From www.bloodjournal.org by guest on October 2, 2016. For personal use only.

Review Series

INHERITED BLEEDING DISORDERS

Optimal treatment strategies for hemophilia: achievements and

limitations of current prophylactic regimens
Johannes Oldenburg
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

Prophylactic application of clotting factor
concentrates is the basis of modern treat-
ment of severe hemophilia A. In children,
the early start of prophylaxis as primary
or secondary prophylaxis has become
the gold standard in most countries with
adequate resources. In adults, prophylaxis
is reasonably continued when started as
primary or secondary prophylaxis in child-
hood to maintain healthy joint function.
Initial data support that adult patients with
already existing advanced joint arthropa-
thy benefit from tertiary prophylaxis with
significantly lowered number of bleeds,
almost complete absence of target joints,
and less time off from work. Current pro-
phylactic regimens, although very ef-
fective, do not completely prevent joint
disease in a long-term perspective. Joint
arthropathy in primary prophylaxis devel-
ops over many years, sometimes over a
decade or even longer time periods. The
ankle joints are the first and most severely
affected joints in those patients and thus
may serve in outcome assessment as an
indicator of early joint arthropathy when
followed by ultrasound or magnetic reso-
nance imaging. Optimized outcome and
best use of available resources is ex-
pected from individualization of therapy
regimens, which comprises the individ-
ual’s bleeding pattern, condition of the
musculoskeletal system, level of physical
activity and the pharmacokinetic profile
of the substituted coagulation factor, and
most recently includes novel products
with extended half-lives. (Blood. 2015;
125(13):2038-2044)

Prophylaxis in hemophilia
The key to a successful long-term outcome in patients with he-
mophilia is an efficient prophylaxis that prevents bleeding in joints
for children and adults with hemophilia. Efficient prophylaxis re-
quires taking into account the available resources (clotting factor
concentrate, trough levels), the bleeding trigger (activity levels,
chronic synovitis, already existing arthropathy), and most impor-
tantly the number of acceptable bleeds, especially joint bleeds
(Figure 1). Depending on the available resources, the treatment
objectives can vary between countries and treatment centers. In an
almost ideal setting, the number of spontaneous bleeds should be
minimized in order to prevent the manifestation of joint arthrop-
athy. The severity of joint arthropathy mirrors as a kind of cumu-
lative memory the number of experienced joint bleeds and, thus,
reflects the overall quality of the prophylactic treatment regimen.
Once joint damage has occurred, it will progress over the patient’s
lifetime even if no further bleeds occur in the affected joints.1 As
a consequence, primary prophylaxis should aim to prevent any joint
damage. Early diagnosis of joint damage currently represents
a challenge with routine imaging and clinical diagnosis tools.
Moreover, joint arthropathy in a patient on primary prophylaxis
develops very slowly, over a decade or even longer time periods.
Both the subtle development of joint arthropathy and the limitations
of its early detection hamper timely diagnosis and adequate action on
treatment regimen.
Depending on the patient’s age and underlying conditions, prophy-
laxis and its subsequent prevention of bleeds have different objectives,
which are reflected by the International Society on Thrombosis and
Haemostasis (ISTH) definitions.2 According to these definitions, primary
prophylaxis begins in early childhood in the absence of documented
joint disease and before the second clinically evident joint bleed and
before the age of 3 years. Patients treated in this way have the potential
of a life without joint arthropathy. Secondary prophylaxis commences
after 2 or more joint bleeds, but before the onset of joint disease as
documented by physical examination and/or imaging studies. These
patients may already have a significant risk of developing joint arthrop-
athy. Tertiary prophylaxis is defined as treatment initiation after the
onset of joint disease at any age of the patient. Objectives in those patients
include slowing down progression of joint disease, reducing pain and
inflammation, and maintaining mobility, especially in adult hemophil-
iacs with already advanced joint disease.
Although primary, and to a lesser extent secondary, prophylaxis
represents the established gold standard for children in most developed
countries, tertiary prophylaxis in adults is just recently becoming in-
creasingly considered.
Current approaches improving prophylaxis outcome include best
use of availablility of factor concentrate and individualization of treat-
ment regimens with respect to dose, intervals, and type of concentrate,
considering trough levels and bleeding triggers in the respective patients.
Initiation of prophylaxis in young children
Prophylaxis in children is most efficient when started at an early age.
Prophylaxis initiated before the age of 2 years3 resulted in a better out-
come than prophylaxis commenced at age 3 to 5 years or 6 to 9 years.4,5

Submitted January 14, 2015; accepted February 11, 2015. Prepublished © 2015 by The American Society of Hematology
online as Blood First Edition paper, February 23, 2015; DOI 10.1182/blood-
2015-01-528414.

2038 BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13

 From www.bloodjournal.org by guest on October 2, 2016. For personal use only.

BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13 OPTIMAL HEMOPHILIA TREATMENT 2039

Dynamics of developing joint arthropathy

Current regimens are efficient, although they do not prevent
joint arthropathy over a lifetime perspective

The onset of joint arthropathy largely depends on the number of bleeds

per year, especially joint bleeds per year, which have become surrogate
markers for outcome in both clinical and postmarketing studies.
Although on-demand treated patients experience 20 to 50 bleeds
per year and develop joint arthropathy early in life,1 patients treated
prophylactically may remain free from joint disease over 1 to 2 decades
or even longer. Manco-Johnson and coworkers performed the first
controlled, randomized, and prospective trial comparing the onset of
joint arthropathy in on-demand treated vs prophylactically treated
young children.5 Joint disease was assessed by magnetic resonance
Figure 1. The prophylaxis triangle. Prophylaxis treatment regimen has 3 main imaging (MRI), an imaging tool allowing diagnosis of early joint
determinants: (1) the given resources/concentrate availability to target a specific
trough level and/or intervals of substitutions, which both reflect the costs; (2) the damage. During an ;4-year observation time, 45% of the on-demand
bleeding trigger, which comprises physical activity, presence and degree of ar- group developed new joint arthropathy as opposed to only 7% in the
thropathy, and presence of chronic synovitis; and (3) the number of bleeds, espe- prophylactic group. This study impressively demonstrated that pro-
cially joint bleeds, that are regarded as acceptable. These 3 determinants form
a triangle. If 1 determinant is changed, the other 2 will adjust. With unlimited re-
phylaxis is largely protective for joint disease over a 4-year period of
sources, zero bleeds and normal physical activity may be targeted; with few re- observation. However, joint disease still occurred during this time in
sources, only 2 low-dose substitutions per week may be given, thus accepting about 7% of the patients treated with an intensive prophylactic regimen
a certain number of bleeds and limited physical activity.
(6000 IU/kg BW at the age of 6 years). Projected to a lifetime treatment,
this means that at the age of 30 to 40 years, most hemophilia patients
will suffer from some joint arthropathy.
National guidelines and recommendations in several European countries
So far, only a few studies have addressed long-term outcomes of
advise starting prophylaxis early.6,7 In the last decade, several studies
prophylaxis in hemophilia patients with observation times ranging from
suggest beginning with a once-weekly regimen.8-10 The rationale behind
5 years to 2 to 3 decades.1,5,15-19 All studies support that, with the cur-
this is either to avoid the placement of central venous access devices
rent treatment regimens, severe hemophilia patients will sooner or later
and to account for the different clinical presentations, thus tailoring
develop joint arthropathy. Fischer et al compared The Netherlands’
therapy and optimizing cost-effectiveness,8,9 or to lower the risk
intermediate-dose prophylaxis (2100 IU/kg per year) with the Swedish
of inhibitor formation.10 The Canadian primary prophylaxis ex-
higher-dose prophylaxis regimen (4000 IU/kg per year).19 After a
perience begins with a once-weekly regimen (50 U/kg body weight
median observation time of 20 years at an age of young adulthood
[BW]), that, depending on number of bleeds, is intensified in a first
between 19 and 30 years, the intermediate prophylaxis regimen showed
step to twice-weekly treatment (2 times 30 U/kg BW) and, in a third
a median Hemophilia Joint Health Score (HJHS) of 7 (range, 2-18)
step, to every-other-day therapy (25 IU/kg BW).11 Median ages at
of 144, whereas the Swedish group presented a median HJHS of
switching to steps 2 and 3 were 4.1 and 9.7 years, respectively.
4 (range, 2-6.8). The number of joint bleeds in the preceding 5 years
Twenty percent of the patients remained on the lowest regimen
in the groups were 2 per year vs 0.5 per year, respectively.19 The
during the observation time of this study. For this regimen, switches
Swedish protocol had a slightly better outcome and the difference
depend on the number of bleeds. Long-term follow-up observa-
between the 2 cohorts is expected to become larger with time. However,
tion of this cohort is needed, in order to assess whether this regimen
even the high-dose Swedish protocol, with only 1 joint bleed every
is still effective against late onset of arthropathy. Kurnik et al
2 years, did not entirely prevent joint arthropathy over a lifetime
presented data that suggest that early initiation of prophylaxis may
perspective. Furthermore, it has to be taken into account that the
prevent inhibitor formation.10 Triggered by observations from
summarized results were mainly clinical scores which are indicating
the CANAL and RODIN studies12,13 where inhibitor formation
joint disease later than MRI.5 A 25-year follow-up of 30 Swedish
was significantly less in the prophylaxis group, compared with the
patients confirmed that early initiation of primary prophylaxis con-
on-demand group, Kurnik et al proposed beginning prophylaxis
tinuing throughout life was successful in virtually eliminating joint
with once-weekly 25 IU/kg BW at a median age of 10 months.10
bleeds and preserving an acceptable, however not normal, joint status.18
The rational behind this regimen was that regularly adminis-
In a 1992 study, Brackmann et al followed 90 German patients with
tered, low factor VIII (FVIII) doses in the absence of bleeds,
severe hemophilia A from 1978 to 1990, and found no worsening of the
intensive treatment periods, and danger signals may induce
joint status over a 12-year period.16 A 26-year follow-up of 49 patients
tolerance to FVIII within the first 20 to 50 exposure days. By the
of the same cohort, however, demonstrated that 90% of these patients
time the first major joint bleeds are expected, tolerance would
treated throughout life with an intensive prophylactic regimen exhibited
already have been achieved. Following this regimen, Baxter com-
joint disease at 30 to 40 years of age.20
menced the prospective Early Prophylaxis Immunologic Chal-
lenge (EPIC) study. However, the EPIC study was stopped after
inclusion of only 19 patients because of the unexpectedly high The ankle joint as arthropathy indicator
incidence of inhibitors. The reasons given for stopping the study
were difficulties in adherence to the complex protocol in a multi- Before the era of prophylaxis (eg, in the 1970s), knee joint bleeds were
national, multicenter study setting and an increasingly unrealis- the most frequently noted joint bleeds and knees were the clinically
tic perspective for achieving a significantly lower inhibitor frequency leading joint in most patients.21 With the beginning of the era of pro-
within this study.14 phylaxis, the knee joint, as a muscle-controlled joint, became more
 From www.bloodjournal.org by guest on October 2, 2016. For personal use only.
2040 OLDENBURG
stable and the ankle joints became the first joints to be affected and,
thus, represent the clinically most indicative joint. Recently, Oldenburg
et al observed higher MRI scores for ankle joints, and the scarcity of
pathologic findings in knees for patients with unaffected ankles in-
dicated that, in most patients, the ankle was the primary target joint
of hemophilic arthropathy.22 These results are consistent with previous
reports showing more hemarthroses and worse joint scores for ankles,
compared with knees or elbows.5,23-26 Krämer et al’s 2013 study20
followed the development of joint arthropathy in the cohort on intensive
lifelong prophylaxis, initially described by Brackmann et al16 in their
article in 1992. During a 26-year follow-up, Pettersson scores based on
plain x-rays were taken every 3 to 5 years and Gilbert scores were
obtained once per year. Ankles were the first joints to be found affected
by Pettersson score, with median pathologic findings after 10 years,
followed by significant effects for knee and elbow joints after about
another 10 years.20 On average, the clinical Gilbert scores became
pathologic about 1 to 2 decades later than the Pettersson scores.20 An
abstraction/simplification of the findings from Krämer in 2013 is il-
lustrated in Figure 2. Our study as well as those by other authors in-
dicate that imaging score-based diagnosis of arthropathy is possible
long before being revealed by clinical scores.5 However, plain x-ray
is too insensitive to diagnose early joint pathology, making it inap-
propriate to diagnose early joint damage. Ankles, as the first affected
joints for the majority of patients, offer an interesting opportunity for
diagnosing early joint disease and subsequently adapting clinical
decisions.
Outcome assessment
Prophylaxis has greatly improved joint health and is challenging joint
outcome assessment. Because of the low number of about 1 joint bleed
every 2 years resulting from intensive prophylaxis programs,5,19,20
clinical manifestation of joint disease has become a subtle process,
starting mildly, subclinically, and progressing slowly over years. Thus,
diagnosing early joint disease and taking timely and adequate action has
become difficult.
Outcome assessment comprises several tools including annual
bleed rates, physical joint examination, and imaging measures such as
plain x-rays, MRI, and ultrasound assessment. Quality-of-life ques-
tionnaires complement the instrumentarium for outcome assessment
(as discussed by Blanchette et al27 in 2014). The HJHS is currently
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
Figure 2. Illustration and schematization of the
long-term outcome results. Results of the 2013 study
by Krämer et al,20 underlining that progression of joint
arthropathy during intensive prophylaxis regimens is a
process with subtle progression over years. Scores $2
are regarded to be pathological. The ankle joints are
the first joints that develop arthropathy after a median
time of 10 years, followed by knee joints and elbow
joints significantly later. The clinical Gilbert scores are
following the Pettersson scores 1 to 2 decades later.
The gray area indicates the initial decade of prophy-
lactic treatment when early joint disease remains un-
detected by the Pettersson score. GS, Gilbert score;
PS, Pettersson score.
regarded as the state-of-the-art instrument for clinical assessment of
joint status. It includes most of the elements of the previously used
Gilbert score.28-31 Plain x-rays scored by the Pettersson scale had been
a useful tool in the past, but are not able to recognize early joint
disease.16,32 MRI is a very sensitive instrument for early detection of
hemarthrosis, including synovial hypertrophy, hemosiderin deposition,
and osteochondral changes. Scoring scales for reliable assessment
of hemophilia arthropathy have been established.33-36 However, MRI
application to young children is limited and also expensive. More
recently, ultrasound has been used for diagnosis of joint disease in
hemophiliacs. Advantages are its wide availability and its low cost.
Soft-tissue changes such as synovial hypertrophy, which precede joint
disease, especially can be effectively diagnosed. Standardized and
simplified ultrasound scanning protocols for early arthropathy detec-
tion in ankles, knees, and elbows have been published.37-40 The joint
measures for long-term outcome with respect to established scores,
potency of detecting early joint disease and follow-up of severe ar-
thropathy, suggested intervals for assessment, and costs are summa-
rized in Table 1.
However, the interrelationships among these scores have not been
established and validated. A potential future perspective to follow joint
health status might start with annual physical and ultrasound scoring in
young children and, at the age of 6 to 8 years, an initial MRI, preferably
of both ankle joints. Further studies are needed that compare these
scores over time and comparatively assess their applicability. Quality-
of-life scales support the benefits of prophylaxis with the aim of an
almost normal lifelong health.2
The annual bleed rate (ABR) has become an important parameter in
clinical studies as a surrogate for the efficiency of prophylaxis regimens.
Some studies have also assessed the annual joint bleed rate. For in-
tensive treatment protocols, the mean total ABRs range from 2 to 5,
whereas the joint bleed ABR is in the order of 0.5.5,20,41-43 Given the
long-term dimension of developing joint arthropathy and the limitations
of diagnosing early joint damage the ABR serves as an important
clinical parameter to adjust treatment regimens.
Prophylaxis in adult patients
Although primary prophylaxis represents the gold standard for pre-
serving joint function in children with severe hemophilia, prophylaxis
in adult patients is still debated. There are 2 groups of adult patients
 From www.bloodjournal.org by guest on October 2, 2016. For personal use only.
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
Table 1. Joint outcome measures for long-term follow-up
Detection of early
Established scores joint disease
HJHS 111 — 111
Plain x-ray (Pettersson score) 111 — 111
MRI 111 111
Ultrasound 11 11
Joint outcome measures for long-term follow-up with respect to established scores, potency of detecting early joint disease, and follow-up of severe arthropathy,
suggested intervals for assessment, and costs.
111 indicates very good; —, no or limited value; 11, good.
who have to be addressed separately. The first group of patients in-
cludes those who started primary or secondary prophylaxis early in their
life and maintained good joint health into adulthood. A small number
of published studies suggest that these patients benefit from lifelong
prophylaxis.16,18-20 These studies reported a follow-up of 12 to 30 years
and demonstrated that hemophilia patients with an ongoing prophylaxis
regimen present with well-preserved joint function and only mild joint
arthropathy at the age of 30 to 40 years.18-20 The patients from The
Netherlands with an intermediate dosage regimen had a slightly worse
outcome at the age of 30 years than Swedish patients with a high-dose
prophylaxis regimen.19 In the German cohort, 90% of patients showed
some, mostly mild, arthropathy, mainly in their ankle joints after a
26-year follow-up.20 There are several reports that a proportion of young
adults are switched to on-demand regimens and that some of these
patients experience only slight bleeding and little joint arthropathy.44,45
However, no follow-up data are available that report joint condition
of these patients at the age of 40 to 50 years or older. As initial joint
damage always progresses, even in the absence of joint bleeds, a
worsening of joint disease can be anticipated. The joint annual bleed
rate might serve as a surrogate for switching those patients back to
a prophylactic regimen. The joint ABR should not be higher than during
an intensive prophylaxis regimen, which is about 1 to 2 joint bleeds
within 2 years.
The second group of adult hemophilia patients are those who
already present with an advanced joint arthropathy and are on a tertiary
prophylactic regimen. There are few studies that impressively dem-
onstrate the reduction of total bleeds and joint bleeds in patients who
are on tertiary prophylaxis compared with an on-demand regimen.
The prospective randomized Trial to Evaluate the Effect of Secondary
Prophylaxis with rFVIII Therapy in Severe Hemophilia A Adult
and/or Adolescent Subjects Compared to That of Episodic Treatment
(SPINART study) found a median of about 54.5 total bleeds per year
in patients treated on-demand compared with a median of 0 total bleeds
in the prophylactic group.41 Interestingly, about 20% of the prophylaxis
group, with 25 IU/kg BW 3 times per week, still had a significant
number of bleeds, indicating the need for further individual adaptation
of the prophylaxis treatment. A recent survey in Europe examined the
use of prophylaxis in people aged 20 to 35 years with severe hemophilia
and found an inverse correlation between time on prophylaxis and
occurrence of major bleeds, presence of target joints and time off from
work. Patients from Sweden who spent the longest period on prophy-
laxis had the best preserved joints and best quality of life.46
A cross-sectional MRI evaluation of joint status in severe hemo-
philia A patients treated with prophylaxis initiated at different ages vs
on-demand therapy demonstrated protective effects of prophylaxis. All
prophylaxis groups had better MRI joint scores than the on-demand
group. MRI scores generally increased with current patient age and later
start of prophylaxis. Ankles were the most affected joints.22 These
results also indicate that adults with already established severe joint
arthropathy benefit from a prophylactic regimen in terms of number of
bleeds, presence of target joints, mobility, and time off from work.
OPTIMAL HEMOPHILIA TREATMENT 2041
Follow-up of severe Suggested intervals for
arthropathy outcome measure Costs
Annually (ankles, knees, elbows) Low
Every 5 y (ankles, knees, elbows) Low
(111) Every 5 y starting at age of 6-8 y (ankles) Very high
— Annually (ankles, knees, elbows) Low
However, long-term follow-up studies are needed to substantiate these
effects.
Individualizing of treatment regimens
Individualization of therapy would not be an issue if the trough factor
levels could be raised in every patient to 15% to 20%, thus allowing an
almost bleed-free life. However, resources are limited and individual-
ization is applied to get the best outcome with the given resources.
On an economic basis, individualization also implicates that a certain
risk of bleeding is taken. An individualized regimen comprises the
individual’s bleeding pattern, the condition of the musculoskeletal
system, level and timing of physical activity, and actual levels as well as
trough levels of coagulation factor.47
Individual bleeding risk: more than factor levels
A subset of 10% to 15% of patients with severe hemophilia A exhibits
a mitigated disease phenotype, with significantly reduced frequencies
of spontaneous bleeding and lower consumption of factor concen-
trates.48 This clinical heterogeneity is also reflected by the late onset of
the first joint bleed and furthermore in development of only minimal
arthropathy. This mitigated clinical phenotype is chiefly determined by
the underlying mutations in the F8/F9 genes.49,50 Missense mutations,
splice site mutations outside conserved regions, and small deletions
within A series were especially associated with less bleeding.51 Fur-
thermore, the inflammatory response to the presence of blood in a joint
varies, which is believed to be in part dependent on genetic variations
in the genes involved in the inflammatory and immune-regulatory
pathways.52-54 This variation may influence the subsequent develop-
ment of chronic synovitis and also, ultimately, joint arthropathy. In-
deed, the Joint Outcome Study reported several boys with multiple
episodes of hemarthrosis who remained free of joint damage. Other
patients showed joint damage in the absence of clinical bleeds.5 In
patients with greater numbers of bleeds or with a stronger inflammatory
response to a bleed, larger factor doses and more frequent application
are required to prevent the onset of joint disease.
Pharmacokinetic variation in patients and new products
Collins et al demonstrated a great variation of pharmacokinetics not
only dependent on age (shorter half-life in young children than in
adults) but also within patient groups of the same age, where he found
an almost 100% difference in time-to-trough levels of .1% after
application of a standardized FVIII dose.55 Several studies have shown
that the level of the VWF has a major influence on the FVIII half-
life.56-58 Higher VWF levels correlate with increasing intervals of FVIII
substitutions.57,58 Therefore, assessment of the patient’s individual phar-
macokinetic profile is regarded as important for individualization
of therapy. Because a classical pharmacokinetic profile is based on
 From www.bloodjournal.org by guest on October 2, 2016. For personal use only.

2042 OLDENBURG BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13

numerous blood draws over 2 or more days, population pharmacoki-
netics presents an elegant approach to assess the pharmacokinetic
profile by routine factor level measurements at regular visits in the
treatment center.59,60 Population pharmacokinetics will become an
important measure for individualized treatment regimens.60
A number of new factor concentrates and drugs based on other
technologies with improved half-lives and alternative administration
routes will soon be available.61 The advances for recombinant factor IX
(FIX) products have been significant, with half-life extensions up to 100
hours, allowing substitution intervals of 1 to 2 weeks. For recombinant
FVIII products, the advances thus far are only moderate, as the half-life
extension is limited to about 15 to 18 hours by the clearance of FVIII
through VWF.61 Using longer-acting coagulation factors with different
pharmacokinetic profiles will further individualize treatment by main-
taining adequate trough levels with fewer infusions.47 On the horizon
are novel products applying new technologies such as a bispecific
antibody that mimics FVIII.61,62 This product has the potential to
almost eliminate bleeds by weekly subcutaneous injections of the
bispecific antibody.63
Prophylaxis in hemophilia B
There is an ongoing discussion about whether the phenotypes of he-
mophilia A and hemophilia B have the same phenotype or whether
hemophilia B patients have fewer bleeds and develop joint disease later
and less severely.64,65 The mutation spectrum varies significantly. Al-
though in hemophilia A about 80% of the patients exhibit null mu-
tations with no endogenous FVIII protein synthesis, hemophilia B
show only about 20% to 30% null mutations.66,67 Hemophilia B espe-
cially is much more commonly caused by missense mutations, which
might be associated with some small amounts of endogenous plasma
FIX protein. In their 2010 study, Santagostino and coworkers showed
that the type of mutation was the only significant parameter influencing
the phenotype.49 Although this different mutation profile is explaining
the different inhibitor incidence,68 it is not clear whether it may also
affect the treatment regimens in hemophilia B patients. Most recently,
Clausen et al reported a total of 582 patients with severe hemophilia A
and 76 with severe hemophilia B from the RODIN study and found
that hemophilia A and hemophilia B did not differ in age at first ex-
posure to clotting factor, age at first bleed, and age at first joint bleed.69
Although these data refer to a very early stage of treatment, decisions
on the prophylactic treatment are made at this time and are based on
criteria such as the onset of bleeds, especially joint bleeds. Therefore,
it appears safe to follow the same principles for prophylaxis in hemo-
philia B patients as has been outlined in this review for hemophilia A
patients. The longer half-life of FIX and especially the new recombinant
FIX products with extended half-lives of up to 100 hours will make
a difference in the prophylactic regimens.
Conclusion
In conclusion, current therapy regimens include early start of prophy-
laxis as primary or secondary prophylaxis. Prophylaxis is increasingly
regarded as a lifelong therapy, also applied as tertiary prophylaxis in
adults with already existing arthropathy. There is a trend toward a more
intensive prophylaxis, achieving an almost quantitative prevention of
joint bleeds. Individualized strategies intend to optimize outcome and
utilization of resources. Current data are limited to a follow-up period of
a maximum of 25 to 30 years. There are no data available demonstrating
outcomes in a lifetime perspective. Future studies are needed to provide
long-term outcome data for current regimens. The parallel development
of gene therapy protocols that are already in place for hemophilia B
and that are at the horizon for hemophilia A may result in a cure for
hemophilia patients, at least with respect to spontaneous bleeds.70 At
the time of clinical availability of gene therapy, the risks and benefits,
also with respect to possible late adverse events, have to be balanced
against the classical prophylaxis regimens with the new products avail-
able at that time.
Authorship
Contribution: J.O. designed the review, studied the literature, and
wrote the manuscript.
Conflict-of-interest disclosure: J.O. received reimbursement for
attending symposia/congresses, and/or honoraria for speaking, and/
or honoraria for consulting, and/or funds for research from Baxter,
Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk,
Octapharma, Swedish Orphan Biovitrum, and Pfizer.
Correspondence: Johannes Oldenburg, Institute of Experimental
Haematology and Transfusion Medicine, University Clinic Bonn,
Bonn, Germany; e-mail: johannes.oldenburg@ukb.uni-bonn.de.

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2015 125: 2038-2044

doi:10.1182/blood-2015-01-528414 originally published
online February 23, 2015

Optimal treatment strategies for hemophilia: achievements and

limitations of current prophylactic regimens
Johannes Oldenburg

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