Nonsevere Hemophilia: The Need for a Renewed Focus and Improved Outcomes

Abstract

People with nonsevere hemophilia (PWNSH) are phenotypically more diverse than those with severe hemophilia. Perceptions relating to a “nonsevere” phenotype have contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance and clinical assessment for affected individuals. In many cases, episodes of abnormal bleeding could, if investigated, have led to earlier diagnosis. Furthermore, the major recent developments in therapy for hemophilia have largely focused on severe disease and, as a group, PWNSH have not been included in many key clinical trials. Benefiting people with severe disease, innovative replacement therapies have generally targeted factor levels that are above those present in a large proportion of PWNSH. Therapeutic advances can lead to improvement in phenotype for people with severe hemophilia over that currently experienced by many PWNSH. As a result, we are approaching a point where PWNSH may, in many countries, have a higher risk of bleeding and restriction in lifestyle than those with severe disease but with more limited therapeutic options. Given the multiple major advances in treatment for people with hemophilia, it is timely to review the aspects of nonsevere disease, to ensure equity in care and management for all individuals with this condition.

Keywords

disease management - factor VIII - factor IX - hemophilia A - hemophilia B

Recent developments with novel therapeutics have considerably advanced hemophilia management[1]; however, progress has largely focused on severe disease. The standard of care for people with nonsevere hemophilia (PWNSH) has not evolved to the same extent. PWNSH comprise a heterogenous group. Encompassing all patients with hemophilia A or B not categorized as “severe,” this involves individuals with factor levels ranging from 1 to 40 IU/dL and varying clinical phenotypes,[2] including women with factor VIII/factor IX (FVIII/FIX) gene mutations and a range of reduced factor levels.[3] Delays in recognizing, diagnosing, and treating individuals in this diverse group increases the risk of avoidable bleeding and resultant complications. With a lack of inclusion of PWNSH in research, clinical trials, and registries, there is an impoverished evidence base, creating uncertainty about appropriate tools for assessing and measuring outcomes in such patients. Consequently, management of nonsevere hemophilia (NSH) is less driven by evidence and guidelines than severe hemophilia.[4] Addressing knowledge gaps will help to improve management and generate good-quality standards for care. Reflecting current knowledge/research and the authors' experience of managing PWNSH, this paper reviews the current clinical landscape and priority areas for future research.

Methods

This narrative review did not lend itself to a systematic literature search. The authors' experience is complemented with reference to published evidence, including articles identified through targeted searches of recent literature. This approach is intended to balance experience- and evidence-based concepts in a current clinical context.

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.

Conclusion

As PWNSH comprise a heterogeneous population with many challenges, to best address these, a range of points should be considered, engaging not only HCPs, but also patients themselves. It is important to raise awareness of diagnosis, including for girls/women. Patients and their families should be empowered to achieve timely diagnosis, informed by suitably selected assays, with genetic analysis providing additional information. Through engagement with health care systems, including specialist centers, the impact of bleeding can be recognized and attempts made to mitigate this. Prophylaxis can benefit selected patients—the changing therapeutic landscape provides options to address barriers to this—and pharmacokinetic assessment can help tailor regimens to individual patient's needs, although we should not forget to make optimal use of existing therapies such as desmopressin. The risk of inhibitor development should be borne in mind, especially when periods of intensive factor replacement are required in PWNSH.

Outcomes for PWNSH will be further improved by obtaining additional evidence from research to address gaps in existing knowledge. This includes tools for assessment of joint health, optimal use of various therapeutic options, and the biology of inhibitors. As more information becomes available, recommendations for treatment guidance can be updated. This will ensure the drive to improve hemophilia care encompasses all patients, including those with nonsevere disease.

Conflict of Interest

G.D. has received medical writing support for this manuscript from Sobi, consulting fees from Pfizer, BioMarin, CSL, Roche, and Sobi, and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Spark Therapeutics, CSL, Bayer, Takeda, Roche, Chugai, and Sobi.

K.F. has received medical writing support for this manuscript from Sobi, grants from Novo Nordisk, CSL Behring, and Sobi, consulting fees from Roche and Sanofi, support for meeting attendance from Sobi, and has participated in data safety monitoring boards/advisory boards for Sanofi and Roche.

P.J.L. has received medical writing support for this manuscript from Sobi, research grants to his institution from Pfizer, Roche, Sanofi, and Sobi, and participated in advisory board meetings for BioMarin, Sanofi, and Takeda.

C.C. has received medical writing support for this manuscript from Sobi, as well as payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events, and support for attending meetings and/or travel, from Sobi, Bayer, Roche, and Novo Nordisk. C.C. has also participated in data safety monitoring boards or advisory boards for Sobi, Bayer, Roche, and Novo Nordisk.

M.L. has received medical writing support for this manuscript from Sobi, research funding from Takeda, consulting fees from Sobi, CSL Behring, Band Therapeutics, and Takeda, payment/honoraria from Takeda, Sobi, and Pfizer, support for meeting attendance from Takeda, and has roles in the WFH, EAHAD, FIGO, and ISTH.

Acknowledgments

This article was written on behalf of the scientific project, Factor Think Tank, which is funded by Sobi. The current members of the Factor Think Tank group are listed at factorthinktank.com. The authors wish to thank Sophie Susen (Centre Hospitalier Universitaire de Lille, Lille, France), who provided feedback on an earlier version of this manuscript. Sobi and Sanofi received the manuscript for courtesy review; however, they did not influence the content. This article represents the views of the authors. Medical writing and editorial support, funded by Sobi, was provided by Andy Lockley, PhD, Bioscript Group, Macclesfield, United Kingdom. Support with manuscript submission, funded by Sobi, was provided by Liz Beatty, Bioscript Group, Macclesfield, United Kingdom.

Authors' Contributions

All the authors developed the initial concept for this manuscript. G.D. and M.L. drafted a version that all the other authors critically revised for intellectual content. All the authors reviewed and approved the final document.

^* All the members of the Factor Think Tank group are listed at factorthinktank.com.

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Publication History

Article published online:
11 May 2024