Received: 13 March 2023 Revised: 7 September 2023 Accepted: 7 September 2023

DOI: 10.1111/hae.14866

REVIEW ARTICLE

Targeting higher factor VIII levels for prophylaxis in

haemophilia A: a narrative review

Lynn Malec1,2 Davide Matino3

1
Versiti Blood Research Institute, Milwaukee,
Wisconsin, USA
2
Division of Hematology & Oncology,
Departments of Medicine and Pediatrics,
Medical College of Wisconsin, Milwaukee,
Wisconsin, USA
3
Division of Hematology & Thromboembolism,
Department of Medicine, McMaster
University, Hamilton, Ontario, Canada
Correspondence
Lynn Malec, 8733 W Watertown Plank Road,
Milwaukee, WI 53226, USA.
Email: LMalec@Versiti.org
Funding information
Medical writing support was funded by Sanofi
Abstract
Introduction: The standard of care in severe haemophilia A is prophylaxis, which
has historically aimed for a factor VIII (FVIII) trough level of ≥1%. However, despite
prophylactic treatment, people with haemophilia remain at risk of bleeds that have
physical and quality of life implications, and that impact everyday life.
Aim: The aim of this review was to evaluate evidence supporting the relationship
between targeting higher FVIII activity levels with prophylaxis and improved outcomes
in people with haemophilia A.
Methods: We conducted a narrative review that defined the unmet needs and treat-
ment goals in people with haemophilia A, evaluated evidence to support targeting
higher FVIII activity levels, and highlighted therapies that may support higher and
sustained FVIII activity levels and improved outcomes for people with haemophilia A.
Results: Despite recent advances in treatment, unmet needs remain, and people with
haemophilia continue to experience joint and functional impairment, acute and chronic
pain, and poor mental health. All these negatively impact their health-related quality of
life. Evidence suggests that FVIII activity levels of up to 50% may be needed to achieve
a near-zero joint bleed rate. However, achieving high FVIII activity levels with current
standard and extended half-life (EHL) FVIII replacement therapies is associated with a
high treatment burden. Innovative treatment options may provide high sustained FVIII
activity levels and improved patient outcomes.
Conclusion: Evidence suggests that FVIII activity levels in people with haemophilia A
should be sustained at higher levels to improve joint and patient outcomes and enable
progression towards health equity.

KEYWORDS
arthropathy, factor VIII, gene therapy, haemophilia A, non-factor replacement therapy, prophy-
laxis, quality of life

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Haemophilia. 2023;1–11. wileyonlinelibrary.com/journal/hae 1


2 MALEC and MATINO
1 INTRODUCTION
Haemophilia A severity is classified as mild (>5%–<40%), moder-
ate (1%–5%), and severe (<1%) based on endogenous factor VIII
(FVIII) activity.1 The severe form is characterised by spontaneous
bleeds, often into joints and muscles.1 The standard of care for severe
haemophilia is regular prophylaxis, which substantially reduces bleeds
compared with on-demand treatment.2 Prophylaxis aims to protect
against spontaneous bleeding episodes and prolonged bleeds after
trauma, thereby preventing or reducing joint disease, maintaining
musculoskeletal health, and improving life expectancy and quality
of life.1 Historically, prophylaxis in severe haemophilia with replace-
ment FVIII therapy has targeted trough FVIII levels in the moderate
haemophilia range, based on the observation that people with moder-
ate haemophilia have a lower risk of bleeds.1 However, there is growing
evidence that even higher FVIII activity levels may improve patient out-
comes and enable people with haemophilia to optimise their health and
lifestyle choices.
This narrative review discusses evidence for targeting higher FVIII
activity levels and highlights treatment goals and unmet needs in
people with haemophilia A. Additionally, this review describes how cur-
rent and investigational therapies may support higher and sustained
FVIII activity levels, potentially improving outcomes for people with
haemophilia A.
2 CURRENT GUIDANCE FOR TARGET FVIII
ACTIVITY LEVELS IN SEVERE HAEMOPHILIA A
2.1 Guidelines for regular prophylaxis
Prophylaxis is defined by the World Federation of Hemophilia (WFH)
as the regular administration of a haemostatic agent(s) with the goal
of preventing bleeds in people with haemophilia while allowing them
to lead active lives and achieve a quality of life comparable to the gen-
eral population.1 Prophylaxis historically targeted a trough level of 1%,
based on the observation that people with moderate haemophilia, who
have a factor activity level of 1%–5%, experience fewer bleeds, usually
trauma-induced, and have a lower risk of arthropathy than people with
severe haemophilia.1,3 The relationship between increasing time below
1% and number of bleeds was demonstrated in a study by Collins et al.3
More recently, the WFH guidelines note that clinicians now preferen-
tially target a trough level of >3%–5% or higher.1 People with severe
haemophilia A should receive regular prophylaxis sufficient to prevent
spontaneous bleeds and prolonged bleeds following trauma.1 Prophy-
laxis should be individualised based on patient bleed phenotype, joint
status, individual pharmacokinetics, and patient self-assessment and
preference.1 Patients who continue to experience bleeding episodes
should have their prophylaxis regimen escalated in dose or frequency.1
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2.2 Tailoring factor activity levels for different
clinical scenarios and physical activity
WFH guidelines provide recommended target factor levels follow-
ing specific bleeds and for surgery.1 Although the guidelines do not
provide recommendations for target factor levels for physical activ-
ity, they recommend that prophylaxis be individualised and note that
active individuals may opt for more frequent infusions for greater
protection.1 Iorio and colleagues used structured expert opinions and
a modified Delphi method to define a range of suggested target fac-
tor levels for use in different scenarios, including surgery and physical
activity (Figure 1).4 Another study that elicited expert opinions sug-
gested minimum FVIII activity levels of 4% and 38% for low and
high-risk activities in people without joint morbidity, and 7% and 47%
in people with joint disease.5
3 TREATMENT GOALS FOR PEOPLE WITH
HAEMOPHILIA A
Recombinant FVIII (rFVIII) replacement and regular prophylaxis have
enabled people with haemophilia to achieve a life expectancy close to
the general population.6 Treatment goals are evolving from prevent-
ing early death, and decreasing spontaneous bleeds and associated
morbidities, towards health equity.6 The recent review article by Skin-
ner et al. presented a 7-step treatment model, including clinical and
patient-relevant outcomes, and provided a progressive definition of
cure for people with haemophilia (Figure 2).6 The final milestone,
functional cure or normal haemostasis, with optimised health and well-
being, would enable health equity and eliminate the need for any
consideration of haemophilia in day-to-day life.6
Freedom from spontaneous bleeds is a key treatment goal in
haemophilia and may enable individuals to live without fear of bleed-
ing episodes.6,7 Reducing bleeding episodes and maintaining muscu-
loskeletal health may improve mobility, the ability to participate in
work and family life, and mental health, and lead to fewer hospital
visits, and less pain.6,7 Another goal is to reduce treatment burden
through reducing injection frequency of FVIII replacement therapies,
which may improve adherence to treatment.8 In addition, the abil-
ity to sustain minor trauma without resultant bleeding could allow
a more unrestricted lifestyle, and the option to undergo surgery or
major trauma without additional intervention could facilitate elective
or emergency care.6
Achieving these treatment goals would allow people with
haemophilia to be free from the psychological burden of constantly
thinking about their haemophilia, dubbed a ’haemophilia-free mind.7
The haemophilia-free mind would provide freedom from consid-
ering treatment, pain, fear, frustration, coping strategies, and their
differences relative to those without haemophilia.7
 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MALEC and MATINO 3

Factor Level (%) Activities Clinical Scenarios

>80 During high-risk surgery, post major surgery/post major trauma

Very high impact

50–80 Acute treatment of major bleeds
physical activities†

Patients who had major surgery after the initial period of high dose
30–50
treatment, treatment after ICH,† resolution of chronic synovitis†

Trough levels in late post-surgery period and minor

15–30 Intensive sport activities†
invasive procedures

Severe comorbidities,† bleeds despite prophylaxis at lower

5–15 High-risk activities
threshold, patients with target joints presenting bleeds

3–5 Mild physical activity Target joints, bleeds despite prophylaxis at lower threshold

Trough levels for most patients on prophylaxis, patients with mild

1–3 Sedentary lifestyle
bleeding phenotype, moderate hemophilia‡

F I G U R E 1 Overview of Iorio et al. Delphi consensus on target factor levels for physical activities and clinical scenarios. ICH, intracranial
haemorrhage. † Discussed but consensus not reached. ‡ Moderate patients with factor levels around 1%–2% presenting spontaneous bleeds, which
requires treatment with factor concentrates.

Optimized health
and well-being
u ity
h eq Normal
alt Not dependent
He on specialized
haemostasis
health care
Undergo surgery or
Patient relevant outcomes

More
major trauma without
unrestricted
additional intervention

Clinical outcomes
lifestyle
Participation in Able to sustain
work, career and minor trauma
family life without
restriction
Attain ‘normal’ mobility
Ability to engage
in low-risk activities

Improved quality Freedom from e

spontaneous bleeds ur
of life; participation alc
n
in activities of io
daily living nct
Minimal joint Fu
Prevent impairment
premature
death Survival

Level of protection

FIGURE 2 Model of patient-relevant outcomes and treatment milestones towards normal haemostasis (reproduced from Skinner et al.).

4 UNMET NEEDS FOR PEOPLE WITH typically in the large synovial joints, are a common cause of pain in
HAEMOPHILIA A people with haemophilia and lead to joint impairment, haemophilic
arthropathy, and poor health-related quality of life (HRQoL).9,10
Despite progression towards health equity for people with Repeated joint bleeds lead to the deposition of haemosiderin, fol-
haemophilia, significant unmet needs remain. Recurrent joint bleeds, lowed by synovial changes including inflammation, hyperplasia, and

4 MALEC and MATINO
angiogenesis.9 Acute synovitis can progress to chronic synovitis,
resulting in a cycle of bleeds, loss of motion, and inflammation, ulti-
mately leading to irreversible damage to cartilage and bone and
impaired joint function.1,9 Even a single joint bleed can result in
permanent joint damage, with irreversible vascular changes mak-
ing the joint more susceptible to repeated bleeds.9 Studies have
demonstrated that a low joint bleed rate is associated with preserva-
tion of joint function and early prophylaxis initiation improves joint
outcomes.11,12 However, the Joint Outcomes Study—Continuation
showed that early prophylaxis (<2.5 years of age) is insufficient to
prevent all joint damage, with only 2 of 14 participants (14%) on
early prophylaxis presenting with no osteochondral damage at study
exit.13 Furthermore, target joints can develop despite standard of
care prophylaxis. In the Cost of Haemophilia in Europe: a Socioeco-
nomic Survey (CHESS) study, ∼40% of young adults receiving primary
prophylaxis presented with target joints.14 Prophylaxis is also unable
to halt or reverse the progression of joint damage after onset,15 and
evidence indicates that subclinical bleeds may contribute to joint
impairment.16,17 Early signs of arthropathy, including joint effusion,
synovial hypertrophy, and cartilage erosion, have been identified in
clinically asymptomatic joints that have never experienced an overt
bleed.18
Pain is a central issue in the lives of people with haemophilia,
due to joint bleeds and haemophilic arthropathy, as well as thera-
peutic interventions.9,10 Individuals can experience pain from a young
age, and almost 50% of people with haemophilia report experienc-
ing chronic pain.19 In the CHESS study, almost half of the patients
receiving primary prophylaxis reported some level of chronic pain
and 8% reported moderate pain.14 Although the frequency of pain
increases with age, episodes of pain are also reported by children.20
Haemophilia-related pain may be underestimated by healthcare
professionals,9 with ∼15%–18% of patients reporting that their pain is
not well managed.20,21
Pain and joint impairment limit the day-to-day lives of people
with haemophilia. Three-quarters of participants in the P-FiQ study
reported pain that interfered with work or housework.22 Joint impair-
ment and haemophilic arthropathy also contribute to reduced range
of motion, impaired mobility, and reduced HRQoL.1,9 These physical
problems led to approximately two-thirds of participants in the P-FiQ
study to limit the type and amount of time spent on activities and work
and meant they accomplished less than they would like.22
People with haemophilia can experience poor mental health, anx-
iety, and depression, at least in part due to pain and functional
impairment.21 In the MIND study, one-third of people with haemophilia
felt that their depression or anxiety was not adequately addressed
by their treatment centre.21 Furthermore, people with haemophilia
who report symptoms of depression are more likely to have symp-
toms of anxiety and lower adherence to factor replacement therapy
than those who do not report any symptoms.23 Approximately one-
third of young adults in the HERO study reported that haemophilia
affects their ability to develop close relationships.24 The current stan-
dard of care prophylaxis does not protect against poor mental health,
as young adults on primary prophylaxis reported levels of anxiety and
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
depression comparable to patients receiving on-demand treatment in
the CHESS study.14
People with haemophilia have decreased bone mineral density
(BMD) and an increased risk of osteoporosis, osteopenia, and bone
fractures compared with the general population, possibly due to joint
bleeds and a sedentary lifestyle.25 Studies have found that patients
receiving prophylaxis have higher BMD than those receiving on-
demand therapy and that patients with severe haemophilia receiving
prophylaxis have a comparable BMD to individuals of the same age
with mild haemophilia.26,27 The pathophysiology of reduced BMD in
people with haemophilia is not fully understood, but recent evidence
suggests that FVIII plays a role in bone remodelling.25
Although recent advances have led to substantial improvements
in patient outcomes, people with haemophilia continue to experience
joint and functional impairment, acute and chronic pain, and poor
mental health, all of which have a negative impact on HRQoL.9,10,13,14
5 RATIONALE FOR AIMING FOR HIGHER FVIII
ACTIVITY LEVELS
A growing body of evidence suggests that targeting factor levels >5%
may improve outcomes (Table 1).
A Dutch study evaluating the association between joint bleed rates
and baseline FVIII activity levels in people with mild and moderate
haemophilia receiving on-demand therapy found that joint bleed risk
approaches zero at a FVIII activity level of >15%.28 A similar, more
recent US study suggested FVIII activity levels of 30% were required to
approach a zero joint bleed rate.29 However, there are limitations when
extrapolating outcomes from the sustained factor levels in people
with mild or moderate haemophilia to people with severe haemophilia
receiving prophylaxis in whom peaks and troughs in FVIII activity
occur.29 People with severe haemophilia receiving FVIII prophylaxis
require frequent FVIII infusions to maintain target trough levels, so
they may potentially have a greater area under the FVIII activity-time
curve than individuals with mild or moderate haemophilia.29 In addi-
tion, individuals receiving prophylaxis will be within the normal range
of FVIII activity for a period due to the peaks that occur following FVIII
prophylactic treatment.29 Therefore, the trough level associated with
a zero bleed rate may be lower in people with severe haemophilia than
those with mild or moderate disease who do not experience peaks of
FVIII activity following prophylaxis.29 Although people receiving pro-
phylaxis have peaks of protection, they may spend a proportion of time
with FVIII activity levels below that of mild or moderate haemophilia,
depending on the target trough level. For example, an individual tar-
geting a trough level of 1% may spend a substantial amount of time
below 5%.30 This may expose them to a higher risk of bleeds than an
individual with moderate haemophilia, with steady state levels of 5%,
who does not experience these low FVIII activity levels. Furthermore,
even FVIII activity levels in the moderate haemophilia range may not
provide sufficient protection for high-risk physical activity, with expert
opinions elicited by Martin et al. suggesting that levels of up to 64% may
be required.5

MALEC and MATINO
TA B L E 1 Summary of studies that evaluate the association between factor level and bleeds.
Reference Study design
Den Uijl I, et al. Retrospective study of 433 patients with mild or moderate
Haemophilia. haemophilia A (FVIII 1–40 IU/dL) receiving on-demand
201128 treatment.
The study population included 119 (27%) patients with
moderate haemophilia (median [range] age, 34 [0–83] years)
and 314 (73%) patients with mild haemophilia (median
[range] age, 37 [0–87] years).
Self-reported data on joint bleed frequency and baseline
clotting factor were collected from patients at Dutch
haemophilia treatment centres.
A multivariate regression analysis was performed to estimate
the association between the number of joint bleeds and
baseline factor level.
Soucie JM, et al. Retrospective study of 4771 patients with mild or moderate
Blood Adv. haemophilia A or B without inhibitors (FVIII/FIX 1–49 IU/dL)
201829 receiving on-demand treatment.
Overall, 21%, 37%, 19%, and 19% of patients were
2–9, 10–24, 25–44, and >45 years of age, respectively.
Data on baseline factor levels and self-reported bleeds were
collected from the US Universal Data Collection system.
Regression analyses were performed to evaluate the
relationship between factor level and number of joint bleeds.
Valentino LA, Post hoc analysis to evaluate the association between peak
et al. FVIII activity levels, AUC, and time with FVIII levels in
Haemophilia. certain ranges, with bleeds during prophylaxis.
201633 Included 34 patients with severe haemophilia A receiving
PK-guided prophylaxis to target a trough level of >1 IU/dL.
Bleeds were self-reported.
Chowdary P, et al. Post hoc analysis to evaluate the relationship between
Thromb estimated FVIII activity levels and reported bleeds.
Haemost. The study was a two-arm, randomised study comparing ABRs
202031 between patients receiving standard prophylaxis or
PK-guided prophylaxis.
Included 63 patients with severe haemophilia A (median
[range] age, 287–59 years) receiving tertiary prophylaxis.
Bleeds were self-reported, and patient-specific PK profiles
were obtained.
Broderick CR, Case-crossover study within a prospective cohort study to
et al. JAMA. evaluate the association of physical activity and factor level
201234 with the risk of bleeds.
Included 104 children and adolescents (aged 4–18 years) with
moderate or severe haemophilia A or B (FVIII/FIX ≤5 IU/dL).
A bleed was defined as an episode of bleeding requiring
treatment with clotting factor. Bleeds were reported by
patients or their parent/guardian.
Tiede A, et al. Population PK model derived from data from 3 Guardian
Haematologica. clinical trials to evaluate the relationship between bleeds
2021.32 and FVIII activity levels.
Included a total of 231 patients, both adult (n = 168) and
paediatric (n = 63), with severe haemophilia A (FVIII ≤1%).
Dosing and bleed data were self-reported and collected from
patient diaries.
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
5
Association between factor levels and bleeds
Annual number of joint bleeds decreased with increased
baseline FVIII activity levels.
An 18% reduction in joint bleed frequency was identified
for every 1% increase in FVIII activity.
Participants with FVIII activity levels <5% had the highest
risk for joint bleeds, with the risk of joint bleeds
approaching zero in those with a FVIII activity level 15%
and higher.
Overall number of joint bleeds declined as baseline factor
activity increased.
The predicted number of joint bleeds approached zero at a
factor activity of 30%.
For every 10% increase in factor activity, the odds of having
an orthopaedic procedure decreased by 40%.
Bleeds decreased by 10% for every 1% increase in factor
activity, although this decrease was not linear.
Lower FVIII activity levels were associated with an
increased risk for all bleeds.
Spontaneous bleeds were prevented when patients had
FVIII activity >27 IU/dL.
Most joint bleeds and traumatic bleeds occurred at
levels <10%.
As the proportion of time participants spent above
20–30 IU/dL per week increased, ABR decreased.
Bleeds occurred at estimated FVIII activity levels of up to
60%, and spontaneous joint bleeds below 35%.
Model-based estimate found a 1 IU/dL increase in factor
activity between 1 and 10 IU/dL was associated with a
2% increase in the percentage of patients with zero
bleeds; between 10 and 30 IU/dL, a 10 IU/dL increase
was associated with a 10%–15% improvement, and
beyond 30 IU/dL there was minimal gain.
For every 1% increase in factor activity, bleed incidence
was found to be lower by 2%.
Bleed incidence decreased as FVIII activity levels
increased.
Overall estimated mean spontaneous and spontaneous
joint ABR approached zero when FVIII was >50%.
At FVIII activity of >15%–50% the mean spontaneous and
spontaneous joint ABR were 0.76 and 0.67, respectively.
(Continues)
 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 MALEC and MATINO

TA B L E 1 (Continued)

Reference Study design Association between factor levels and bleeds

Klamroth R, et al. Phase 3 prospective, randomised study to evaluate the safety
Blood. 2021.35 and efficacy of PK-guided prophylaxis targeting FVIII trough
levels of either 1%–3% (reference) or 8%–12% (elevated).
Included 115 patients (aged 12–65 years) with severe
haemophilia A (FVIII <1%) and an ABR ≥2 during the
12 months prior to study entry.
Patients were assigned 1:1 to either the reference or elevated
cohort.
In the full analysis set the percentage of patients (95% CI)
with zero total, spontaneous, and spontaneous joint
bleeds in the reference and elevated trough cohorts,
respectively, were 42% (29%−55%) versus 62%
(49%−75%) (p = .055), 60% (47%–72%) versus 76%
(86%–88%) (p = .101), and 65% (53%–77%) versus 85%
(75%–95%) (p = .026). The percentage of patients with
zero total bleeds was numerically higher, but not
significant.
In the per-protocol analysis set, the percentage of
participants with zero bleeds was significantly higher in
the elevated trough cohort than in the reference cohort,
67% (95% CI, 52%, 81%) versus 40% (95% CI, 27%, 55%)
(p = .015).
The percentage of patients with zero joint bleeds was 81%
and 60% in the 1%–3% cohort and 8%–12% cohort,
respectively; corresponding values for percentage of
zero spontaneous joint bleeds were 91% and 65%.

Abbreviations: ABR, annualised bleed rate; AUC, area under the curve; CI, confidence interval; FIX, factor IX; FVIII, factor VIII; PK, pharmacokinetic.

Further studies have evaluated the FVIII activity level at which the
bleed risk approaches zero. A post hoc analysis by Chowdary et al.
of 63 patients with severe haemophilia A receiving tertiary prophy-
laxis reported bleeds occurring at estimated FVIII activity levels of
up to 60% and spontaneous joint bleeds up to 35%.31 A population
pharmacokinetic (PK) model further supported this, with modelling
indicating that FVIII activity levels of >50% may be required to achieve
a near-zero spontaneous annualised bleed rate (ABR).32 In a post hoc
analysis of a study with 34 patients receiving PK-guided prophylaxis,
spontaneous bleeds were prevented when patients had FVIII activity
levels >27%, and most joint and traumatic bleeds occurred at <10%.33
A 1% increase in factor activity between 1% and 10% was associated
with a 2% increase in the percentage of patients with zero bleeds in
the study by Chowdary et al.31 Similar results were observed in a case
crossover study assessing the bleed risk in 104 children and adoles-
cents with severe and moderate haemophilia A and B participating in
physical activity, with bleed incidence lowered by 2% for every 1%
increase in factor activity.34
PROPEL was a prospective randomised controlled study that evalu-
ated the efficacy and safety of PK-guided prophylaxis with rurioctocog
alfa pegol in patients with severe haemophilia A.35 A total of 115 partic-
ipants were randomised 1:1 to receive PK-guided prophylaxis targeting
a trough level of either 1%–3% (reference) or 8%–12% (elevated).35 In
the full analysis set, the percentage of patients with zero bleeds was
numerically higher in the elevated cohort than in the reference cohort,
62% (95% confidence interval [CI] 49%, 75%) versus 42% (95% CI, 29%,
55%) (p = .055).35 Moreover, in the per-protocol analysis set, the per-
centage of participants with zero bleeds was significantly higher in the
elevated trough cohort than in the reference cohort, 67% (95% CI,
52%, 81%) versus 40% (95% CI, 27%, 55%) (p = .015).35 These results
indicate that targeting a higher trough level may be beneficial and can
reduce the number of bleeds.35
The factor activity levels discussed here vary between studies due
to the heterogeneity of patient populations studied, with differences in
patient age and type and severity of haemophilia. Further differences
in the patient populations in these studies include type of treatment
(on-demand vs. prophylaxis) and product, joint health and presence of
pre-existing joint damage, and levels of physical activity. In addition,
these studies rely on patient-reported joint bleeds, which are per-
ceived by pain, and may be misclassified, particularly in older patients
with pre-existing joint damage, without objective assessment such as
ultrasound.17,36
Current data suggest that FVIII activity levels of 15%–50% may be
needed to achieve a near-zero joint bleed rate (Figure 3). However, the
appropriate target level remains a topic of debate.
6 EXISTING DATA GAPS
There are substantial challenges associated with evaluating trough
levels >10% in people with haemophilia A; therefore, data gaps exist
on the potential benefits of a treatment regimen achieving FVIII
activity levels higher than this. PROPEL was the first prospective study
in this field but only considered safety and efficacy outcomes related
to bleed frequency35 ; further studies are needed to confirm these
results. The impact of higher FVIII activity levels on other clinical and
patient-reported outcomes will need to be evaluated.37 Spontaneous
bleed rates observed with current standard of care treatment are
approaching zero; however, highly active patients are still at risk of
traumatic bleeds.5,37 Furthermore, older individuals with haemophilic
arthropathy may still experience functional impairment and have
abnormalities in their gait,38 and thus may have a greater bleed risk in
the normal range given the presence of pre-existing joint damage.37
Therefore, bleed rates alone may not accurately measure overall bleed
 13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MALEC and MATINO 7

Disease FVIII activity

severity† levels (%)
100 Tiede A, et al Haematologica. 2021.
Normal Based on a population PK model to evaluate the relationship between
(>50) FVIII activity levels and bleeds

Chowdary P, et al. Thromb Haemost. 2020.

Near-normal 50 50%
Based on PK models used to predict FVIII activity levels associated with FVIII activity levels of
(>40–<50) 40 zero bleeds in people with severe hemophilia A
35% 15%–50% are associated
30 30% Soucie J, et al. Blood Adv. 2018.
with a near-zero joint
Based on a regression model to predict joint bleeds in people with mild bleed rate
20 and moderate hemophilia A
Mild
(>5–<40) 15% den Uijl I, et al. Haemophilia. 2011.
Based on a multivariate model to estimate joint bleeds in people with mild
10 and moderate hemophilia A

5
>3-5%: Target trough preferred by clinicians
(World Federation of Hemophilia 2020 Guidelines)
Moderate 3
(1–5)
2

Severe 1 1%: Historical target trough

(<1)

F I G U R E 3 FVIII activity levels associated with a near-zero bleed rate in haemophilia A. FVIII, factor VIII; PK, pharmacokinetic. † The World
Federation of Hemophilia defines FVIII activity levels of <1% as severe haemophilia, 1%–5% as moderate haemophilia, >5%–<40% as mild
haemophilia, and 50%–100% as normal.1 FVIII activity levels of >40%–<50% are defined here as near-normal.

risk across different haemophilia populations37 ; an assessment of gait
abnormalities may also be useful to provide a more complete profile of
bleed risk.39
7 NON-FACTOR REPLACEMENT THERAPIES
AND FVIII EQUIVALENCE
7.1 Emicizumab
There are an increasing number of non–factor replacement therapies,
those that partially restore haemostasis, but do not achieve elevated
FVIII activity levels. These therapies may be used for prophylaxis
and to prevent bleeding episodes, but not for perioperative man-
agement or bleed treatment. The non-factor therapy emicizumab
mimics activated FVIII, providing partial co-factor activity by bridging
activated FIX and FX to substitute for the function of the missing or
defective activated FVIII.40,41 Emicizumab is indicated for routine
prophylaxis to prevent or reduce the frequency of bleeding episodes
in adult and paediatric patients with haemophilia A, with and without
inhibitors.42 Data from the HAVEN studies demonstrate that emi-
cizumab maintains low bleed rates, reduces target joint bleeds, and
improves HRQoL compared with prior treatment.40,41 Emicizumab is
administered subcutaneously and can be dosed every week, 2 weeks,
or 4 weeks, decreasing the treatment burden compared with prior
FVIII replacement therapy.40,41 Experiments in non-human primate
and mouse models suggest emicizumab has a FVIII equivalence of
approximately 9%–20%.43,44 The substantial inter-patient variability
of emicizumab trough levels and inconsistency of assays mean that
it has not been possible to accurately determine FVIII equivalence in
humans.30 The FVIII equivalence of emicizumab may not be sufficient
to prevent breakthrough bleeds, protect joints, and allow participation
in high-risk physical activities.4,5,30 Furthermore, emicizumab provides
steady-state levels; thus, is it not possible to provide peak protection
at times of transient increase in bleeding risk, such as contact sports
or major surgery, as with FVIII replacement.30 In these instances,
FVIII replacement therapy or bypassing agents may be required to
provide additional protection.30 Routine monitoring of emicizumab
is challenging, limiting the ability to predict responses and tailor
treatment.43
7.2 Investigational non-factor replacement
therapies
Currently, emicizumab is the only licensed non-factor replacement
therapy for haemophilia A, but additional FVIIIa mimetics are in
development, including Mim8 and NXT004 to 07.45,46 NXT004 to 07
are further engineered emicizumab molecules that incorporate non-
commonised light chains and replace amino acids in the variable and

8 MALEC and MATINO
constant regions with the aim of improving haemostatic activity and
pharmacokinetics.46
Another investigational non-factor therapy is fitusiran, a small inter-
fering ribonucleic acid (RNA) therapeutic that targets antithrombin
messenger RNA, thus preventing antithrombin protein synthesis.47
Fitusiran is being developed for people with haemophilia A and B, with
and without inhibitors, and is dosed subcutaneously every month or
every other month.47 Recently published results from the Phase 3
ATLAS-A/B and ATLAS-INH studies report that fitusiran is generally
well-tolerated.48,49 Observed treatment adverse events were gener-
ally consistent with previously identified risks of fitusiran, including
hepatotoxicity, cholecystitis, symptomatic cholelithiasis, and throm-
botic events.48,49 Risk mitigation measures for hepatotoxicity and
thrombosis have been implemented in ongoing Phase 3 studies, includ-
ing transaminase monitoring, breakthrough bleed management guide-
lines, and a revised dose and dosing regimen, which aim to balance the
risks and benefits of fitusiran.48,49 In the ATLAS-A/B and ATLAS-INH
studies fitusiran prophylaxis provided consistent protection against
bleeding.48,49 The estimated mean (95% CI) overall ABR for partic-
ipants receiving fitusiran was 3.1 (2.3–4.3) in the ATLAS-A/B study,
with over 50% of participants reporting no treated bleeds during
the efficacy period.48 Furthermore, participants with inhibitors in the
ATLAS-INH study had an estimated mean (95% CI) overall ABR of 1.7
(1.0–2.7) in the efficacy period, with 66% of participants reporting zero
treated bleeds.49
There are several investigational anti-tissue factor path-
way inhibitor (TFPI) antibodies, (concizumab,50 marstacimab,51
MG111352 ) that inhibit TFPI and enhance the initiation phase of
coagulation through an increase in activated FX production and
enabling thrombin generation. Both concizumab and marstacimab
are being developed for people with haemophilia A and B, with and
without inhibitors.50,51 Concizumab is dosed subcutaneously daily, and
marstacimab is dosed subcutaneously once weekly.50,51 Results from
the Phase 3 explorer7 study in participants with haemophilia with
inhibitors reported concizumab was well-tolerated, with no throm-
botic events following restart of treatment with revised dosing.53 The
estimated mean (95% CI) ABR for treated spontaneous and traumatic
bleeds was 1.6 (0.9–2.8) for participants with haemophilia A with
inhibitors receiving concizumab in the study.53 In addition, results
from the Phase 3 explorer8 study in participants with haemophilia
without inhibitors demonstrated that concizumab prophylaxis was
superior to no prophylaxis, with an estimated mean (95% CI) ABR of 2.7
(1.6–4.6) for those on concizumab compared with 19.3 (11.3–33.0) for
participants not receiving prophylaxis.54 However, non-inferiority of
concizumab to previous prophylaxis was not confirmed and the median
(IQR) ABR for participants with haemophilia A on prior prophylaxis
was 2.2 (0.8–6.2) versus 2.3 (0.0–4.7) for concizumab prophylaxis.54
The Phase 2 long-term study of marstacimab in participants with
haemophilia A and B, with and without inhibitors, reported that
marstacimab was generally well-tolerated with no thrombotic events
or treatment-related serious adverse events reported.55 Furthermore,
mean overall ABR was 1.5 for the cohort receiving 300 mg cohort
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
weekly, and 2.7 for the cohort receiving 150 mg once weekly after a
loading dose of 300 mg.55
These non-factor therapies have different mechanisms of action
than FVIII replacement therapies, aiming to partially restore
haemostasis by acting on different points of the coagulation pro-
cess. As such, monitoring the pharmacodynamics of these non-factor
therapies, when they do not directly increase FVIII activity levels, is
challenging; alternative assays may be needed to evaluate the haemo-
static efficacy of these therapies. Preclinical animal model experiments
indicate that the FVIII equivalence of fitusiran and concizumab is
≥20%.43 For people receiving fitusiran prophylaxis, the target thera-
peutic range of antithrombin at steady state is 15%–35%.56 Modelling
in a virtual population of individuals with severe haemophilia A showed
that, for this level of antithrombin, peak thrombin corresponds to a
10–20 IU/kg FVIII.56 As noted for emicizumab, the FVIII equivalence
achieved by non-factor therapies may not be sufficient to prevent
breakthrough bleeds, protect joints, and allow participation in high-
risk physical activities.5,30 More data are needed to determine if the
FVIII equivalence of these therapies is sufficient to protect against all
bleeds and if there are mechanistic differences in the clot formation
achieved.
8 THERAPIES THAT MAY SUPPORT ACHIEVING
HIGH FVIII ACTIVITY LEVELS
8.1 Standard and extended half-life FVIII
replacement therapies
People receiving regular prophylaxis with standard half-life (SHL)
FVIII replacement typically require infusions 3−4 times per week.1
Extended half-life (EHL) FVIII replacement therapies can have a half-
life 1.4–1.6-fold higher than SHL therapies and thus can be injected
less frequently, or if injected at the same frequency can provide
higher levels of bleed protection.1 However, these SHL and EHL FVIII
replacement therapies are limited by the half-life of endogenous von
Willebrand factor (VWF), which stabilizes and protects FVIII from
degradation and clearance but also subjects FVIII to a half-life ceiling
of ∼14–19 h.57 Data from the PROPEL study suggest that targeting
elevated trough levels can reduce bleed rates. However, to achieve ele-
vated trough levels, 12% of participants were required to dose daily
and 60% every other day.35 Although increasing dosing frequency can
achieve elevated factor levels, this approach comes with challenges,
including the potential need for central venous access devices (CVAD)
in young children, and the possibility of reduced adherence in older
children and adults.1,8 There is a balance between the benefits of
increasing dosing frequency and the negative impact this has on bur-
den of treatment and HRQoL.58 In the CHESS study, improvements in
HRQoL were observed in participants with severe chronic pain who
increased their dosing frequency; however, participants with mild or
moderate pain did not experience improvements in HRQoL, potentially
due to the negative impact of additional infusions on their HRQoL.58

MALEC and MATINO
8.2 High sustained FVIII replacement therapies
Efanesoctocog alfa is a first-in-class, high sustained FVIII replacement
therapy composed of recombinant B-domain deleted FVIII, an Fc
domain that facilitates recycling via the neonatal Fc receptor pathway,
covalent linkage to a VWF D’D3 FVIII binding domain to stabilise
and decouple rFVIII from endogenous VWF, and 2 XTEN polypep-
tides to shield efanesoctocog alfa from proteolytic degradation and
clearance.59–61 The covalent linking of the D’D3 domain of VWF to
rFVIII prevents endogenous VWF binding, enabling efanesoctocog alfa
to overcome the VWF-imposed half-life ceiling.60,61 Efanesoctocog
alfa was recently approved by the US FDA for adults and children with
haemophilia A for routine prophylaxis, treatment of bleeding episodes,
and perioperative management.62 Results from the Phase 3 XTEND-1
study showed that once-weekly prophylaxis with efanesoctocog
alfa 50 IU/kg provided mean factor activity levels in the normal to
near-normal range (>40 IU/dL) for most of the dosing interval and
at 15 IU/dL at Day 7.59 Furthermore, efanesoctocog alfa had a mean
half-life of 47 h, which is three- to four-fold longer relative to SHL and
EHL FVIII products, respectively.59 Once-weekly efanesoctocog alfa
provided superior bleed protection compared with prior standard of
care FVIII prophylaxis, with the mean ABR (95% CI) decreasing 77%
from 2.96 (2.00–4.37) to 0.69 (0.43–1.11) (p < .0001).59 The indepen-
dence of efanesoctocog alfa from VWF may reduce the inter-patient
PK variability of efanesoctocog alfa compared to other rFVIII products
and improve the predictability of FVIII activity levels over time.59
Furthermore, patients receiving efanesoctocog alfa prophylaxis
experienced statistically significant and clinically meaningful improve-
ments from baseline to Week 52 in physical health, pain, and joint
health.59
8.3 Gene therapies
There are several gene therapies for haemophilia A at various stages
of clinical development. Valoctocogene roxaparvovec is currently the
only approved gene therapy for haemophilia A following approval in
August 2022 in Europe. In the recently reported primary 104-week
results of the ongoing Phase 3 study of valoctocogene roxaparvovec
in 134 adult males, an increase in mean (95% CI) FVIII activity levels
of 22.0 (16.4, 27.7) IU/dL, p < .0001 was observed from baseline to
Week 104.63 The mean (95% CI) change in annualized treated bleed-
ing event during the study compared with baseline was −4.1 (−5.3,
−2.9) bleeding events per year (p < .0001), a reduction of 84.5%.63
Modelling predicted 1.0 treated joint bleed events (95% CI, 0.7, 1.5)
per year with a FVIII activity level of 5 IU/dL. Estimated mean FVIII
activity levels 5 years after treatment were 11.8 IU/dL, extrapolated
using the estimated mean (95% CI) typical half-life of the transgene-
derived FVIII production system of 123 (84, 232) weeks.63 Evidence
from this study suggests that FVIII activity levels will remain in the mild
haemophilia range for at least 5 years after gene transfers, although
expression of FVIII is predicted to decline over time.63 Further study
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
9
is needed to determine if repeat treatment is needed or possible.64
Furthermore, intra- and inter-patient variability in FVIII activity lev-
els following gene therapy have been observed, with 4.5%, 9.1%, and
59.8% of participants with FVIII activity levels consistent with severe,
moderate, and mild haemophilia, and 26.5% of participants with FVIII
levels >40 IU/dL at year 2.63 The causes of this variability are poorly
understood and may include molecular events related to gene transfer
and expression.64
9 CONCLUSION
Substantial unmet needs exist for people with haemophilia, and
progress is required to optimise health and achieve health equity.6
Targeting higher FVIII activity levels may reduce bleed risk,28,29,31–35
and improve joint health and patient quality of life. Further research,
including a wider range of patient-relevant outcomes, is needed to
support the hypothesis that higher FVIII levels improve HRQoL.
Current data suggest that FVIII activity levels of up to 50% may be
needed to achieve a near-zero joint bleed rate. Achieving elevated
FVIII levels for longer is possible with more frequent and higher dosing
of current SHL and EHL FVIII replacement therapies35 ; however,
this increases treatment burden.1,8 Efanesoctocog alfa, the recently
approved first-in-class FVIII replacement therapy, is able to overcome
the VWF-imposed half-life ceiling and can provide high-sustained
FVIII activity levels in the normal to near-normal range for most of
the weekly dosing interval.59,62 Non-factor therapies aim to partially
restore haemostasis and can be convenient because they can be dosed
subcutaneously and, in some cases, may be dosed less frequently
than FVIII replacement therapies. However, it is not yet clear if the
FVIII equivalence achieved by these therapies is sufficient to pre-
vent breakthrough bleeds, protect joints, and allow participation in
physical activities with high bleed risk.5,30 Elevations in FVIII activity
levels across multiple years have been achieved by gene therapy
and may be a promising long-term option for many people with
haemophilia A. Concerns remain over high levels of inter-patient
variability in FVIII activity levels achieved, and long-term safety
outcomes.
In conclusion, evidence suggests that FVIII activity levels should be
sustained at a higher level to improve patient outcomes, and several
treatment options, which may achieve this, exist or are in development.
AUTHOR CONTRIBUTIONS
All authors contributed to the drafting, critical review, and revision of
the manuscript, with medical writing support funded by Sanofi, accord-
ing to Good Publication Practice (GPP4). All authors granted approval
of the final manuscript for submission.
ACKNOWLEDGEMENTS
Medical writing support was provided by Sarah Rupprechter, PhD, of
Fishawack Ltd., part of Fishawack Health. Funding for medical writing
support was provided by Sanofi.

10
CONFLICT OF INTEREST STATEMENT
Lynn Malec has received research support from Sanofi. She has
received consultancy fees from Bayer, CSL, Sanofi, Spark, Takeda, Sobi,
and Novo Nordisk. Davide Matino reports research grants paid directly
to the institution (McMaster University) from: Bayer, Pfizer, Novo
Nordisk, Sanofi, Spark, Octapharma, and Roche. Fees as paid consultant
outside of the submitted work from Sobi, Sanofi, Novo Nordisk, Bayer,
Pfizer, Octapharma, for participation in advisory boards, lectures, and
preparation of education material.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were gener-
ated or analysed during the current study.
ETHICS STATEMENT
This review is based on previously conducted studies and does not
report any new data; therefore, ethical approval was not required.
REFERENCES
1. Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines
for the management of Hemophilia. Haemophilia. 2020;26(Suppl 6):
1-158.
2. Olasupo OO, Lowe MS, Krishan A, Collins P, Iorio A, Matino D. Clot-
ting factor concentrates for preventing bleeding and bleeding-related
complications in previously treated individuals with haemophilia A or
B. Cochrane Database Syst Rev. 2021;8(8):Cd014201.
3. Collins PW, Blanchette VS, Fischer K, et al. Break-through bleed-
ing in relation to predicted factor VIII levels in patients receiving
prophylactic treatment for severe hemophilia A. J Thromb Haemost.
2009;7(3):413-420.
4. Iorio A, Iserman E, Blanchette V, et al. Target plasma factor levels for
personalized treatment in haemophilia: a Delphi consensus statement.
Haemophilia. 2017;23(3):e170-e179.
5. Martin AP, Burke T, Asghar S, Noone D, Pedra G, O’Hara J. Under-
standing minimum and ideal factor levels for participation in physical
activities by people with haemophilia: an expert elicitation exercise.
Haemophilia. 2020;26(4):711-717.
6. Skinner MW, Nugent D, Wilton P, et al. Achieving the unimaginable:
health equity in haemophilia. Haemophilia. 2020;26(1):17-24.
7. Krumb E, Hermans C. Living with a “hemophilia-free mind”—The
new ambition of hemophilia care? Res Pract Thromb Haemost.
2021;5(5):e12567.
8. Thornburg CD, Duncan NA. Treatment adherence in hemophilia.
Patient Prefer Adherence. 2017;11:1677-1686.
9. van Vulpen LFD, Holstein K, Martinoli C. Joint disease in haemophilia:
pathophysiology, pain and imaging. Haemophilia. 2018;24(Suppl 6):44-
49.
10. Stromer W, Pabinger I, Ay C, et al. Pain management in
hemophilia: expert recommendations. Wien Klin Wochenschr.
2021;133(19-20):1042-1056.
11. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis ver-
sus episodic treatment to prevent joint disease in boys with severe
hemophilia. N Engl J Med. 2007;357(6):535-544.
12. Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a
large cohort of adult patients with severe haemophilia: a beneficial
effect on orthopaedic outcome and quality of life. Eur J Haematol.
2012;88(4):329-335.
13. Warren BB, Thornhill D, Stein J, et al. Young adult outcomes of child-
hood prophylaxis for severe hemophilia A: results of the joint outcome
continuation study. Blood Adv. 2020;4(11):2451-2459.
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
MALEC and MATINO
14. O’Hara S, Castro FA, Black J, et al. Disease burden and remaining
unmet need in patients with haemophilia A treated with primary
prophylaxis. Haemophilia. 2021;27(1):113-119.
15. Manco-Johnson MJ, Lundin B, Funk S, et al. Effect of late prophylaxis
in hemophilia on joint status: a randomized trial. J Thromb Haemost.
2017;15(11):2115-2124.
16. Bhat V, Olmer M, Joshi S, et al. Vascular remodeling underlies rebleed-
ing in hemophilic arthropathy. Am J Hematol. 2015;90(11):1027-1035.
17. Kidder W, Nguyen S, Larios J, Bergstrom J, Ceponis A, von Drygalski
A. Point-of-care musculoskeletal ultrasound is critical for the diag-
nosis of hemarthroses, inflammation and soft tissue abnormalities
in adult patients with painful haemophilic arthropathy. Haemophilia.
2015;21(4):530-537.
18. Di Minno MN, Iervolino S, Soscia E, et al. Magnetic resonance imag-
ing and ultrasound evaluation of “healthy” joints in young subjects with
severe haemophilia A. Haemophilia. 2013;19(3):e167-173.
19. Paredes AC, Teixeira P, Almeida A, Pinto PR. Prevalence and Inter-
ference of chronic pain among people with hemophilia: a systematic
review and meta-analysis. J Pain. 2021;22(10):1134-1145.
20. Kalnins W, Schelle G, Jost K, Eberl W, Tiede A. Pain therapy in
haemophilia in Germany. Patient survey (BESTH study). Hamostaseolo-
gie. 2015;35(2):167-173.
21. Steen Carlsson K, Winding B, Astermark J, et al. Pain, depression
and anxiety in people with haemophilia from three Nordic coun-
tries: cross-sectional survey data from the MIND study. Haemophilia.
2022;28(4):557-567.
22. Buckner TW, Batt K, Quon D, et al. Assessments of pain, functional
impairment, anxiety, and depression in US adults with hemophilia
across patient-reported outcome instruments in the pain, func-
tional impairment, and quality of life (P-FiQ) study. Eur J Haematol.
2018;100(Suppl 1):5-13.
23. Witkop ML, Lambing A, Nichols CD, Munn JE, Anderson TL, Tortella
BJ. Interrelationship between depression, anxiety, pain, and treatment
adherence in hemophilia: results from a US cross-sectional survey.
Patient Prefer Adherence. 2019;13:1577-1587.
24. Witkop M, Guelcher C, Forsyth A, et al. Treatment outcomes, quality of
life, and impact of hemophilia on young adults (aged 18–30 years) with
hemophilia. Am J Hematol. 2015;90(Suppl 2):S3-10.
25. Cadé M, Muñoz-Garcia J, Babuty A, et al. FVIII at the crossroad of
coagulation, bone and immune biology: emerging evidence of biolog-
ical activities beyond hemostasis. Drug Discov Today. 2022;27(1):102-
116.
26. Klintman J, Akesson KE, Holme PA, Fischer K. Bone mineral density
in haemophilia—a multicentre study evaluating the impact of different
replacement regimens. Haemophilia. 2022;28(2):239-246.
27. Gamal Andrawes N, Hashem Fayek M, Salah El-Din N. Atef Mostafa
R. Effect of low-dose factor VIII prophylaxis therapy on bone min-
eral density and 25(OH) vitamin D level in children with severe
haemophilia A. Haemophilia. 2020;26(2):325-332.
28. den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR,
Plug I. Analysis of low frequency bleeding data: the association of
joint bleeds according to baseline FVIII activity levels. Haemophilia.
2011;17(1):41-44.
29. Soucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA. The fre-
quency of joint hemorrhages and procedures in nonsevere hemophilia
A vs. B. Blood Adv. 2018;2(16):2136-2144.
30. Berntorp E, Hermans C, Solms A, Poulsen L, Mancuso ME. Optimising
prophylaxis in haemophilia A: the ups and downs of treatment. Blood
Rev. 2021;50:100852.
31. Chowdary P, Fischer K, Collins PW, et al. Modeling to predict factor viii
levels associated with zero bleeds in patients with severe hemophilia
A initiated on tertiary prophylaxis. Thromb Haemost. 2020;120(5):728-
736.
32. Tiede A, Abdul Karim F, Jiménez-Yuste V, et al. Factor VIII activity
and bleeding risk during prophylaxis for severe hemophilia A: a

MALEC and MATINO
population PHARMACOKINETIC model. Haematologica.
2021;106(7):1902-1909.
33. Valentino LA, Pipe SW, Collins PW, et al. Association of peak factor
VIII levels and area under the curve with bleeding in patients with
haemophilia A on every third day pharmacokinetic-guided prophy-
laxis. Haemophilia. 2016;22(4):514-520.
34. Broderick CR, Herbert RD, Latimer J, et al. Association between phys-
ical activity and risk of bleeding in children with hemophilia. JAMA.
2012;308(14):1452-1459.
35. Klamroth R, Windyga J, Radulescu V, et al. Rurioctocog alfa pegol PK-
guided prophylaxis in hemophilia A: results from the phase 3 PROPEL
study. Blood. 2021;137(13):1818-1827.
36. Ceponis A, Wong-Sefidan I, Glass CS, von Drygalski A. Rapid mus-
culoskeletal ultrasound for painful episodes in adult haemophilia
patients. Haemophilia. 2013;19(5):790-798.
37. Konkle BA, Skinner M, Iorio A. Hemophilia trials in the twenty-
first century: defining patient important outcomes. Res Pract Thromb
Haemost. 2019;3(2):184-192.
38. Cruz-Montecinos C, Pérez-Alenda S, Querol F, Cerda M, in
MaasHChanges. Muscle activity patterns and joint kinematics
during gait in Hemophilic arthropathy. Front Physiol. 2019;10:1575.
39. Forneris E, Andreacchio A, Pollio B, et al. Gait analysis in children with
haemophilia: first Italian experience at the Turin Haemophilia centre.
Haemophilia. 2016;22(3):e184-191.
40. Skinner MW, Négrier C, Paz-Priel I, et al. The effect of emicizumab pro-
phylaxis on long-term, self-reported physical health in persons with
haemophilia A without factor VIII inhibitors in the HAVEN 3 and
HAVEN 4 studies. Haemophilia. 2021;27(5):854-865.
41. Callaghan MU, Negrier C, Paz-Priel I, et al. Long-term outcomes
with emicizumab prophylaxis for hemophilia A with or without FVIII
inhibitors from the HAVEN 1–4 studies. Blood. 2021;137(16):2231-
2242.
42. Genentech I, Hemlibra Prescribing Information.2022. Accessed
November 3, 2022. https://www.gene.com/download/pdf/hemlibra_
prescribing.pdf
43. Lenting PJ. Laboratory monitoring of hemophilia A treatments: new
challenges. Blood Adv. 2020;4(9):2111-2118.
44. Ferrière S, Peyron I, Christophe OD, et al. A hemophilia A mouse
model for the in vivo assessment of emicizumab function. Blood.
2020;136(6):740-748.
45. Østergaard H, Lund J, Greisen PJ, et al. A factor VIIIa-mimetic bis-
pecific antibody, Mim8, ameliorates bleeding upon severe vascular
challenge in hemophilia A mice. Blood. 2021;138(14):1258-1268.
46. Teranishi Y, Soeda T, Koga H, et al. New factor VIII function-mimetic
bispecific antibodies engineered from emicizumab for further improv-
ing the treatment of Hemophilia A [abstract]. Res Pract Thromb
Haemost. 2022;4(Suppl 1).
47. Pasi KJ, Lissitchkov T, Mamonov V, et al. Targeting of antithrom-
bin in hemophilia A or B with investigational siRNA therapeutic
fitusiran-Results of the phase 1 inhibitor cohort. J Thromb Haemost.
2021;19(6):1436-1446.
48. Srivastava A, Rangarajan S, Kavakli K, et al. Fitusiran prophylaxis in
people with severe haemophilia A or haemophilia B without inhibitors
(ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.
Lancet Haematol. 2023;10(5):e322-e332.
49. Young G, Srivastava A, Kavakli K, et al. Efficacy and safety of fitusiran
prophylaxis in people with haemophilia A or haemophilia B with
inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase
3 trial. Lancet. 2023;401(10386):1427-1437.
50. Shapiro AD, Angchaisuksiri P, Astermark J, et al. Long-term efficacy
and safety of subcutaneous concizumab prophylaxis in hemophilia A
and hemophilia A/B with inhibitors. Blood Adv. 2022;6(11):3422-3432.
13652516, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/hae.14866 by Institute Of Hematology And, Wiley Online Library on [05/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
11
51. Cardinal M, Kantaridis C, Zhu T, et al. A first-in-human study of the
safety, tolerability, pharmacokinetics and pharmacodynamics of PF-
06741086, an anti-tissue factor pathway inhibitor mAb, in healthy
volunteers. J Thromb Haemost. 2018;16(9):1722-1731.
52. Kwak H, Lee S, Jo S, et al. MG1113, a specific anti-tissue factor pathway
inhibitor antibody, rebalances the coagulation system and promotes
hemostasis in hemophilia. Res Pract Thromb Haemost. 2020;4(8):1301-
1312.
53. Frei-Jones M, Cepo K, d’Oiron R, Goh AS, Mathias M, Odgaard-Jensen
J. Subcutaneous concizumab prophylaxis in patients with hemophilia a
or b with inhibitors: efficacy and safety results by Hemophilia subtype
from the phase 3 explorer7 trial. Blood. 2022;140(Supplement 1):466-
468.
54. Chowdary P, Angchaisuksiri P, Apte S, et al. Concizumab prophylaxis in
patients with haemophilia A or B without inhibitors: efficacy and safety
results from the primary analysis of the phase 3 explorer8 study. 2023.
55. Mahlangu J, Luis Lamas J, Cristobal Morales J, et al. Long-term safety
and efficacy of the anti-tissue factor pathway inhibitor marstacimab
in participants with severe haemophilia: phase II study results. Br J
Haematol. 2023;200(2):240-248.
56. Kaddi C, Tao M, Leiser R, et al. Development of a quantitative
systems pharmacology model to explore hemostatic equivalency of
antithrombin lowering [abstract]. 2022.
57. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, Lillicrap D. Life in the
shadow of a dominant partner: the FVIII-VWF association and its clin-
ical implications for hemophilia A. Blood. 2016;128(16):2007-2016.
58. Pedra G, Christoffersen P, Khair K, et al. The impact of factor infusion
frequency on health-related quality of life in people with haemophilia.
The Journal of Haemophilia Practice. 2020;7(1):102-109.
59. von Drygalski A, Chowdary P, Kulkarni R, et al. Efanesoctocog alfa pro-
phylaxis for patients with severe Hemophilia A. New England Journal of
Medicine. 2023;388(4):310-318.
60. Seth Chhabra E, Liu T, Kulman J, et al. BIVV001, a new class of factor
VIII replacement for hemophilia A that is independent of von Wille-
brand factor in primates and mice. Blood. 2020;135(17):1484-1496.
61. Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 fusion protein
as factor VIII replacement therapy for Hemophilia A. N Engl J Med.
2020;383(11):1018-1027.
62. Inc BT, ALTUVIIIO Prescribing Information. 2023. Accessed February
24, 2023 https://www.fda.gov/media/165594/download
63. Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year outcomes
of valoctocogene roxaparvovec therapy for Hemophilia A. N Engl J Med.
2023;388(8):694-705.
64. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec
gene therapy for Hemophilia A. N Engl J Med. 2022;386(11):1013-
1025.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Support-
ing Information section at the end of this article.
How to cite this article: Malec L, Matino D. Targeting higher
factor VIII levels for prophylaxis in haemophilia A: a narrative
review. Haemophilia. 2023;1-11.
https://doi.org/10.1111/hae.14866