Prophylaxis and Arthropathy

Prophylaxis & Arthropathy
On-Demand and Prophylaxis Treatment
Coagulation factor replacement may be given when a bleed occurs (on-demand
therapy) or before bleeding occurs, to prevent bleeds (prophylactic therapy).
The goal of prophylaxis treatment is to reduce the number of bleeds that occur, and to
prevent progressive joint damage.
You may wonder why this is necessary.
Why not just treat a bleed once it has occurred (ie, on-demand)?
Compared with on-demand treatment, prophylaxis results in a reduced risk of
hemarthroses (bleeding into the joint space) and has been shown to protect joints from
the development and progression of arthropathy (disease/damage of the joint)
This is thought to happen by preventing subclinical joint bleeds, that is, bleeding into
the joint that you do not notice. Over time, this bleeding into the joint leads to
arthropathy. Damage may become permanent.
1
femur
artery
joint capsule
inflammed synovium
blood
cartilage
distended joint cavity
meniscus
fibula
Research carried out over the
past decade has shown that
even brief exposure to blood,
as can occur after a limited
number of bleeding episodes
(or as a result of sub-clinical
bleeding), can result in lasting
cartilage damage.
tibia
2
femur
artery
outgrowths of synovium
eroding cartilage
blood
fibula
tibia
As a result of joint bleeding,
the components of red blood
cells can accumulate in the
joint space. One of these
components is hemosiderin,
an iron-containing complex.
When it accumulates in
tissues it can cause damage.
Prophylaxis is required to
break the cycle of repeated
bleeding and to prevent joint
damage.
3
femur
artery
outer swelling
outgrowths of synvoium
bone erosion
shrinking patella
loss of joint
height
severe cartilage damage
bone cyst formation
Iron deposits can be detected
within the joints of people with
hemophilic arthropathy. Iron
can cause joint damage by
triggering inflammation of the
synovial tissue. This leads to
chronic inflammation and
accumulation of tissuedestructive enzymes.
These enzymes may damage
both cartilage and bone. Iron
can also destroy cartilage by
interfering with the ability to
make proteoglycans, an
important component of
cartilage.
fibula
tibia
4
femur
artery
severe bone erosion
and cyst formation
complete loss of cartilage
complete loss
of joint
height and
flexibility
fibula
tibia
fibrous adhesions
Once joint damage occurs,
many patients can be
managed conservatively with
clotting factor replacement,
therapeutic exercises, antiinflammatory drugs, orthotics,
and activity restriction.
However, some patients have
severe pain and disability and
may require interventions
such as synovectomy, joint
fusion, and joint replacement.
Which Joints Are Most Commonly
Affected?
Shoulder: 3%
Incidence of bleeding
into different joints
Elbow: 30%
Hip: 2%
Wrist: 3%
Knee: 45%
Ankle: 15%
Who Needs Prophylaxis?
The decision to begin prophylaxis is yours and your hemophilia treatment team’s.
Which type (frequency and dose) will be tailored to your needs. The majority of
people using some form of prophylaxis in Canada have severe hemophilia. However,
sometimes prophylaxis is recommended for patients with moderate or mild
hemophilia. Your hemophilia treatment centre can help determine if prophylaxis is
right for you.
There are many different possible treatment regimens. Your hemophilia treatment
centre and physician will help find the optimal regimen for you.
How Does Prophylaxis Work?
Prophylaxis is defined as the infusion of factor concentrate in a non-bleeding state, in
order to prevent bleeding.
Much of the sub-clinical bleeding into the joint can be prevented by maintaining at least
1% (or 1 IU/dL) of the normal levels of factor in the blood. Routine prophylaxis
consists of infusions provided in a routine timeline that attempts to maintain levels at or
above this target. Likewise, episodic prophylaxis may be given in anticipation of
activities or events where a bleed is expected, and the goal is to maintain factor levels
at an adequate level to prevent bleeding.
A prophylaxis regimen is tailored based on dose and frequency of dosing. Frequency
of treatment is important as factor is slowly cleared from the body over time. Doctors
often refer to “half-life”, which means the amount of time required for half the factor that
was infused to disappear, or be cleared from the body. In general, for hemophilia A the
factor has a half-life of ~12 hrs. The half-life of factor IX, used for hemophilia B, is ~18
hrs. Prophylaxis regimens for hemophilia A are often administered three times per
week or more, while those for hemophilia B are often administered twice weekly.
Infusion
Infusion
Infusion
Without the next infusion,
factor level dips below the
target level; joint bleeding
may occur
100
Hemophilia A
% Factor
80
60
40
20
Target level
of factor
0
0
12
24 36 48 60
72 84 96 108 120 132 144 156
Time (Hours)
Infusion
Infusion
100
Hemophilia B
% Factor
80
60
40
20
Target level
of factor
0
0
12
24 36 48 60
72 84 96 108 120 132 144 156
Time (Hours)
How Do We Know Prophylaxis Makes a
Difference? The Pediatric Experience
There is now good evidence that the early initiation of prophylactic treatment in children
with severe hemophilia results in fewer joint bleeds, reduced arthropathy and improved
quality of life.
65 Boys
One study by Dr Marilyn Manco-Johnson and
others examined the benefit of prophylaxis in
65 boys with hemophilia. The boys received
either prophylactic therapy (32 boys received
this treatment) or on-demand therapy (33
boys), and the two groups were compared.
Percent of Patients
with Joint Damage
60%
50%
40%
45%
30%
20%
10%
0%
7%
Prophylaxis
32 Boys treated
with prophylaxis
therapy
33 Boys treated
with on-demand
therapy
(infusions of 25 IU of factor
VIII per kilogram of body
weight every other day)
(treated only at the time of
clinically
recognized joint hemorrhage)
Boys included in this study were younger than
30 months, with severe hemophilia (factor VIII
activity level of <2 IU/dl) and a history of
bleeding into joints. By the time the boys
reached 6 years of age, 45% of those in the ondemand therapy group already had joint
damage as seen by magnetic resonance
imaging (MRI). Only 7% of those in the
prophylaxis group had detectable joint damage
On-Demand
In another study, called ESPRIT (Evaluation Study on Prophylaxis: a Randomized
Italian Trial), 40 children were studied. They had severe hemophilia A, aged <7 years,
with no detected joint damage and at least 1 bleed during the previous 6 months.
They received prophylactic therapy (factor VIII 25 IU/kg body weight 3 times a week) or
on-demand therapy (25 IU/kg body weight when they experience a bleed, treated daily
until complete resolution of the bleed).
Children on prophylactic treatment had fewer breakthrough bleeds compared to
children treated on-demand and fewer bleeds into joints. X-rays showed signs of joint
damage in 29% of patients in the prophylaxis group, compared to 74% in the ondemand group.
References: Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. Manco-Johnson
MJ, et al. N Engl J Med. 2007 Aug 9;357(6):535-44. Prospective controlled studies on prophylaxis: an Italian approach.
Gringeri A. Haemophilia 2003: 9(s1): 38 – 43.
How Do We Know Prophylaxis Makes a
Difference? The Canadian Experience
The Canadian Hemophilia Primary Prophylaxis Study looked at a tailored
prophylaxis approach to see if clotting factor use could be reduced (to keep cost at a
minimum) while still preventing joint damage. Ten Canadian hemophilia clinics
participated in this study that enrolled twenty-five children with severe hemophilia A.
All children were initially treated with prophylaxis at a
dose of 50 IU/kg weight, once weekly. The frequency
and weekly dosage of rFVIII replacement was
increased (see steps in diagram), when one of the
following happened:
•
At least 3 bleeds into any one joint (target joint)
over a consecutive 3-month period); or
•
At least 4 bleeds –either significant soft tissue
bleeds or joint bleeds – into any number of joints
over a consecutive 3-month period; or
•
At least 5 bleeds occurred into any one joint while
on the same dosage (step) of factor therapy over
any period of time.
Step 1
50 IU/kg once weekly
Step 2
30 IU/kg) twice weekly
Step 3
25 IU/kg alternate days
(may increase by 5 IU/kg)
In this study, most children appeared to have little bleeding if treated with onceweekly FVIII prophylaxis, at least for several years. Just over half of the children
(52%) eventually required an increase (Step 2) in their regimen. By 5 years, almost
one-third (28%) of the children required alternate-day prophylaxis (Step 3).
As almost one-half of all children were able to have good outcomes with onceweekly dosing, this step-wise, tailored prophylaxis, would appear to require
considerably less FVIII than some other reported prophylaxis strategies. This may
make it a cost-effective approach. Tailored prophylaxis was associated with good
joint function and normal or near-normal X-rays of joints in the preschool and early
school-age years.
Reference: Feldman BM, Pai M, Rivard GE, Israels S, Poon MC, Demers C, Robinson S, Luke KH, Wu JK, Gill
K, Lillicrap D, Babyn P, McLimont M, Blanchette VS; Association of Hemophilia Clinic Directors of Canada
Prophylaxis Study Group. J Thromb Haemost. 2006 Jun;4(6):1228-36.
How Do We Know Prophylaxis Makes a
Difference? The Adult Experience
Most studies of prophylaxis have been carried out in children. However, there are a
few studies that have examined the value of prophylaxis in adults either continuing
on prophylaxis that they started as a child, or starting a prophylaxis regimen as an
adult (secondary prophylaxis).
A recently reported study looked at the benefits of secondary prophylaxis in adults with
severe hemophilia. Twenty men (aged 30-45 years) participated in the study and used
“on-demand” treatment for 6 months, followed by “prophylaxis” for 7 months.1
While treated with prophylaxis,
30
25.3
there were fewer joint bleeds.
25
There were also fewer bleeds
20.5
19.8
of any kind and fewer
20
15
spontaneous bleeds. In fact,
13.5
15
the median number of bleeds
On-demand
during the months on
10
Prophylaxis
prophylaxis was zero. The
5
Gilbert score, which measures
0
0
0
joint function, was also
0
improved.
Joint Bleeds Any Bleeds Spontaneous Gilbert Score
Bleeds
In another study conducted in Italy, prophylaxis reduced the annual number of total and
joint bleeds.2 There was also a meaningful improvement in orthopaedic score ( a
measure of joint function) in adolescents.
40
36.9
33.7
33.9
29.3
30
On-demand
Prophylaxis
20
10
0
2.5
1.8
Total Bleeds
Joint Bleeds
Adolescents
(30 patients)
5.4
4.1
Total Bleeds
Joint Bleeds
Adults
(54 patients)
References: 1. Collins P, Faradji A, Morfini M et al. J Thromb Haemost. 2010; 8:83-89. 2. Tagliaferri A,
Franchini M, Coppola A et al. Haemophilia. 2008; 14: 945–951.
The Impact on Your Daily Life
Aside from reduced number of bleeds, the benefits of prophylaxis may also have an
impact on your daily activities. One study showed that those treated with prophylaxis
have fewer days lost from school or work, as well as fewer days spent in the hospital.1
Another more recent study2 showed that, in addition to fewer days lost from work or
school, those on prophylaxis had fewer surgeries (arthrodeses, prostheses
implantations and synovectomies), compared to those receiving on-demand treatment.
The median annual number of days lost from work for those on prophylactic treatment
was zero.
Annual number of days lost from work from 1989 to 1999. Demonstrated from
retrospective case-book data and an 11-year panel of 156 Norwegian and Swedish
patients with severe hemophilia A (n=133) and B (n=23) treated on-demand vs_
prophylaxis. Adapted from Steen Carlsson K, et al. Haemophilia 2003
References: 1. Aledort LM, Haschmeyer RH, Pettersson H. J Intern Med. 1994; 236(4):391-9. 2. Steen
Carlsson K, Höjgård S, Glomstein A, et al. Haemophilia. 2003;9(5):555-66.
If I’m Less Active Now Than When I Was
Younger, Do I Still Need Prophylaxis?
Adults are often less physically active than children and therefore less prone to
trauma-induced bleeds. However, the need for prophylaxis often remains. Subclinical
bleeding can be a big concern for adults who have joint damage.
You may wonder if prophylaxis is necessary since you may have joint disease already;
but, prophylaxis (routine or episodic) prevents new bleeds from occurring, which can
impact your quality of life and your ability to work and remain active.
In the Italian study described previously, prophylaxis was started in adults at a median
age of 30 (range from 18 to 72 years). Even starting prophylaxis at this age, resulted
in fewer work/school days lost, fewer days of hospitalization, clinic visits, and
orthopaedic visits, compared to on-demand treatment. This suggests a benefit to
starting prophylaxis, even if damage already exists.
40
34.6
10
30
20
10
On-demand
8
Prophylaxis
6
3
0
Work/school days lost
2.9
4
2
0
On-demand
Prophylaxis
6.8
0.8
2.6
1.1
0.1
Hospitalizations
Hemophilia clinic visits
Orthopedic vistis
As you move through your life, your prophylaxis requirements may change
and treatment doses and times may need to be adjusted. You may continue
taking routine prophylaxis after adolescence, or you may start secondary
prophylaxis later in life, either short-term or for prolonged periods.
You and the hemophilia treatment centre will evaluate all factors to develop a
prophylaxis plan that is right for you.
1.
Tagliaferri A, Franchini M, Coppola A et al. Haemophilia. 2008; 14: 945–951.
Glossary
Arthrodeses - the surgical fixation of a joint, ultimately resulting in bone fusion
Arthroplasty - surgical repair of the joint; the joint surface may be remodelled, realigned, or actually
replaced
Arthropathy - a disease or abnormality of a joint
Hemarthroses - bleeding into joint spaces.
Hemosiderin - an iron-storage complex
Median - relating to or constituting the middle value in a distribution of numbers
Regimen - a systematic plan (as of diet, therapy, or medication) especially when designed to improve and
maintain the health of a patient
Subclinical - describes an early stage or mild form of a medical condition, no symptoms of which are
detectable
Synovectomy - surgery done to remove inflamed joint tissue (synovium)
Where Can I Read More About Prophylaxis?

The Canadian Hemophilia Primary Prophylaxis Study.
http://www.ncbi.nlm.nih.gov/pubmed/16706965

Manco-Johnson study in New England Journal of Medicine.
http://content.nejm.org/cgi/content/short/357/6/535

ESPRIT study by Gringeri and others
http://www3.interscience.wiley.com/journal/118851033/abstract?CRETRY=1&SRETRY=0

Results of the 2006 Canadian national haemophilia prophylaxis survey
http://www3.interscience.wiley.com/journal/120775269/abstract

Efficacy and safety of secondary prophylactic vs. on-demand surcose-formulated recombinant
factor VIII treatment in adults with severe hemophilia A.
http://www3.interscience.wiley.com/journal/122647727/abstract?CRETRY=1&SRETRY=0

A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The
Orthopaedic Outcome Study Group. http://www.ncbi.nlm.nih.gov/pubmed/7931042

EmbraceLife.ca was created to inspire active living and well-being for Canadians with
hemophilia. http://www.embracelife.ca/en/home/
Prepared by Georgina Floros, RN, BScN.
Developed with input by the Canadian Association of Nurses in Hemophilia Care. 2011