Of interest,
In 1975, the US Congress appropriated money
hemophilia patients using self-treatment at home were
for the creation of a national network of Hemophilia
noted to use a higher FVIII dose, based on perceived ef-
Diagnostic and Treatment Centers by Section 1131 of
ficacy.31 International recommendations endorsing home
the Public Health Service Act.22 The first centers were
therapy were published in 1979.32 Home therapy avoids
established the next year. The system was expanded grad-
time delay and expense associated with emergency room
ually to the current 135 federally funded hemophilia treat-
visits, allows treatment in a comfortable environment,
ment centers. Similar national programs were developed
and continues as a keystone in hemophilia therapy. In
in Canada and several European countries. The initial
2001, the US CDC Surveillance Project reported that
charge to the treatment centers was to establish and main-
home therapy and hemophilia comprehensive care cen-
tain high-quality reference coagulation laboratories with
ters were each independently associated with a reduced
validated assays to identify accurately persons with the
rate of hospitalization for bleeding episodes.33
hemophilias and other congenital bleeding disorders.
The goal of home therapy for young children
Comprehensive clinic programs staffed by a team of spe-
with hemophilia is to facilitate prevention or early treat-
cialists were developed to provide comprehensive evalu-
ment of bleeding events in hopes of preventing target
ation and generate an integrated treatment plan.20 The
joint disease. Venous access is often problematic in chil-

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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 29, NUMBER 6 2003
dren below the age of 4 or 5 years. Placement of in-
donor products.46 The US National Institutes of Health
dwelling central venous access devices (CVADs) has
convened a consensus conference to discuss the preva-
made primary prophylaxis available to many children who
lence and potential consequences of non-A, non-B hep-
live far away from treatment centers. CVADs carry po-
atitis in 1975.47 Hepatitis C was later identified as the
tential morbidities of infection, mechanical malfunction,
offending viral agent in most transfusion-associated hep-
and large vessel thrombosis. Short-term observations of
atitis, and most hemophilia patients who had been ex-
single centers (median, 30 months) yielded low infec-
posed to blood products manifested positive serologic
tion rates of 0.14 and 0.19 per 1000 catheter days in
evidence of hepatitis C infection.48 Heat treatment of
contrast to a national US nursing survey that found in-
factor concentrates was the first effective viral attenuation
fection in 45% of 568 CVADs.34–36 Infection within the
procedure, inactivating several logs of lipid-encapsulated
port is more common than systemic bacteremia.37 All
viruses, including human immunodeficiency virus (HIV)
studies have found a higher rate of infection in CVADs
and hepatitis B and C.49 Isolation of FVIII by affinity
used to induce immune tolerance of inhibitors.38 Symp-
chromatography employing monoclonal antibodies pro-
tomatic thromboses appear to be rare.39 Despite com-
vided the next significant advancement in blood product
plications, CVADs have greatly increased therapeutic
purity and safety in 1989.50 Hepatitis A and Parvovirus
options for very young children with hemophilia while
B19, lacking a lipid capsule, were more difficult to inac-
decreasing cost and stress.
tivate using heat and solvent detergent.51,52 The appli-
cation of several procedures including donor screening
and donor unit testing for viral antibody, antigen, and
DEVELOPMENT OF SAFE, EFFECTIVE
nucleic acids, in addition to improved viral inactivation,
REPLACEMENT PROTEINS
have increased the safety of products derived from human
The development of safe, effective coagulation proteins
blood.53,54 Still, fears of emerging infections such as West
for replacement therapy has been paramount in the ad-
Nile virus (which has been determined to be transmissi-
vancement of hemophilia care. The history of plasma
ble through blood transfusions) and variant Creutzfeldt-
product safety has been reviewed recently.40 The trans-
Jacob disease (which has not been determined to be trans-
mission of viral pathogens to children with hemophilia
missible through blood transfusions) continue to exert
through blood products caused untold pain and suffer-
pressure for the development of alternative treatment
ing in the hemophilia community and substantially de-
products to human blood-derived proteins.55,56
layed implementation of preventive strategies including
The FVIII gene was first sequenced in 1984.8 Fac-
prophylaxis and immune tolerance (see the following sec-
tor VIII produced in cell culture by recombinant tech-
tions). However, remarkable advances came even from
nology was first applied to human trials in 1989.57 Two
the tragedy of human immunodeficiency virus (HIV) in
full-length recombinant FVIII molecules are available
the form of basic scientific discoveries in virology and
commercially with excellent performance for clinical ef-
immunology as well as application of the hemophilia
ficacy and safety.57 More recently, a -domain-deleted
comprehensive care system to creation of comprehensive
FVIII (BDD FVIII) has allowed more efficient yield
pediatric HIV programs. Emerging knowledge regard-
from tissue culture systems and has contributed to an
ing hepatitis transmission through blood products stim-
increased availability of FVIII.58 BDD FVIII is clini-
ulated the development of rational approaches to prospec-
cally comparable to the full-length recombinant mole-
tive safety studies of new products through the ISTH
cule.58,59 However, assay of BDD FVIII by clotting ac-
Subcommittee for factors VIII and IX.41
tivity yields results approximately 50% compared with
Early attempts to develop concentrates of “anti-
the full-length molecule; this phenomenon is related to
hemophilic globulin” from animal and human plasmas
the phospholipids in the assay.60 Using a chromogenic
were initiated in the United Kingdom, France, and Swe-
assay, function of BDD FVIII and the native molecule
den. However, the 1965 description by Judith Graham
are comparable. There is one recombinant FIX mole-
Pool et al42,43 of a FVIII concentrate made using cryo-
cule.61 Recombinant FIX lacks phosphorylation at serine
precipitation in a procedure easily adaptable to most blood
158, has decreased tyrosine sulfation, and has a variably
banks led to immediate large-scale clinical application of
decreased peak plasma concentration following injection
FVIII replacement therapy to hemophilia A. Concen-
(known as plasma recovery) as compared with plasma-
tration of FIX in prothrombin complex concentrates was
derived FIX.61 Still, the hazards of emerging infectious
described the same year.44 Routine treatment of joint
risks, such as prions, that could contaminate plasma or
and muscle bleeds became widespread shortly thereafter.
recombinant clotting proteins has driven a demand for
However, the emergence of viral transmission through
recombinant proteins completely devoid of human pro-
blood products, in the form on hepatitis B as well as
teins.62 Currently, third-generation recombinant FVIII
non-A, non-B hepatitis was recognized soon after wide-
molecules are being developed with no human proteins
spread application of human plasma products for infu-
either in the cell culture or in final stabilization of the
sion.45,46 It was observed that the risk of hepatitis was
lyophilized recombinant protein. To date, tens of mil-
greater with the use of pooled in comparison to single-
lion units of recombinant FVIII and IX have been in-

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CHILDREN WITH HEMOPHILIA/MANCO-JOHNSON ET AL
589
fused worldwide with no evidence of HIV or hepatitis
impairment. Prophylaxis in hemophilia refers to a treat-
C transmission.53,57 Recombinant clotting factor con-
ment strategy of infusing factor concentrate preven-
centrates have increased the world supply of hemophilia
tively, prior to the onset of bleeding. Prophylaxis using
treatment products and, owing to their excellent safety
lyophilized plasma was first given to halt intractable
profile, have fostered more liberal application of preven-
bleeding events by John Johnson at Howard University
tive treatment protocols for young children and recon-
in 1942.71 Limitations in the quantity and safety of fac-
structive surgeries for adults. To date, however, recom-
tor concentrate limited preventive therapy for at least
binant FVIII molecules have not fulfilled physician and
two decades. During the 1960s, early reports of prophy-
patient expectations of unlimited factor quantity at a
laxis were published from Sweden, Canada, the United
price affordable for widespread use in many countries.
States, and The Netherlands.72–75 Clinical trials to de-
termine optimal dose and dose frequency were con-
ducted in the late 1960s and early 1970s primarily in
DEVELOPMENT OF OTHER THERAPIES
patients with a long history of joint hemorrhage.73–79 A
In addition to specific factor concentrates, the develop-
single case study of Shanbrom and Thelin74 reported
ment of a small number of other therapies has con-
the response of 100% FVIII correction given daily, five
tributed enormous benefit for prevention or treatment
times a week, three times a week, and weekly, and
of bleeding episodes in persons with hemophilia. The
showed a minimal effective dose of 50 U/kg given
efficacy of the fibrinolytic inhibitor epsilon-aminocaproic
weekly. The US National Institutes of Health published
acid in dental extractions was first reported from the
pharmacokinetic data on FVIII prophylaxis and related
Cardeza Foundation in Philadelphia in 1964.63 Epsilon-
clinical cessation of bleeding events to a trough FVIII
aminocaproic acid is still a mainstay for adjuvant ther-
level of 2%, achieved giving 60% correction every 36
apy of mucus membrane bleeding including mouth and
hours.76 Incremental effects of increasing prophylactic
gum bleeding and menorrhagia. A controlled trial of the
dosing were shown by Kasper et al77 and demonstrated
fibrinolytic inhibitor tranexamic acid was reported in
optimal efficacy using daily dosing with 50% reduction
1973.64 Tranexamic acid causes less gastrointestinal dis-
of bleed frequency using 250 U of FVIII per day and
tress as compared with epsilon-aminocaproic acid and is
75% reduction with 500 U/day. The effect of higher
equally effective. 1-Deamino-8-D-arginine vasopressin
doses was limited to 3 or 4 days. A double-blind, placebo-
(DDAVP), a synthetic vasopressin, was found to increase
controlled crossover trial performed by Aronstam et al78
plasma levels of FVIII and von Willebrand factor in pa-
in children with hemophilia given 25% FVIII correction
tients with mild hemophilia A and von Willebrand dis-
once weekly showed reduced frequency of bleeding by
ease.65 This nonblood-product therapy can be used for
15% overall, with most of the effect in the first 3 days.
either prevention or treatment of bleeding in individuals
The same authors showed that 30% correction twice a
with an adequate response. Seizures secondary to hypo-
week was superior to 15%, with most of the effect in the
natremia have been reported, especially in infants; ac-
first 48 hours.79 Although availability and safety of fac-
cordingly, DDAVP is not recommended for children
tor concentrates limited broad application of prophylaxis
younger than the age of 2 years.66 Activated recombi-
to children, Inga Marie Nilsson80 continued to pioneer
nant FVII (rFVIIa) was first successfully employed to
regular infusions of FVIII to prevent joint bleeding in
control hemostasis in a hemophilia patient with inhibitory
young Swedish children with hemophilia. In observa-
antibodies in 1991.67 rFVIIa has been demonstrated to
tional studies, Nilsson et al81 were able to demonstrate
bypass factors VIII and IX in the activation of FX on
physical and radiologic evidence of improved joint out-
the platelet surface in the absence of tissue factor, and in
come in children treated with early prophylactic regi-
addition, may aid tissue factor-mediated generation of
mens. Initiation of prophylaxis after the onset of joint
activated FX.68 rFVIIa has become a first-line therapy
changes was determined to improve physical functioning
for bleeding in children with inhibitors.69 Finally, a local
and pain, but did not reverse or halt progressive arthritic
hemostatic agent concocted from a combination of pro-
changes.82 However, the cost and effort of factor infu-
teins including fibrinogen, thrombin, FXIII, and apro-
sion three to four times weekly is enormous and long-
tinin was developed in Israel as a topical agent to pro-
term compliance is a significant issue.83 Less intensive
mote hemostasis.70 Fibrin glue is particularly useful in
preventive strategies had not been well-studied in
oral bleeding.
young children with healthy joints.
Currently, there is an ongoing US prospective,
randomized clinical trial of every other day prophylaxis
PROPHYLAXIS
versus an intensified episode-based therapy in 65 young
The most costly and prevalent complication in persons
children < 2.5 years of age with FVIII
2% that will
with severe hemophilia is progressive degenerative arthri-
compare joint outcome using very sensitive magnetic
tis following recurrent episodes of hemorrhage into joints.
resonance imaging (MRI) and a physical evaluation tool
Hemophilic arthropathy results in debilitating chronic
specifically developed for young children.84 The US
pain, decreased range of motion of joints, and functional
prophylaxis study will be completed in 2005. A recently

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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 29, NUMBER 6 2003
completed single-arm trial of escalating prophylaxis in
quality of life is markedly diminished.94 Nilsson95,96 re-
young children has been conducted in Canada and will
ported regimens using a combination of factor and cy-
be analyzed shortly.84 The rationale of dose-escalation
toxan to suppress the inhibitory response to FIX and
in prophylaxis is to decrease the cost of factor and limit
FVIII in 1973 and 1974, respectively. After many mod-
the need for CVADs by treating children with less fre-
ifications of the original therapy, Nilsson et al97 published
quent infusions of factor replacement based on clinically
the Malmö regimen for immune tolerance induction em-
evident bleeding rate. There is no doubt that prevention
ploying FVIII exposure (100 U/kg/day) with monthly
of bleeding episodes, overall, conveys a better outcome
courses of cytoxan and intravenous immune globulin
for hemophilic arthropathy as well as life-threatening
(IVIG) in 1988. A German immune tolerance regimen
bleeding events, such as intracranial hemorrhage. Like-
dubbed the Bonn protocol, first reported in 1976, em-
wise, the widespread use of CVADs has fostered earlier
ployed higher doses of FVIII (100 U/kg bid) without
home therapy and more effective treatment of acute
immunosuppressive therapy and showed similar efficacy.98
bleeding events in addition to prophylactic infusions.
A Dutch adaptation was shown to achieve tolerance with
Clinical trials such as the US and Canadian studies de-
as little FVIII as 50 U/kg three times weekly.99 A recent
scribed will refine prophylaxis and determine optimal
retrospective review of immune tolerance suggests that
dose, dose frequency, and age of initiation to achieve the
up to 90% of young children with high-titer inhibitors
best outcome with the least morbidity and cost.
can achieve tolerance.100 Doses of 100 U/kg/day or
higher, and initiation within a year of inhibitor onset,
predicted successful tolerance induction. However, there
IMMUNE TOLERANCE
are many unanswered questions including the optimal
One of the most significant morbidities of hemophilia
dose schedule, treatment product, and window of thera-
therapy is the development of inhibitors.85 Inhibitors are
peutic efficacy following diagnosis of an inhibitor. Cur-
immunoglobulin G (IgG) antibodies (most frequently
rently, an international study is ongoing to determine
subclass IgG ) that bind to specific FVIII epitopes, pri-
relative benefits and costs of high-dose versus low-dose
4
marily active sites in the A2 and C2 regions of the mol-
immune tolerance.101
ecule.86,87 Inhibitory antibodies cause irreversible inac-
tivation of FVIII, limiting the usefulness of replacement
factor therapy. Inhibitor titer is determined in the
ORTHOPEDIC INTERVENTIONS FOR
Bethesda assay in which serial dilutions of patient plasma
JOINT DISEASE
are incubated with an equal volume of pooled normal
Despite the greater availability of safe, effective factor
plasma for 2 hours at 37°C.88 The titer is defined as the
concentrate for treatment and prevention of acute bleed-
plasma dilution that inactivates 50% of the FVIII in
ing episodes, persons with severe hemophilia continue
normal plasma and expressed in Bethesda units (BU).
to develop synovitis and arthropathy.102 Local therapies
High-titer inhibitors are variously defined as those higher
targeted to the affected joint are indicated for children
than 5 or 10 BU. Inhibitor formation always follows ex-
with mild hemophilia, children in whom most bleeding
posure to exogenous FVIII. In prospective studies of
events are localized to one joint, and in areas of the world
young children given recombinant FVIII, the incidence
where prophylaxis is not available or affordable. Intra-
of inhibitors was approximately 30%, with half being high
articular injections of P32, termed radiosynoviorthesis,
titer; the median time to development of an inhibitor
were first applied to persons with rheumatoid arthritis.103
was 9 exposure days to recombinant FVIII, with most
P32 radiosynoviorthesis has been applied to children and
inhibitors presenting within 50 exposure days.57
adolescents with hemophilia. Radiosynoviorthesis in chil-
The predisposition to inhibitor formation is de-
dren, particularly with early synovitis, is effective in
termined partly by the nature of the gene mutation and
long-term reduction in bleeding rate.104 The procedure
partly by the immune constitution of the patient.89–93
is effective, well tolerated even by children as young as
The risk of inhibitor development is increased in pa-
4 or 5 years, inexpensive, and appears to be safe.104,105
tients with large deletions, the intron 22 inversion, and
Radiosynoviorthesis should not be considered an equal
nonsense mutations, and decreased in patients with mis-
alternative to prophylaxis in children with recurrent he-
sense mutations and small deletions. In addition, the
morrhages into multiple joints. However, radiosynovior-
immune response elicited by FVIII is a mixed Th1 and
thesis has been so successful that it is being recom-
Th2 response. Inhibitor formation may be modulated
mended as a first approach to local therapy of hemophilic
by blockade of costimulatory molecules important in
arthropathy in many hemophilia centers.
optimal T-cell activation.93
Synovitis has also been treated with surgical re-
Persons with inhibitors cannot be treated optimally
moval of synovium. Early synovectomies were performed
for bleeding events. As a consequence, they suffer more
in open joint procedures. Open surgical synovectomy is
severe and extensive hemophilic arthropathies, recurrent
effective in decreasing the rate of joint hemorrhage,106
intracranial hemorrhages, and other bleeding complica-
but is expensive, requires protracted physical therapy
tions. The cost of care is significantly increased and
and factor replacement, and is accompanied by a high

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CHILDREN WITH HEMOPHILIA/MANCO-JOHNSON ET AL
591
rate of decreased joint range of motion and functional
apy trials that have enrolled subjects with hemophilia
gait abnormalities. Arthroscopic synovectomy appears
have been reviewed recently.112 Exciting progress has been
to have less damaging effects on range of motion and
made. Long-term expression of the transgene product
gait.107 Arthroscopic synovectomy is limited technically
has been demonstrated in dogs and safety of gene ther-
by the small size of the joint in young children, particu-
apy has been demonstrated in human adults. To date,
larly the elbow and the ankle; results are dependent on
however, gene therapy is not a therapeutic option for
the skill and experience of the surgeon.
children with hemophilia. Children with other disorders
have experienced adverse outcomes following gene ther-
apy. An adolescent with a metabolic liver disease devel-
EXPANDING HEMOPHILIA CARE TO
oped liver failure following receipt of a hepatic-directed
DEVELOPING COUNTRIES
adenoviral vector and two children have developed leu-
During the last decade extensive work has been per-
kemia following gene therapy for severe combined im-
formed by the World Federation of Hemophilia to de-
munodeficiency. Despite these setbacks, enthusiasm for
velop hemophilia programs for children throughout the
the cure of hemophilia persists and will ultimately be
world.108 Success has been achieved by twinning pro-
achieved.
grams that link personnel from established hemophilia
centers with interested physicians and other healthcare
personnel in developing countries, in addition to link-
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