Does intense prophylaxis always lead to the
desired outcomes?
Despite the plethora of data showing the
advantages of standard rFVIII and rFIX therapies,
prophylaxis with these products may delay versus
prevent the onset of joint disease. A German
study followed up 49 patients with haemophilia A
for 28 years and revealed that they developed
joint disease despite intensive prophylactic
treatment, most prominently located in the
ankles. Moreover, this linear pathological process
only became apparent approximately ten years
after treatment initiation. 25
A cross-sectional study using magnetic
resonance imaging to evaluate joint status in
patients with severe haemophilia A, according
to time of initiation of primary prophylaxis,
confirmed that the ankle was the most frequently
affected joint. Interestingly, it was observed that
only patients who started their prophylactic
regimens before reaching two years of age did not
develop arthropathy during the 28-year follow-up
period; by contrast, patients who started
treatment when they were aged 2–6 years
developed joint disease as young adults. 26
The Joint Outcome Study further pointed to
a reduction of 83% in the risk of developing joint
damage in patients on prophylaxis over 4–5 years
versus those receiving on-demand treatment, but
7% of the patients still showed worsening of their
articular status. The number of total and joint
bleeds was 3.27 and 0.63 per patient per year,
respectively, for patients on prophylactic
regimens compared with 17.69 and 4.89 for
those following an enhanced episodic infusion
schedule. 27 Another study conducted in Sweden
evaluated the effects of lifelong prophylaxis in
adults with severe haemophilia A or B, confirming
that early prophylaxis (starting at or before three
years of age) was effective in controlling joint
bleeding and preserving joint status. 28
Altogether, these data indicate that although
prophylactic treatment with conventional /
standard half-life therapies has substantial
benefits versus on-demand treatment, these
may not be sufficient from a lifetime perspective
to prevent the onset of joint disease. In fact,
breakthrough bleeds may still occur throughout
prophylactic treatment, and there may be joint
damage without overt bleeding. In addition, most
patients develop joint damage over time, and it
progresses once arthropathy is present, even in
the absence of bleeding.
These observations of the limitations with
current prophylaxis raise the issue of how intense
treatment should be to improve outcomes related
to joint health. A 3%–5% threshold of FVIII
activity levels has been shown to protect against
spontaneous joint bleeds, 29 but the ultimate
aim is to eliminate spontaneous bleeding, in
particular in the joints, and to reduce the risk
of clinically silent bleeds and chronic synovitis.
Therefore, personalised and more intensive
regimens are needed to control arthropathy
in haemophilia.
prolong survival by reducing severe life-threatening
bleeds, and improve QoL by reducing pain and
improving mobility. Prophylaxis is most effective
when started early after the diagnosis, 25,30,31 but the
frequency of injections is dependent on the half-life
of the clotting factors being administered, 30 which
may in turn have an impact on treatment
adherence. In fact, it has been shown that there is
an increased risk of bleeds when factor levels fall
below 1IU/dl in severe haemophilia A patients. 32
Prophylaxis can be personalised with the use
of clotting factors with extended half-lives (EHL),
and some aspects related to the entire ecosystem
around the patients must be taken into
consideration when switching to such agents.
A schedule of 2–3 weekly injections is common
for children and adolescents, but not so much for
adults, who might prefer a less demanding dosing
schedule with more time between injections.
Also, practicalities are important. It is important
to identify the patients who will benefit the most
from the switch, for example, those who prefer
a more flexible and convenient dosing schedule,
those who need more intensive treatment but do
not wish to initiate or escalate prophylaxis with
conventional FVIII, those who are at risk of
Protecting people with haemophilia A:
From practicalities to treatment outcomes
Despite its achievements in preventing bleeding,
prophylaxis in haemophilia ultimately aims to
increase function by reducing joint bleeds,
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