Nonsevere Hemophilia Challenges
Key challenges faced by PWNSH are considered below and summarized in [Table 1 ].
Table 1
Challenges relating to nonsevere hemophilia
Area posing challenge
Comments, showing implications for clinical practice and research (R)
Lack of disease awareness with possibility of delayed diagnosis
● Increase awareness among nonspecialist HCPs and patients (CP)
● Ensure comprehensive assessment of family history in individuals with an established
diagnosis of hemophilia to identify potentially affected family members and offer
formal genetic counseling (CP)
● Investigate unusual bleeding in patients of any age (CP)
Variable bleeding
phenotype
● Educate nonspecialist HCPs and patients about bleed heterogeneity and unpredictability,
affirming the value of ongoing engagement with HTCs (CP)
● Additional validation of tools to assess bleeding is needed (R)
Bleeding complications
ICH
Joint bleeds
Other bleeds
● Provide specialized care and long-term follow-up, bearing in mind increased risk
of mortality from ICH (CP)
● While some data show morbidity associated with joint bleeds, more information is
required on the burden of arthropathy, including in relation to tools for assessing
musculoskeletal health, in PWNSH (R)
● Ensure management of hemostasis after trauma and when affected by surgery or age-related
morbidity (CP)
Diagnostic methodology
● Appreciate the limitations of various factor assays and the value of genotypic
analysis (CP)
Management
On-demand treatment
Prophylaxis
Surgery
● Rapid arrest of bleeding through timely product administration is best achieved
with home treatment, but this may not be a practical option for many PWNSH (CP)
● PWNSH who experience frequent severe bleeds will benefit from early prophylaxis
(CP)
● For most PWNSH, the role and intensity of prophylaxis remains to be fully determined
(R)
● Patient engagement is crucial to ensure provision of adequate hemostatic cover
for surgical procedures (CP)
● Intensive treatment with FVIII concentrate confers a risk of developing inhibitors
(CP)
● More data are required relating to endogenous levels of FVIII and FIX required
to support hemostasis over the range of surgical procedures (R)
Inhibitors
● Lifelong possibility of inhibitors creates a need for ongoing surveillance and
patient education (CP)
● With evidence about inhibitors largely obtained from patients with severe hemophilia
A, an evolving treatment landscape and lack of consensus for management, reassessment
of unmet needs is required (R)
Women and girls
● Traditional “carrier” terminology may have impeded adequate access to health care
services; new nomenclature may help to increase awareness (CP)
● Women with hemophilia face many of the same bleeding issues as men, with additional
challenges from menstruation, pregnancy, and childbirth (CP)
● There is a need for standardized plans for follow-up of affected females, to help
address possible disengagement from health care services, as well as to facilitate
prenatal and antenatal care, as required (CP)
Drug development and research
● Current research, and drug development, is largely focused on patients with severe
disease, for whom therapeutic advances may confer a better phenotype than for a subgroup
of PWNSH (R)
● To avoid disparity in care, more research/clinical trial data are required for
PWNSH, including for females (R)
Abbreviations: CP, clinical practice; FVIII, factor VIII; factor IX; HCP, health care
provider; HTC, hemophilia treatment center; ICH, intracranial hemorrhage; PWNSH, people
with nonsevere hemophilia; R, research.
Disease Awareness and Detection
Compared with severe hemophilia, spontaneous bleeding is less common in moderate hemophilia
and relatively unusual in mild hemophilia[2 ]; spontaneous bleeding is generally elicited by minor trauma and may present later
in life. This, in addition to lack of awareness in health care providers (HCPs) and
families,[5 ] often leads to delayed diagnosis. In PWNSH who have an established diagnosis, comprehensive
assessment of family history is vital to enable identification of potentially affected
family members and offer formal genetic counseling. However, although family history
presents opportunities for early diagnosis of some patients,[6 ] female carriers of NSH may be less aware of their status than carriers of severe
disease,[7 ] which may result in inadequate genetic counseling, missed preventive opportunities
at childbirth, and delayed diagnosis of affected children. This may partly explain
why, in many PWNSH, the condition may only be identified after prolonged bleeding
following injury or medical intervention, with postsurgical bleeding the presenting
issue in some undiagnosed cases; it is well recognized that many of those with mild
hemophilia are not diagnosed until adulthood.[8 ] In many PWNSH, retrospective review of clinical histories identifies episodes of
abnormal bleeding that could, if investigated, have led to earlier diagnosis, emphasizing
the educational imperative that unusual bleeding should be investigated in patients
of any age.
Patients and nonspecialist HCPs may be inappropriately reassured by the nomenclature
“nonsevere hemophilia,” missing opportunities for preventing bleeding or early treatment.
Symptoms and the risk of complications may be underestimated. Perceptions may impede
referral to, and engagement with, hemophilia treatment centers (HTCs), resulting in
fragmented care.
Bleeding Phenotype and Risk
Bleeding phenotype can vary for a given factor level ([Fig. 1 ]).[9 ]
[10 ] Patient and HCP education on phenotypic variability in PWNSH, including consideration
of bleed heterogeneity and unpredictability, is important. Given the key role of trauma,
physical activity, and invasive procedures in precipitating bleeding, PWNSH should
have continuous education throughout their lives, affirming the value of regular HTC
engagement. For all PWNSH, it is important to recognize that bleeding risk may alter
over time. After a lifetime of minimal bleeding and/or challenges, PWNSH may underestimate
and underappreciate bleeding risk, thus ongoing HTC engagement is essential.
Fig. 1 Kaplan–Meier analysis: age at first bleed in a cohort of 304 individuals from the
DYNAMO study (234 with mild and 70 with moderate hemophilia).[10 ] Analysis was conducted according to hemophilia severity (A ) and categories within mild hemophilia (B ). The lines represent cumulative incidences, the shaded area (A ) shows 95% confidence intervals, and crosses represent right-censored patients (who
had not experienced the event at the end of follow-up). (Reproduced fromKloosterman
et al[10 ] with permission from The American Society of Hematology.) Variation in age at first
bleed shows bleed heterogeneity in patients with nonsevere hemophilia.
Scoring systems have been proposed to help estimate bleed risk in patients with bleeding
disorders.[11 ]
[12 ]
[13 ] Tools have been applied to conditions such as von Willebrand disease and platelet
function defects and, although not completely validated for NSH, may still be helpful
here. Given evolving bleeding phenotype with age,[14 ] studies of PWNSH have largely used the International Society on Thrombosis and Haemostasis
(ISTH) Bleeding Assessment Tool (BAT), with analyses adjusted accordingly.[14 ]
[15 ]
[16 ] The DYNAMO study found higher ISTH BAT bleeding scores (BS) in those with moderate
than mild hemophilia (median 10 vs. 7).[15 ] Another study of 111 PWNSH (mild, n = 86; moderate, n = 25) provided similar results, with the difference driven largely by joint and muscle
bleeds in moderate hemophilia.[16 ] Interestingly, postprocedural (dental/surgical) bleeding and mucocutaneous BS did
not differ between mild and moderate disease.[16 ] In contrast to common belief, no significant differences in BS have been observed
between those with hemophilia A or B.[14 ]
[15 ]
[16 ] In men with hemophilia, lower FVIII/FIX levels are associated with increased numbers
of bleeding episodes.[15 ]
[16 ] However, for female carriers of the condition, factor levels only weakly correlate
with BS and abnormal BS have been recorded in the absence of factor deficiency.[17 ] This has prompted a change in classification for affected females (see below).
Bleeding Complications in People with Nonsevere Hemophilia
Intracranial Hemorrhage
PWNSH have an increased risk of dying from intracranial hemorrhage (ICH). In one study,
ICH accounted for 11% of deaths among PWNSH not infected by HIV (64/560 deaths in
2,796 patients) between 1977 and 1999.[18 ] This resulted in a standardized mortality ratio (observed deaths/expected deaths)
of 9.29 compared with the general population, with no difference between hemophilia
A and B.[18 ] In subsequently reported results from the INSIGHT study involving PWNSH A, around
12% of deaths (17/148 deaths in 2,709 individuals) were attributable to ICH (both
spontaneous [n = 13] and traumatic [n = 4]) and the all-age ICH mortality rate between 1996 and 2010 was 3.5 times higher
than for the general population (95% confidence interval 2.0–5.8).[19 ] Data from the EMO.REC retrospective–prospective registry of patients with hemophilia
showed 45% of adults with ICH (14/31) to have mild hemophilia.[20 ] Such data illustrate the importance of specialized care and long-term holistic follow-up
for PWNSH.
Joint Bleeds
In individuals with severe hemophilia, as joint bleeds and hemophilic arthropathy
are major clinical issues, preventing joint disease is a primary focus of the treatment.[21 ] Recent decades have generated robust evidence for the efficacy of prophylaxis in
preventing or ameliorating joint disease in severe hemophilia.[21 ] However, the burden of arthropathy in PWNSH is currently not well-known, as individuals
with NSH have been less extensively studied. Clinical trials have largely focused
on severe disease. There is less consensus on optimal management of NSH, particularly
with respect to prophylaxis.[22 ] PWNSH can have joints with a reduced range of motion, pain, impairment of activities
of daily living, and reduced quality of life.[23 ]
[24 ] Some PWNSH A may have a severe bleeding phenotype[25 ] and a degree of articular damage comparable with that in severe disease.[26 ]
Other data for PWNSH are also informative. In a cohort of 104 PWNSH (hemophilia A)
the median (interquartile range [IQR]) annualized bleeding rate (ABR) and annualized
joint bleeding rate (AJBR) were 1.1 (0.5–2.6) and 0.3 (0.1–0.7), respectively, with
median (IQR) ABRs for those with moderate and mild disease of 1.6 (0.6–3.5) and 0.8
(0.3–2.5), respectively.[27 ] Despite a low frequency of bleeding episodes, in a subsequently published evaluation
of 51 adults with NSH (hemophilia A), magnetic resonance imaging showed 19, 71, and
71% of patients to have soft tissue changes (International Prophylaxis Study Group
[IPSG] subscore >0) in their elbows, knees, and ankles, respectively, with corresponding
osteochondral changes (IPSG subscore >0) in 0, 20, and 35% of patients.[28 ] Hemosiderin deposition in 14% of bleed-free joints suggested bleeds occurred unnoticed.
Factors most strongly associated with the IPSG score included age and AJBR.[28 ]
In the MoHEM study involving 104 patients with moderate hemophilia (A or B), pain
and problems with mobility were reported by 49 and 30%, respectively; hemophilic arthropathy
negatively impacted physical activity and quality of life.[29 ] In another recent study, evaluation of a cohort of 85 patients with mild hemophilia
(A or B), showed 36.5% to have arthropathy (assessed via the Hemophilia Joint Health
Score and Hemophilia Early Arthropathy Detection with Ultrasound), with the risk of
developing arthropathy declining by 7.7% with every 1 U/dL increase in clotting factor.[30 ] In addition, recent evidence has shown that up to 19% of carriers may be affected
by hemarthroses, and the possibility of carriers experiencing subclinical joint bleeds
has been proposed.[3 ]
As current assessment tools for joint health were primarily designed for use in patients
with severe disease, it is unclear whether they are sensitive enough for surveillance
and assessment of joint disease in PWNSH. A recently published critical review of
outcome measures for use in the assessment of musculoskeletal health in patients with
hemophilia highlights the importance of identifying a “core” set of outcome measures
for clinical use[31 ]; these should be applicable to all people with hemophilia.
Other Bleeds
Failure to identify individuals with NSH puts patients at risk of serious hemorrhage
through interventions such as surgery, or after trauma, where the need for hemostatic
support is not recognized.
As life expectancy of all individuals with hemophilia increases,[32 ] age-related morbidity is more frequently encountered, with possible subsequent complications.[6 ] These include concomitant cardiovascular disease potentially requiring antiplatelet/anticoagulation
therapies, development of degenerative joint disease, hypertension as a risk factor
for ICH, increased need for surgery due to oncological disease (or other age-related
morbidity), and fall-related injuries. Such issues necessitate thoughtful management
of the hemostatic balance. Patient-centered multidisciplinary approaches are required
to support healthy aging; these should employ both risk assessment and collaborative
decision-making.
Diagnostic Methodology
In the diagnosis and classification of hemophilia, the ISTH FVIII and FIX Subcommittee
currently recommends preferential use of factor levels over bleeding symptoms.[33 ] Different assays used to measure factor levels can yield different results, as comprehensively
reviewed elsewhere.[34 ] Assay discrepancies are particularly relevant in relation to NSH,[35 ] potentially affecting disease classification.[2 ]
[36 ] Differences between one- and two-stage methodologies have been reported in around
30% of patients with mild hemophilia A.[35 ] Two-stage or chromogenic assays may yield lower results than one-stage assays, although
the reverse pattern may be found.[34 ] For both patterns of assay discrepancy, specific mutations in the FVIII gene are
usually present.[34 ]
[35 ] Although recent data suggest that assay discrepancies may largely be a consequence
of laboratory variables,[37 ] both one-stage and chromogenic assays are recommended for diagnosing mild hemophilia
A.[38 ] Fewer data are available for hemophilia B, but in some patients with mild bleeding
phenotypes, two-fold or greater differences have been reported, with higher results
predominantly found on chromogenic testing.[39 ] Again, such data support recommendations for using both types of assays to ensure
correct diagnosis and classification.[40 ]
While definitive diagnosis of hemophilia is based on factor assays, genotype analysis
may also yield important information in relation to diagnosis and management, helping
to inform treatment and monitoring of individuals who require replacement therapy
as well as assessing the risk of inhibitor development.[2 ]
Management of People with Nonsevere Hemophilia
On-Demand Treatment and Home Therapy
While regular prophylaxis may not be indicated for all PWNSH, targeted prophylaxis
and on-demand treatment invariably are. Desmopressin (1-deamino-8-D-arginine vasopressin
[DDAVP]) can produce a clinically important rise in FVIII in PWNSH and may be underused.[41 ] In those individuals who do not have a contraindication, a trial of DDAVP to assess
responsiveness provides useful information for patient management. Nevertheless, most
patients require factor concentrate under certain circumstances, for example, major
trauma, surgery, head injury. A central tenet of hemophilia treatment, rapid arrest
of bleeding through timely administration of factor concentrate or DDAVP, is best
achieved with home treatment. However, as attaining competency and confidence in administering
intravenous injection may be difficult with infrequent use, PWNSH may lack access
to home treatment with factor concentrate. The feasibility and patient acceptability
of training on intravenous self-injection is debatable in this setting, particularly
when treatment is sporadic. Providing a stock of factor concentrate is also an issue
and risks wastage. For all patients, maintaining good-quality education/training to
recognize bleeds requiring urgent treatment and ready access to urgent advice is essential
to ensure timely care. Advances in information technology, social media, websites,
and eHealth may offer real opportunities, particularly when patients are located far
from HTCs.
What is the Role of Prophylaxis in People with Nonsevere Hemophilia?
Prophylaxis, the standard of care for patients with severe hemophilia,[2 ] historically aimed to maintain factor levels ≥1 IU/dL, thereby converting the bleeding
phenotype to that of moderate/mild hemophilia.[42 ] In this patient group, tailored prophylaxis, taking into account factors such as
age, lifestyle, and clinical phenotype,[43 ] has subsequently been shown to be more effective, and the advent of treatment schedules
with reduced burden of prophylaxis can improve adherence.[44 ]
PWNSH generally have a less severe bleed phenotype, with more heterogenous bleeding
episodes, than those with severe hemophilia; therefore, the role and intensity of
prophylaxis has to be addressed from a more specific and personalized perspective.
Data have emerged to suggest that a factor trough level of 1 IU/dL is insufficient
to prevent bleeds in individuals with severe hemophilia, particularly those with higher
levels of activity.[45 ]
[46 ] Thus, by extrapolation, many individuals with moderate hemophilia may also benefit
from regular prophylaxis.[4 ] There is also emerging evidence that prophylactic therapy in patients with severe
hemophilia may result in better musculoskeletal outcomes compared with some patients
with moderate disease receiving episodic treatment.[22 ] Recent reevaluation of patients with nonsevere disease for whom prophylaxis may
provide benefit includes children with moderate hemophilia, particularly if baseline
factor levels are between 1 and 3 IU/dL, with recommendations for primary prophylaxis
initiated immediately after a first joint bleed or before 24 months of age, and all
other patients who have joint or any other clinically significant bleeding.[22 ]
[47 ] Evidence and knowledge gaps relating to use of factor prophylaxis in PWNSH have
been the subject of recent discussion, with some clinicians describing a “strong rationale”
for early prophylaxis in individuals experiencing frequent severe bleeds.[48 ] It is also appropriate to note that while recommendations for prophylaxis extend
to those with a severe bleeding phenotype,[2 ] without formal definition of the term, it is important to ensure this does not inadvertently
create a barrier to prophylaxis. It may, for instance, be needed to cover higher risk
of bleeding, such as periods of anticoagulation/antiplatelet therapy in patients with
mild hemophilia.
It is not clear to what extent the burden of intravenous injections may constitute
a barrier to commencing prophylaxis in those with NSH. In severe hemophilia the benefit:burden
ratio is well-accepted in favor of treatment, but this ratio may not be perceived
as advantageous for NSH by patients and HCPs. However, the advent of treatments that
may substantially reduce the treatment burden, extended half-life products (particularly
factor concentrates facilitating weekly intravenous administration or even longer
dosing intervals), as well as other therapeutic agents, warrant reevaluation of therapeutic
options for individuals with NSH. Nevertheless, for nonfactor therapy, although the
HAVEN 6 study investigated prophylaxis with emicizumab in PWNSH,[49 ] experience in such individuals is limited, and such agents may not be available
for PWNSH who do not have a “severe” phenotype.[50 ] For example, in the European Union (EU), emicizumab is the only available nonfactor
therapy for hemophilia, with licensed prophylaxis restricted to patients with hemophilia
A who have inhibitors, severe hemophilia, or moderate hemophilia with a severe bleeding
phenotype.[51 ]
How to Optimally Manage Surgery in People with Nonsevere Hemophilia
Surgery represents a significant challenge for all individuals with hemophilia. For
those with severe disease, perioperative bleeding risk is well-recognized and understood
by patients, families, and treaters, with the close and longstanding relationship
between patients and HTCs ensuring appropriate treatment and monitoring by expert
hemophilia teams. For PWNSH, particularly those who rarely bleed or require treatment,
there may be a lack of understanding, by patients and surgical teams, of the surgical
risk. Such patients may not attend HTCs on a regular basis and even be lost to follow-up,
possibly through false perceptions that regular engagement is unnecessary. This creates
a dangerous situation whereby PWNSH may fail to receive appropriate hemostatic cover
for procedures, with consequent risk of life-threatening bleeding. It supports needs
for comprehensive registers of those with hemophilia of all severities, patient-held
information about their bleeding disorders, and keeping primary care teams fully informed,
highlighting the importance of being proactive in maintaining regular contact and
assessment for all patients—patient engagement with HTCs should be addressed.[52 ]
An interesting challenge for surgery in PWNSH is the relative paucity of data about
endogenous levels of FVIII and FIX required to support hemostasis over the range of
procedures, from minor (e.g., many dental surgeries) to more major. “Milder” patients
with hemophilia A may experience an acute-phase response in the postsurgical setting.
FVIII is protected from premature clearance by von Willebrand factor (VWF), and levels
of VWF antigen show transient postoperative increases in hemophilia A patients, particularly
for individuals with non-O blood type.[53 ] Given possible thrombotic complications,[54 ] careful monitoring of FVIII levels will help prevent excessive dosing.
Almost all patients with severe hemophilia have been trained to self-administer factor
concentrates and postsurgery prophylaxis does not constitute a major issue. For PWNSH,
this can be a major barrier to delivering care at home. Paradoxically, therefore,
planning and delivery of surgical care for PWNSH may be more problematic than for
those with severe hemophilia. Although extended half-life concentrates may reduce
administration frequency, enhanced community care arrangements, training, and support
of patients/families should be considered in any preoperative plan.
For many individuals with NSH A, surgery may be the only time they require intensive
treatment with factor concentrate—a setting in which they may be at risk of developing
inhibitors against FVIII.
Inhibitors
The cumulative incidence of inhibitors in PWNSH is lower than in severe hemophilia
A, approximately 5 to 10 versus 30% in the overall hemophilia A population.[2 ] Inhibitors occur less often in hemophilia B, with a published incidence of between
1.5 and 3% for patients of all severities.[55 ] Mild hemophilia B appears to confer very low inhibitor risk.[56 ]
Evidence relating to inhibitors has largely been obtained from patients with severe
hemophilia A, in whom the majority of inhibitors develop during the first 50 exposure
days, after which the risk of inhibitor development decreases to <1%.[57 ] In contrast, for patients with nonsevere disease, inhibitor risk has been calculated
as 6.7% and 13.3% at 50 and 100 exposure days, respectively.[57 ] There is a lifelong possibility of inhibitor occurrence,[58 ]
[59 ] with a bimodal age distribution of inhibitor formation that is influenced by intensive
treatment and surgery as patients get older. This creates a need for ongoing inhibitor
surveillance in PWNSH, particularly following intensive periprocedural factor exposure,
and education to ensure patients remain aware of the need for, and risks of, hemostatic
support for procedures later in life. Detailed documentation of treatment history
for PWNSH will improve patient management.[6 ]
Data from the INSIGHT study have shown that the bleeding rate in PWNSH can increase
by around 10-fold if inhibitors develop,[60 ] with a 5-fold increase in mortality rate also observed.[58 ] Subsequently published results from the American Thrombosis and Hemostasis Network
(ATHN) dataset did not corroborate this, but differences between the evaluated populations
may have influenced the results.[61 ]
Potential differences in the immunologic mechanisms underlying inhibitor development
in severe and NSH A may help explain possible differences in response to different
factor replacement products.[62 ] Conflicting data from patients with severe hemophilia A suggested a difference in
risk of inhibitor development with different therapeutic concentrates, but case–control
data from the INSIGHT study (75 patients with inhibitors and 223 controls) have shown
no increased risk of inhibitors in patients with nonsevere disease for any type of
FVIII product.[63 ]
For PWNSH affected by inhibitors, the approach to immune tolerance induction is advocated
on a case-by-case basis[64 ] and the importance of close follow-up has been stressed.[58 ] Inhibitors may disappear spontaneously or after therapy intended to result in eradication,
including immune tolerance and immunosuppression, but anamnestic responses can occur
when rechallenged.[64 ] While traditional options for treating bleeds in inhibitor patients include recombinant
activated VII, activated prothrombin complex concentrate, tranexamic acid, and, for
hemophilia A only, DDAVP,[6 ] emicizumab is now also available for prophylaxis in patients with hemophilia A with
inhibitors.[51 ] In an evolving treatment landscape with a lack of consensus for management, reassessment
of unmet needs will help determine optimal strategies.[65 ]
Women and Girls with Hemophilia
As an X-linked recessive disorder, severe and moderate disease is rare in females,
but, in U.S. HTCs, women and girls comprise 16% of those with mild hemophilia A and
almost one-quarter of patients with mild hemophilia B.[66 ] Although females carrying a hemophilia-associated mutation have traditionally been
termed “carriers,” this terminology has been subject to debate,[66 ] and may impede adequate access to health care services. Consequently, a recent communication
from the Scientific and Standardization Committee of the ISTH defines new nomenclature[67 ]: females with factor levels ≥40 IU/dL should be termed “asymptomatic/symptomatic
carriers,” according to their bleeding phenotype, and those with factor levels <40 IU/dL
should be referred to as “women/girls with mild/moderate/severe hemophilia,” in-line
with the traditional classification applied to males. In women/girls with hemophilia,
extremely variable bleeding tendency can result not only from variations in the F8 or F9 genes, but also as a consequence of structural anomalies in the X chromosome and
irregular X-chromosome inactivation.[68 ] Although lyonization affects FVIII/FIX levels, heterogeneous bleeding may also be
apparent in individuals with similar factor levels. A recent study of the ATHN dataset,
which includes the world's largest “carrier” dataset (2,418 individuals), reported
BS from 922 “carriers.”[69 ] BS were normal in 59.4% of “carriers” with factor levels <40 IU/dL and abnormal
in 23.5% of those with factor levels greater than this.[69 ]
While women with hemophilia face many of the same bleeding issues as men, they can
also experience additional challenges from menstruation, pregnancy, and childbirth.[70 ]
[71 ] For heavy menstrual bleeding, tranexamic acid can decrease blood loss; desmopressin
can also be used in those with hemophilia A who are responsive.[72 ] Such therapy can thus provide targeted prophylaxis.
Hemophilia-specific care relating to pregnancy and childbirth should include prenatal
counseling and thorough pedigree analysis; the potential need for hemostatic cover
for fertility and gynecologic treatment; preimplantation genetic diagnosis (where
applicable); antenatal monitoring; provision of multidisciplinary advice for mother
and child pertaining to delivery and the postpartum period; minimizing risk of delayed
postpartum hemorrhage postdischarge; appropriate follow-up for potentially impacted
offspring. This is beyond the scope of the current article but considered in other
publications.[6 ]
[73 ]
[74 ]
[75 ] It is appropriate, however, to highlight that contact with HCPs during pregnancy
provides opportunities to reassess bleeding phenotype in individuals who may have
disengaged from health care services. When interpreting factor levels measured during
pregnancy it is important to be aware of the physiological rise in FVIII that occurs
during pregnancy and that FVIII drops quite dramatically postpartum with ensuing risk
of bleeding complications.[2 ] There is a need for standardized plans for follow-up of females with hemophilia,
to help facilitate early prenatal and antenatal care.
Drug Development and Research
Current research, and drug development, is largely focused on severe disease. As therapies
and targets for people with severe hemophilia evolve, so too must treatment for those
with nonsevere disease, to avoid disparity in care.[50 ] For patients with severe disease, therapeutic advances may confer a better phenotype
than for a subgroup of PWNSH. There has been, and is, a lack of recruitment of PWNSH
into clinical trials. For example, in November 2023, searching ClinicalTrials.gov
with the term “mild hemophilia” identified approximately 10 studies, whereas over
250 were retrieved with the term “severe hemophilia.” As severe hemophilia is very
rare in women, they are rarely represented or included in clinical studies. This may
create potential issues arising from extrapolating data derived from men to inform
treatment of women; thus, current approaches neglect potential sex-specific pharmacological
differences.
A further consideration is that if products have been licensed but PWNSH are not included
in study groups, limitations in licensing/or reimbursement approval are likely to
be encountered.
Encouragingly, both the EU[76 ] and United Kingdom,[77 ] have initiatives specifically targeted at individuals with rare diseases, defined
by a threshold of affecting 1 person in 2,000. Hemophilia affects fewer individuals
than this (around 1 in 10,000[78 ]—hemophilia A and B comprise ∼80 and 20% of cases, respectively[2 ]), with the majority of individuals in such regions diagnosed with nonsevere disease.[79 ] Consequently, such initiatives may encourage the inclusion of PWNSH in research
and new treatment options. They may further promote the consideration of specific
issues in this population and generate appropriate tools for assessment and outcome
measures.
