Guideline on the use of prophylactic factor VIII
concentrate in children and adults with severe
haemophilia A
A UKHCDO Guideline approved by the British Committee for
Standards in Haematology
Address for correspondence:
BCSH Secretary
British Society for Haematology
100 White Lion Street
London
N1 9PF
e-mail [email protected]
Writing group:
Michael Richards1, Michael Williams2, Elizabeth Chalmers3, Ri
Liesner4, Peter Collins5, Vicky Vidler6, John Hanely7
Disclaimer
While the advice and information in these guidelines is believed to be true and
accurate at the time of going to press, neither the authors, the British Society for
Haematology nor the publishers accept any legal responsibility for the content of
these guidelines.
Date for guideline review September 2014
1
2
3
4
5
6
7
St James‟s University Hospital, Leeds
Birmingham Children‟s Hospital, Birmingham
Royal Hospital for Sick Children, Glasgow,
Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children, London
University Hospital of Wales, Cardiff
Sheffield Children‟s Hospital, Sheffield, UK
Newcastle Hospitals NHS Trust, UK
1
SUMMARY
Evidence-based guidelines are presented on the role of prophylactic
administration of factor VIII concentrate in children and adults with severe
haemophilia A. The timing of initiation of prophylaxis, the choice of prophylactic
regimen, monitoring, management of breakthrough bleeding and education of the
patient and family are discussed.
Keywords: haemophilia A, factor VIII, prophylaxis, child, adult
INTRODUCTION
Coagulation factor replacement in patients with haemophilia A or B may be given
in response to a bleed (on-demand therapy) or given regularly to prevent such
bleeds (prophylactic therapy). Guidelines for prophylactic treatment of children
with haemophilia A or B were last produced by the UKHCDO in 1994 and were
mostly based on the prophylactic regimens used successfully in Sweden since
the 1960s. In the last 15 years, significant information has been derived from
international studies which have resulted in changes in the practice of
prophylaxis. High level evidence based studies of prophylaxis in boys have been
published recently and there is now a widespread recognition of the efficacy of
the early implementation of prophylaxis in the prevention of arthropathy in
children and young adults. The role of prophylaxis in adults is evolving, but
prophylaxis will be of benefit in many individuals.
These guidelines address the optimum use of prophylaxis in children and adults
with haemophilia A and give evidence based recommendations where
appropriate. Similar recommendations for patients with haemophilia B are not
provided given the paucity of published evidence. The guidance will be of value
to physicians, nurses, laboratory scientists and patients and those with a
responsibility for funding services.
METHODOLOGY
The information contained in this review was gathered from an appropriate
literature search. The writing group produced the draft guideline which was
subsequently revised by consensus by members of the UKHCDO Advisory
Board. It was reviewed by the Haemostasis and Thrombosis Task Force of the
British Committee for Standards in Haematology (BCSH) and the sounding board
of the British Society of Haematology, comments being incorporated where
appropriate. Grading of evidence was assigned according to the
recommendations of the Grades of Recommendation, Assessment,
Development, and Evaluation (GRADE) Working Group (Atkins et al, 2004).
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INTRODUCTION.
The aim of prophylactic administration of factor VIII to patients with haemophilia
A is to reduce their number of bleeds. Compared with on demand treatment,
prophylaxis results in a reduction in the frequency of haemarthroses which has
been demonstrated to protect joints from the development and progression of
arthropathy. This may in part reflect a reduction in the incidence of sub-clinical
joint bleeds. A protective effect of prophylaxis in reducing the frequency of
intracranial haemorrhage in patients over the age of 2 years with severe
haemophilia and no inhibitor has also recently been demonstrated (Witmer et al.
2008). The practice of prophylaxis can be considered in four phases:
 the initial introduction of prophylaxis to a child during the first three years
of life,
 the establishment of a regular pattern of factor administration in an older
child,
 the modification of prophylaxis to compensate for enhanced physical
activity in the teenage years and
 the potential for modification to reduced intensity prophylaxis in adults.
EVIDENCE FOR PROPHYLAXIS REGIMENS IN CHILDREN WITH SEVERE
HAEMOPHILIA A
There is now good evidence that the early commencement of prophylactic
administration of factor concentrate to children with severe haemophilia results in
fewer joint bleeds, reduced arthropathy and improved quality of life. This
evidence has until recently been based on retrospective cohort studies. (Ahlberg,
1965, Van Creveld, 1969, Nilsson et al, 1970, Hirschman et al, 1970, Kasper et
al, 1970, Robinson et al,1967, Rabiner and Telfer, 1970, Shanbron and Thelin,
1969, Ramsay and Parker, 1973, Rizza and Matthews, 1972; Nilsson et al,
1976, Aronstam, A et al 1976, Morfini et al 1976, Schimpf et al 1977, Petrini et
al 1991, Nilsson et al 1992, Liesner et al 1996, Smith et al 1996, Lofqvist et al
1997, Astermark et al 1999, van den Berg et al 2001, Fischer et al 2002). The
previous absence of randomised studies was criticised by a recent Cochrane
report (Stobart, 2005), but such criticisms have now been addressed by the
publication of a North American randomised controlled study (Manco-Johnson et
al, 2007), and the interim results of another prospective study (Gringeri et al,
2009).
Manco-Johnson et al reported a study in which sixty-five boys with haemophilia
were randomly assigned to prophylaxis (32 boys) or enhanced on-demand
therapy (33 boys) (Manco-Johnson et al, 2007). Eligibility criteria included an age
of less than 30 months, a factor VIII activity level of <2 iu/dl, a history of <2
haemorrhages into each index joint and normal baseline joint imaging. The mean
age at enrolment in both groups was 1.6 years. A previous haemarthrosis had
been sustained in 56% of the prophylaxis group and 39% of the on-demand
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group. The factor VIII dose in the prophylactic regimen was 25 iu/kg body weight
on alternate days; the enhanced on-demand infusion schedule consisted of at
least three doses totalling a minimum of 80 iu/kg of factor VIII at the time of a
joint haemorrhage. When assessed at the age of 6 years, of the 32 patients in
the prophylaxis group, one (4%) had evidence of joint damage by plain
radiography and 2 (7%) by Magnetic Resonance Imaging (MRI) in contrast to 5
(19%) and 13 (45%) in the on-demand group (p=0.006). The relative risk of MRIdetected joint damage with on-demand therapy as compared with prophylaxis
was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of
joint bleeds and total haemorrhages were higher at study exit in the on-demand
group than in the prophylaxis group (p<0.001 for both comparisons). The annual
use of factor VIII in the prophylaxis group was 6000 iu/kg in contrast to
approximately 2500 iu/kg in the on-demand group.
There was only a weak correlation between the numbers of haemarthroses with
MRI scores; joint abnormalities were not apparent on physical examination. The
history of previous haemarthroses in some patients at trial entry implies that
some joint damage may have existed at this time point; this may have
contributed to the MRI appearances seen at completion of the study. However,
the evidence of joint disease by MRI assessment at completion of the study was
lower in the prophylaxis group despite a higher incidence of previous joint bleeds
at study entry. The authors proposed that chronic micro-haemorrhage into the
joints or subchondral bone in young boys with haemophilia may cause
deterioration of joints without clinical evidence of haemarthroses and that
prophylaxis prevents this subclinical process (Manco-Johnson et al, 2007).
Preliminary data from the Italian ESPRIT (Evaluation Study on Prophylaxis: a
Randomized Italian Trial) have been published in abstract form (Gringeri et al,
2009). Forty children with severe haemophilia A (FVIII <1 iu/dl), aged < 7 years
(median 2 years), with negative clinical-radiological joint scores at entry and at
least 1 bleed during the previous 6 months were randomized to receive
prophylactic factor VIII 25 iu/kg body weight 3 times a week or on-demand
treatment with 25 iu/ kg body weight daily until complete resolution of the bleed.
Ten of 21 children on prophylaxis required indwelling catheters compared to
none of 19 children receiving on-demand treatment. Children on prophylactic
treatment showed a significantly lower total number of breakthrough bleeds
compared to children treated on-demand (0.52 vs.1.08 bleeds/patient/month
respectively, p < 0.05) and fewer joint bleeds/month (0.20 vs.0.52, p < 0.02).
Radiological evaluation showed signs of haemophilic arthropathy in 6 patients on
prophylaxis (29%) (median Pettersson score 5; range: 3–14) and in 14 ondemand patients (74%) (median score 8; range: 2–12) (p < 0.05). Prophylaxis
was more effective when started at younger ages (≤ 36 months).
The higher factor VIII consumption associated with prophylaxis would suggest
that this option will be more expensive than using on-demand therapy. However,
studies of young adult patients have indicated that the annual factor consumption
in patients who are currently and have always been treated on-demand is no
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different from the consumption in those on long term intermediate dose
prophylaxis, although the on-demand cohort was noted to have more severe
arthropathy (Fischer, 2003). Patients with demonstrable joint damage may need
increasing coagulation factor support as arthropathy deteriorates and the need
for joint replacement emerges. In contrast, patients who have received
prophylaxis who have better preserved joints may have a more stable factor
requirement and improved school and work attendance. This suggests that in the
long term prophylaxis may be clinically and economically more attractive than ondemand treatment.
A recently published multinational cohort study, the CANAL study, has
suggested that prophylaxis introduced at a median number of exposure days of
16 (inter-quartile range 8-28 days) was associated with a 60% reduction in the
risk of inhibitor development compared to on-demand therapy (Gouw et al 2007).
This has not yet been substantiated by further adequately powered studies.
RECOMMENDATION
It is recommended that children with severe haemophilia receive
prophylactic infusions of factor VIII with the aim of preventing
haemarthroses and other bleeding episodes. (Grade of evidence: High).
PROPHYLACTIC REGIMENS IN CHILDREN.
Recent studies have provided additional data about factor VIII pharmacokinetics
in younger children and the role of trough factor VIII levels in the prevention of
bleeds; these data have implications for the practice of prophylaxis. It has been
established that there is significant variability of factor VIII pharmacokinetics in
children. One study has demonstrated that the half life of a recombinant factor
VIII concentrate varied from 6.8-15.4 hours in a group of children between 1 and
6 years and increasing age was associated with increasing half-life (Blanchette et
al, 2008). A recent study has suggested that the number of soft tissue bleeds
and haemarthoses which occur in children on prophylaxis is related to the period
of time spent with plasma factor VIII concentrations <1 iu/dl. Although in this
study a lack of adherence to prophylaxis was an important contributor to low
plasma factor VIII levels, the rate of bleeding in children aged 1-6 years was also
influenced by factor VIII half-life and clearance (Collins et al, 2009). This study
provides confirmation that, for patients on prophylaxis, increasing time with a low
factor VIII increases the risk of bleeding but does not necessarily imply that all
patients should have their factor VIII level maintained above 1 iu/dl.
In patients who are phenotypically severe, it is unclear how many joint bleeds are
needed to cause arthropathy and this may be subject to inter-individual variation.
Although it is theoretically attractive to introduce prophylaxis at an early age
before the first joint bleed, this may present practical difficulties; the technical
challenge posed by the intravenous administration of coagulation products in
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young children may necessitate the insertion of a permanent indwelling
intravenous catheter. It has also been recognised that individuals with severe
haemophilia may exhibit clinical phenotypes of varying severity. This has been
reflected in the variable age at which patients with severe haemophilia suffer
their first bleed and the variable time period which may elapse before they
experience their second bleed. These observations have prompted the concept
of individualised therapy, whereby patients with a mild clinical phenotype may be
able to start prophylaxis at a later age and receive concentrate at less frequent
intervals, using less concentrate to achieve a bleed-free existence (Astermark et
al, 1999, Astermark, 2003, Petrini, 2001).
Although the principle of prophylaxis in severe haemophilia is widely accepted,
the details of concentrate administration in prophylactic regimens vary
internationally. There have been no prospective randomised studies comparing
the efficacy of different regimens. Retrospective cohort studies exist that have
compared the outcomes of children within a single country treated during
successive time periods, whilst other comparisons have been made between the
outcomes of similar patients in different countries. The two principal models of
prophylaxis that have been used are (i) administration of factor concentrate with
combined clinical and pharmacokinetic monitoring to prevent bleeds (Swedish
model) and (ii) factor concentrate dose based on clinical end points (Dutch
model).
i) The practice of prophylaxis in Sweden has been to initiate factor administration
when the patient is 1-2 years of age, to administer treatment either on alternate
days or a minimum of three times a week, at a dose sufficient to prevent
bleeding. This group reported a trend in improving orthopaedic and radiological
joint scores over a twenty year review period (Lofqvist et al, 1997). The last two
cohorts of nine and six patients (each of which included one patient with
haemophilia B) started treatment at the age (range) 1.3 years (1-2) and 1.2 years
(1-1.5) respectively; annual consumption of factor VIII/IX concentrate / kg body
weight (range) was 5741 iu (4730 to 7817) for the older of the two groups and
6354 iu (5305 to 8915) for the younger group. These patients had no evidence of
joint damage as assessed by clinical examination or plain radiology at the age of
7-10 years. No benefit from the increased factor consumption in the youngest
cohort has been demonstrated within the current follow up period.
ii) The experience in the Netherlands has also been reported (van den Berg et al,
2001). The time period during which treatment was started in the most recent
Dutch cohort overlaps that relevant to the most recent Swedish cohort.
Prophylaxis was started after one or two joint bleeds or when more than two
other bleeds per month required treatment. The mean age of starting treatment
was 3.9 years in the 27 patients. The mean (standard error) clinical orthopaedic
score when assessed at 7.9 (0.4) years was 0.2 (0.2) and the Pettersson
radiological score 1.1 (0.4). The mean annual product consumption was 2900
iu/kg/year.
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A comparison of the Swedish and Dutch experience indicated that patients
receiving prophylaxis in Sweden had fewer joint bleeds over a period of 3 years
and a slight reduction of arthropathy after 17 years of follow-up but with
significantly higher treatment costs (Fischer et al, 2002).
A study of prophylaxis introduction is currently underway in Canada in which
tailored increase in factor VIII dosing is dependent on breakthrough bleeding
(Feldman et al, 2006). Concentrate administration is introduced at a dose of 50
iu/kg once weekly and is escalated through two steps to prophylaxis at a dose of
25 iu/kg factor VIII on alternate days. An interim analysis of an inception cohort
with a median follow up period of 55 months indicated median clinical joint scores
(range) of 0 out of 56 (0-15) for knees, 0 out of 52 (0-13) for elbows and 2 out of
56 (0-22) for ankles (Blanchette et al, 2009).
The descriptions of the various models of prophylaxis outline differences in the
thresholds used for introduction of treatment, in the concentrate dose used and
the manner in which prophylaxis is introduced. Outcome measures have varied;
one study has used MRI and the remainder clinical assessment and plain
radiology. Although there is evidence to suggest that MRI is a more sensitive tool
to detect joint damage, its significance in predicting progressive arthropathy and
functional impairment is unclear.
Pharmacokinetic modelling suggests that the maintenance of trough factor VIII
levels above a desired level is achieved more effectively and at a lower cost
using an alternate day regimen compared to three times a week (Collins et al
2008a).
RECOMMENDATIONS
1. Prophylaxis should be commenced by the second joint bleed or
significant soft tissue bleed. (Grade of evidence: Low).
2. Prophylaxis may be introduced by initially administering factor
concentrate once weekly but escalating treatment rapidly to more frequent
administration as venous access permits in order to prevent the
occurrence of any joint or soft tissue bleeds. (Grade of evidence: Low).
3. Prophylaxis should consist of a factor VIII concentrate dose (25-50 iu/kg)
administered ideally every 48 hours unless circumstances dictate
otherwise such as the need for attendance at the haemophilia centre for
prophylaxis administration. If three times a week administration is used,
the practice of giving a higher dose on the third day is not recommended.
An additional dose should be considered in order to ensure that the
maximum interval between doses does not exceed 48 hours. (Grade of
evidence: Low).
4. The minimum dosage of factor concentrate which prevents breakthrough
bleeds should be used. Daily injections can significantly reduce the
amount of concentrate required to prevent bleeds and maintain trough
7
factor levels >1 iu/dl and should be considered in very active older boys or
where breakthrough bleeds are occurring on a less frequent prophylactic
regimen. (Grade of evidence: Low).
5. Prophylactic doses should be tailored to provide maximum cover for
particular physical activities, e.g. school, physical education lessons, sport
training sessions. Prophylaxis should be administered ideally in the
morning to optimize factor VIII levels (Grade of evidence: Low).
6. Children and neonates with severe haemophilia who have had a
spontaneous central nervous system bleed should continue long term
prophylaxis following initial treatment of the bleeding episode. (Grade of
evidence: Very low).
7. Insertion of an indwelling venous access device should be considered if
venous access and/or adherence to treatment are difficult. (Grade of
evidence: Low).
8. The prophylaxis dose should be rounded up to the nearest whole vial
size. (Grade of evidence: Very low).
MONITORING OF PROPHYLAXIS
The use of a single mode of monitoring prophylaxis is inadequate; the
combination of clinical, laboratory and radiological methods provides a more
effective approach.
a) Clinical monitoring
Clinical monitoring is currently the single most informative mode for the
evaluation of prophylaxis. It includes the regular physical assessment of the
patient and the accurate evaluation of breakthrough bleeds, the latter including
the number of breakthrough bleeds, the nature and cause of the bleeds, the
number of days taken off school or work and days away from regular physical
activities. In addition it is essential that the number and quantity of extra
treatments given for breakthrough bleeds are recorded. As patients on
prophylaxis are usually on home treatment programmes, the monitoring of
adherence to the prophylaxis regimen and of the recognition, documentation and
treatment of breakthrough bleeds are dependent on good quality treatment
records being kept by the patients or their carers.
The regular clinical assessment of a patient receiving prophylaxis should include
well-defined physical examination scores designed to identify not only
progressive haemophilic arthropathy but the early detection and quantification of
joint disease. Physical examination scales designed in the 1980s are now too
insensitive for the detection of early signs of joint disease in children receiving
regular prophylaxis and modifications to such scores have been introduced in the
USA and Europe (Manco-Johnson et al 2004). A Haemophilia Joint Health Score
has been proposed by an expert international group of treaters (International
Prophylaxis Study Group, IPSG) which consolidates the American and European
systems and has been shown to have high intra and inter-rater reliability (Hilliard
8
et al 2006). Prospective use of this system will be necessary to confirm its
potential for detecting joint problems in children receiving long term prophylaxis.
b) Laboratory monitoring
Laboratory assessment of prophylaxis includes the assay of trough levels of
factor VIII and the determination of factor half life. More detailed pharmacokinetic
studies are difficult to perform in children given the frequency of blood sampling
required with standard methods. Although there is no doubt that laboratory
monitoring is of crucial importance in ongoing checks of a prophylaxis
programme it is essential that results are interpreted alongside evidence of
clinical efficacy.
i) Trough levels. As one of the principal purposes of prophylaxis is to convert
the severity of haemophilia from severe to moderate (factor level  1 iu/dl), it has
been routine practice in many haemophilia centres to monitor whether this has
been achieved. Monitoring is most often performed by measuring the „trough‟
level of FVIII taken 48 or 72 hours after the last dose of concentrate and just
before the next dose is due so that the lowest level of FVIII between treatments
is measured. Review visits should be planned with parents and the child in such
a way that prophylaxis is due on the day the patient attends. This enables a
representative trough level to be taken prior to the due prophylaxis dose being
given. Sensitive inhibitor screening should be considered when the 48 hour
trough FVIII level is <1iu/dl.
ii) Half life studies. Factor VIII half life studies may be helpful in guiding
individualised dosing and frequency of prophylaxis. It is often difficult in practice
to obtain sufficient data points for standard half life calculations but for patients
with sparse data, a Bayesian approach may be more applicable (Ahnström et al,
2004). Shortened half life results require formal inhibitor studies (Lee et al, 2001,
Shapiro et al, 2005, van Dijk et al, 2005a, Bjorkman and Berntrop, 2001).
c) Radiological monitoring.
The main benefit of widespread radiological monitoring is likely to be in the
setting of prospective studies. Radiology is useful in assessing the joint in certain
clinical situations such as the presence of target joints or chronic synovitis.
RECOMMENDATIONS
1. A combination of clinical and laboratory monitoring is required for
children on prophylaxis. (Grade of evidence: Low).
2. Standardised clinical examination scores should be incorporated into
the prospective assessment of patients receiving prophylaxis such as the
HJHS score. (Grade of evidence: Low).
3. Adherence and bleed history should be recorded. (Grade of evidence:
Very low).
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4. Trough factor levels should be measured at routine clinic visits. In the
absence of bleeds, maintenance of trough levels >1 iu/dl is not always
necessary. (Grade of evidence: Low). Half life studies may be useful if
trough factor VIII levels remain <1 iu/dl in the absence of an inhibitor.
(Grade of evidence: Low).
5. There is no requirement for radiological surveillance of joints unless
there is a specific clinical indication. (Grade of evidence: Very low).
MANAGEMENT OF BREAKTHROUGH BLEEDING
PATIENTS RECEIVING REGULAR PROPHYLAXIS.
IN
HAEMOPHILIA
There is a wide variation in the factor VIII doses used for breakthrough bleeds in
patients receiving prophylaxis (Gringeri, 1999, Feldman et al, 2006, MancoJohnson et al, 2007, Gringeri et al, 2009). The efficacy of these treatment
schedules for breakthrough bleeds is unknown. Adequate treatment to ensure
complete resolution of the bleed and return of the joint to normal function is
essential.
RECOMMENDATIONS
1.Breakthrough bleeds should be treated according to site and severity
until complete resolution. (Grade of evidence : Low).
2. The prophylaxis regimen should be reviewed accordingly. (Grade of
evidence: Low).
HOME TREATMENT AND PROPHYLAXIS
Adherence to a prescribed regimen of prophylaxis is essential to ensure the full
benefits of prophylaxis are realised (Hacker et al 2001). Much of the burden of
prophylaxis administration in children is unseen as it is undertaken by parents
and then by the child when he is able to be taught self administration. This is a
significant commitment for any lay person. Successful prophylaxis involves
several key components:
 Competent venous access techniques
 Ensuring an available supply of clotting factor concentrate and other
disposable equipment
 Knowledge of appropriate storage and safe disposal of used items
 Detailed data collection
 Sensitivity to deal with psychological and emotional distress in the child
 Knowledge of symptoms of specific spontaneous and traumatic bleeds
and their necessary treatment
 Knowledge of how and when to seek professional advice from
haemophilia specialists.
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The needs of individual families will differ depending on the age of initiation of
prophylaxis, the personalities involved and the family dynamics. Achieving
competence and confidence in parents and older patients requires formal
education, supervision and on-going support to families which in turn provides
reassurance to these families and also accountability to healthcare professionals.
(Vidler, 1999). The multidisciplinary team framework which underpins the
successful management of patients with haemophilia is essential in ensuring this
education and support for parents. Education about prophylaxis and involvement
in treatment should begin with the first treatment administered; if possible, both
parents should be involved in venous access training and treatment
administration (Herrick et al 2004).
Rarely, there are complicating factors that affect the ability of families to
administer effective prophylaxis. These can range from anxiety and distress in
the child which renders intravenous access difficult to non-adherence caused by
complex family dynamics and circumstances.
Prophylaxis does much to improve the quality of life of the individual with
haemophilia (Fischer et al, 2002) but does not cure the disorder; it offers the
possibility of participation in many sporting and leisure activities that would
previously have been considered to be dangerous. A dilemma is then created as
to the most appropriate level of participation in such sporting activities and which
sporting activities are considered to carry a low level of risk of injury (Seuser et
al, 2007). Careful consideration and discussion are needed between healthcare
professionals and the family if the sporting activities being pursued result in
coagulation factor consumption in excess of that needed for routine prophylaxis.
This can lead to tension when the family‟s expectations of a “normal” lifestyle
have to be reconciled with the responsibilities of health care professionals to
ensure the appropriate utilisation of expensive resources. The use of lower dose
daily prophylaxis may partly address this issue.
RECOMMENDATIONS
1. Early education and training for prophylaxis is an essential component
of haemophilia care in the young child and their family and is best provided
within the Multidisciplinary framework of the Haemophilia Service. (Grade
of evidence: Very low).
2. Involvement of both parents in this process should be encouraged where
possible. (Grade of evidence: Very low).
3. Continuing and regular contact with the family together with the regular
review of prophylaxis are essential for the early recognition of problems
with home prophylaxis programmes. (Grade of evidence: Very low).
4. Agreement is essential with individuals and their families about physical
activities and sports. Competitive contact sports particularly in patients
11
aged over 10 years will increase the risk of haemarthroses and arthropathy;
sports with a high risk of head injury should be avoided at all ages.
Alternative activities such as racket sports, athletics or swimming should
be encouraged, facilitating full participation in school activities with peers
and promoting musculoskeletal development and general good health.
(Grade of evidence: Very low).
PROPHYLAXIS IN ADULT PATIENTS
The use of prophylaxis is becoming more common in adults. Patients may
continue taking routine prophylaxis after adolescence, may use intermittent
prophylaxis tailored to their sporting activities and potential traumatic episodes or
may start secondary prophylaxis later in life either short term or for prolonged
periods.
a) Management of young adults treated with prophylaxis in childhood
Most people with severe haemophilia reaching adulthood in the UK will have
received prophylactic treatment during childhood. Prophylactic regimens will
have been started at different ages and with variable intensity resulting in
variable numbers of joint bleeds during childhood, as a consequence some
patients reaching adulthood will have near normal joints and others will have
evidence of arthropathy. Adults are often less physically active than children and
hence less prone to trauma induced bleeds. It is also possible that normal adult
joints may be less vulnerable to bleed induced arthropathy than developing joints
(Roosendaal et al, 2000). However the existence of arthropathy may increase the
risk of haemarthroses in older patients. It has been shown that approximately
30% of young adults with severe haemophilia can stop regular prophylaxis; these
patients continue with targeted prophylaxis for specific activities (Fischer et al,
2001, van Dijk et al, 2005, Richards et al, 2007).
It is standard practice to involve the individual adult patient in a discussion
regarding potential modification of prophylaxis in early adult life. Reduction in the
intensity of prophylaxis carries attendant risks if those patients with milder clinical
phenotypes cannot be reliably identified. Haemarthroses occurring during
reduced prophylaxis may cause damage in joints, the health of which had been
preserved throughout childhood and adolescence by consistent prophylaxis. In
some individuals who have demonstrated a much milder phenotype, modification
of prophylaxis may be appropriate. Intermittent prophylaxis should be maintained
for sport or other potential traumatic events. Careful monitoring is essential if a
change of prophylaxis is introduced; full prophylaxis should be reinstated if
spontaneous bleeds occur that interfere with education or employment or
significant haemarthroses occur that carry the risk of development of arthropathy.
b) Secondary prophylaxis in adults
Secondary prophylaxis may be short term to treat a target joint or long term.
There are very few published data relating to secondary prophylaxis in adults
12
with haemophilic arthropathy (Valentino, 2004). Patients with longstanding
arthropathy and disability may benefit from prophylactic treatment if recurrent
bleeding episodes are interfering with mobility or employment. A prolonged
period free of bleeds may improve quality of life, mobility and musculature by
allowing more intensive physiotherapy (Loverin et al, 2000). Initially, relatively
high prophylactic doses may be required to prevent bleeds but smaller or less
frequent infusions of concentrate may be sufficient to prevent haemarthroses
after a period of sustained prophylaxis. Prophylaxis in this context decreases
bleeding episodes leading to improved mobility, less pain, fewer days off work
and improved quality of life (Miners et al, 1998, Tagliaferri et al, 2008, Loverin et
al, 2000, Fischer et al, 2005, Saba et al, 2000, Collins et al, 2008b). There are
only limited data related to whether prevention of bleeds in adults with
established arthropathy delays progression of joint disease as has been shown in
children. One study suggests that prolonged prophylaxis in this patient group did
delay progression of joint disease (Fischer et al, 2005). More data are required to
investigate the effect of secondary prophylaxis on progression of haemophilic
arthropathy, mobility, pain, employment, quality of life and cost effectiveness.
c) Prophylactic regimens and dose adjustment in adult patients
The standard prophylaxis regimens used in children may not be appropriate for
adult patients although comparative data are not available. Adult patients with
severe haemophilia have a wide variation in pharmacokinetics following an
infusion of factor VIII, the half life varying between 8 and 23 hours (Bjorkman,
2003, Morfini, 2003). The longer factor VIII half life in adults compared to children
results in a reduced total weekly requirement of factor VIII to achieve a given
trough level. In order to attain a specified target trough factor VIII level in an
individual, widely varying amounts of concentrate will be required. More frequent
infusions result in a reduced factor concentrate requirement to sustain a target
factor VIII level (Carlsson, 1997, Bjorkman, 2003). Knowledge of an individual
patient‟s pharmacokinetics is likely to improve cost effectiveness of prophylactic
dosing. Adult patients usually tolerate more regular infusions and more detailed
pharmacokinetic analyses than children and are better able to discuss
individualised prophylactic regimens.
Prophylactic regimens in adults should be individualised to bleeding phenotype
and
pharmacokinetics. The infusion frequency may vary between every 3-4 days for
individuals with a long factor half life to alternate day or low dose daily treatment
for those with shorter factor half lives. Factor VIII doses prescribed to ideal
weight for height may be more appropriate than using actual weight.
RECOMMENDATIONS
1. Adolescent and adult patients with severe haemophilia should be
encouraged to continue regular prophylaxis at least until they have
reached physical maturity. (Grade of evidence: Low).
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2. In some individuals who have demonstrated a much milder phenotype,
adapting formal prophylaxis to a more targeted policy may be considered
but in such cases, there must be an agreed plan for monitoring and
reintroduction of prophylaxis if necessary. (Grade of evidence: Low).
3. If significant haemarthroses occur after discontinuing prophylaxis,
prophylaxis should be reinstituted to prevent joint damage and to maintain
quality of life. Prophylaxis should particularly be restarted if bleeding
interferes with education or employment. (Grade of evidence: Low).
4. The dose and frequency of infusions should be adjusted, based on
bleeding phenotype and ideally individual pharmacokinetics. The minimum
amount of concentrate should be used to prevent haemarthroses
irrespective of trough levels. (Grade of evidence: Low).
5. Pharmacokinetic studies may help dose adjustment and improve cost
effectiveness. At a minimum, trough levels should be monitored but more
information can be obtained from half life studies over a period of 48-72
hours. (Grade of evidence: Low).
6. Patients on long term prophylaxis should have their regimens critically
reviewed at least every 6 months. If no break through bleeds have occurred
a trial of dose reduction is appropriate, especially if the trough level >1
iu/dl. (Grade of evidence: Low).
7. Short or long term secondary prophylaxis should be considered in
patients with advanced arthropathy if recurrent bleeding episodes
significantly interfere with work or mobility. (Grade of evidence: Low).
8. Long term secondary prophylaxis is indicated following intracranial
haemorrhage if no underlying cause can be corrected(Grade of evidence:
Low).
DISCLOSURES
Disclosures made annually by all authors to Chairman of UKHCDO.
DISCLAIMER
While the advice and information in these guidelines is believed to be true and
accurate at the time of going to press, neither the authors, the UKHCDO, the
British Society for Haematology nor the publishers accept any legal responsibility
for the content of these guidelines.
14
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