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Health issues in women and girls affected by haemophilia with a focus on nomenclature, heavy menstrual bleeding, and musculoskeletal issues

Abstract Introduction Women and girls affected by haemophilia, including haemophilia carriers (WGH) are at risk of bleeding symptoms that may go unrecognized, including heavy menstrual bleeding (HMB) and musculoskeletal bleeding. Terminology continues to evolve. Aim To describe the current recommendations for nomenclature surrounding WGH, and the current understanding of HMB, iron deficiency, and musculoskeletal complaints in these patients. Methods Literature was reviewed and summarized. Results With regards to nomenclature, women with factor levels less than 50% should be classified as having haemophilia, while carriers with normal levels should be characterized accordingly to symptomatology. HMB and resultant iron deficiency are common among WGH, have a multitude of downstream effects, and maybe overlooked due to stigma around menstruation. Musculoskeletal bleeding and resultant joint changes are increasingly recognized in this population but do not necessarily correlate with factor levels. Conclusion Although progress has been made in the care of WGH, much work remains to further improve their care.

F I G U R E 1 Revised nomenclature for haemophilia carriers. The original proposal did not allow for inclusion of transgender persons, used a factor threshold of 40% rather than 50% and did not provide context on bleeding tendency disorders (IBD). Menstruation is stigmatized within society and patients, as well as providers, may not know what a normal menstrual cycle is, or maybe hesitant to discuss this topic. 33 Appropriate identification and management are necessary as HMB and IDA are both associated with decreased quality of life.
In addition to menstrual bleeding, WGH are also at risk for musculoskeletal symptoms once thought to only affect their male counterparts. Although this type of bleeding is increasingly described, it is complicated by the lack of correlation between bleeding and factor levels, uncertainty of a mitigation plan and further study is warranted. INTRODUCTION

Nomenclature for women with haemophilia and haemophilia carriers
The precept that haemophilia only affects males and leads to an unaffected pathological state in women and girls has led to decades of marginalization in haemophilia carriers. Some of the first descriptions of excessive bleeding in haemophilia carriers were reported in 1951 by Merskey and Macfarlane followed by mostly limited case series up until the 1980s. 1 When a haemophilia carrier does present with bleeding, typically alternative diagnoses are sought out-delaying acknowledgement of the diagnosis. 2,3 The bleeding tendency of WGH has been well described over the last 20 years, yet the community still feels marginalized and not heard. 4 In response, programs and community efforts like Peer/Advocacy groups from HFA sisterhood, WFH publications "Symptomatic Carriers of Hemophilia" and "Carriers and Women with The prevalence of haemophilia carriers is not fully known but it is estimated that for each male with haemophilia there are approximately three to five possible carriers and 1.5 definite carriers per affected male. 2 Nearly 1/3 of haemophilia carriers or heterozygotes will have a level in the haemophilia (FVIII and FIX <50%) range 5 while nearly one in five persons with mild haemophilia is a female. 6 Since the majority of haemophilia carriers with a factor deficiency have mild haemophilia, there should be a concerted effort to characterize this group with observational and interventional prospective studies. The majority of sponsored haemophilia trials conducted are in males with moderate to severe disease, mostly focused on demonstrating hemostatic efficacy to achieve regulatory drug approval. In these studies on males with moderate or severe disease, rarely are females allowed participation.
Some of this exclusion is due to lack of drug toxicity data in neonates or in pregnant women (or of reproductive age) thus double barrier birth control protection is required or females are just excluded altogether. We certainly can do better and should advocate for more studies focused on the non-severe deficiency state as many future hemostatic therapies may continue to be out of reach of many non-severe patients.
Recently we proposed a novel nomenclature for haemophilia carriers in an effort to facilitate communication amongst providers, patients and community members fostering respect and improving shareddecision making. 7 We sought to acknowledge the patient journey of these women and girls as well as reported bleeding tendency. The collaborative project of the Scientific and Standardization Committee of ISTH proposal was initially constructed to start this conversation and we desired to create a living document 7 To that end, our research group felt the need to provide some clarification and modifications shortly following publication. Firstly, we wanted to be inclusive of the complexity of haemophilia carrier genetics and transgender persons.
Secondly, stratification of the haemophilia carrier remained based on baseline factor level. This divides haemophilia carriers into those with levels in the haemophilia severity range and those with levels above that range (FVIII/FIX ≥ 50%). Bleeding phenotype does not factor into categorization if factor levels are reduced, mirroring the construct used in males with haemophilia. We did adjust the diagnostic threshold to be more in line with the CDC guidelines on haemophilia with the upper limit of mild deficiency diagnosis being a FVIII or FIX of 50% rather than 40%. This is based on the increased bleeding tendency of haemophilia carriers being demonstrated in those with levels above 40%. 8 This creates three new categories that are in line with males with hemophilia, severe haemophilia (FVIII/FIX <1%), moderate haemophilia (FVIII/FIX 1%-5%) and mild haemophilia (FVIII/FIX >5 and <50%). Thirdly, we adjusted the term from women and girls with mild, moderate or severe haemophilia replacing simply with haemophilia as aforementioned. We feel that using the same nomenclature regardless of gender will allow women equal access to resources. Fourthly, we sought to clarify the difference between asymptomatic and symptomatic haemophilia carrier when the baseline factor level is 50% or higher (the normal range).
Although, multiple groups have demonstrated the increased bleeding tendency of haemophilia carriers, particularly those with normal levels, a significant portion have little to no significant bleeding. Therefore, we propose a symptomatic haemophilia carrier as having an abnormal bleeding score of ≥6 in teenage or adult females and ≥3 in young girls using either the ISTH BAT or ISTH SELF-BAT. 9

Genetics of haemophilia carriers
Our improved understanding of the complex genetics of haemophilia should supplement our usage of the most recent proposed nomenclature (See Figure 1). 7  inactivation (XCI) is a process in which inactivation occurs in one of the two X-chromosomes in females, allowing a single functional X chromosome matching the state in males. 11 This process occurs early in life in the embryonic stage and is theorized to be unbiased and random. The "silenced chromosome" is packaged in an inactive structure called heterochromatin. This leads to an XCI ratio of 50:50 in normal females. 12 When it is skewed to the affected allele, particularly an 80:20 ratio or HMB can be the earliest sign of a bleeding disorder. One in five adults and one in three adolescents with HMB are found to have an underlying bleeding disorder. 28,29 Conversely, HMB is the most common symptom in women with IBD, and occurs in 64% of haemophilia carriers. 18 When looking at all IBDs, about 50% of menstruating individuals present with HMB at menarche. 30 Others may present with HMB once their cycles become ovulatory. Overall, up to 90% of women with IBDs will experience HMB. 31 Menstrual bleeding patterns in women and girls with IBDs may also vary compared to the general population with longer menstrual duration, increased frequency of flooding, and heavy bleeding throughout menstruation. 32 Women and girls with IBD may also experience bleeding with ovulation which can lead to hemorrhagic ovarian cysts as well as hemoperitoneum.
It is important to obtain a detailed menstrual history in all menstruating patients. Given the stigma around menstruation, patients may not volunteer their symptoms or recognize them as abnormal. 33 Specific details that signal the need for further evaluation include: bleeding longer than seven days, menstrual flow that requires double protection, soaking more than five sanitary product per day, flow that requires sanitary product change overnight, passing clots greater than an inch in diameter, the sensation of gushing, personal history of anaemia, personal history of excessing bleeding or bruising, and family history of a bleeding disorder. 34 2, only to be tested in select patients. 37 As mentioned above, both one-stage and chromogenic FVIII levels should be measured when Haemophilia A is suspected. Testing for a coagulopathy in the setting of HMB can be complicated by elevations of VWF in the setting of HMB, as well as delayed platelet aggregation in the setting of anaemia (haemoglobin <10 g/dl). 38,39 As such, repeat testing may be needed outside of the acute setting.

Iron deficiency and iron deficiency anaemia
Iron deficiency is the most common cause of anaemia, accounting for more than 60% of cases and is of particular concern in girls and women of reproductive age, 40 49 COCs can be prescribed cyclically or continuously and those with shorter hormone free intervals are associated with less withdrawal bleeding. 50 The levonorgestrel intrauterine system has been found to be safe and efficacious in patients with IBD although there are concerns about higher rates of expulsion. 51,52 Antifibrinolytic therapy following placement may help avoid this problem. 53 Nonhormonal treatments include antifibrinolytics, desmopressin, and factor replacement. Tranexamic acid (TXA) is the most studied antifibrinolytic for HMB and has been shown to decrease MBL by 26%-54%. 49 Tranexamic acid is particularly helpful in those wishing to conceive and those with heavy bleeding with normal duration. A retrospective study by Chaudhury et al found that antifibrinolytics were the most utilized treatment (used in 50%) for HMB in WGH, followed by desmopressin and factor concentrates (used in 29% and 14%, respectively). 54 Non-steroidal anti-inflammatory drugs (NSAIDs) are used for HMB in the general population but are not recommended in patients with IBD given their antiplatelet effects. Desmopressin can be used in patients with VWD or Haemophilia A who have been shown to be responsive. The most recent international guidelines on management of VWD suggest the use of hormonal therapies or TXA over the use of desmopressin. 53 This recommendation was based on expert opinion, a randomized clinical trial that found a greater decrease in MBL with the use of TXA over desmopressin, and an observational study comparing desmopressin and hormonal therapy. 55,56 Similar guidelines for management of HMB in WGH do not currently exist. Factor replacement can also be used for the management of HMB and has been shown to be effective in patients with a range of factor deficiencies. 54,57-61

Bleeding and musculoskeletal issues among WGH
Contrary to historical belief, non-vaginal bleeding symptoms in WGH appear to be similar to those experienced by males with haemophilia. 62 In fact, musculoskeletal bleeding is increasingly described amongst WGH. 21,63,64 Our understanding of type, severity, impact and mechanism (in those with normal factor levels) of bleeding experienced by these women is in evolution, and we will likely play knowledge acquisition catch-up for years to come as many women remain undiagnosed in the absence of a family history in males. [65][66][67][68] It is becoming increasingly clear that severity of haemophilia carrier bleeding poorly correlates with factor activity levels. 16 18 Moreover, others have published that bleeding appears to impact carrier health-related quality of life (HR-QoL). 63,74 The impact of bleeding in carriers and lack of correlation with plasma factor activity levels was further highlighted by haemophilia A carriers with normal levels of factor VIII:C (median: .79 IU/ml) having significantly poorer scores in "Pain" and "General Health" categories in the Rand 26-Health Survey 1.0, 63 and significantly lower scores in the mental health, general health and social functioning domains compared to normal controls. 74 Disparity between factor levels and impact on health among carriers, while confusing for health care providers, must be acknowledged-as independent investigators have come to the same conclusions time and time again. Thus, comprehensive and meaningful care for WGH requires a leap of faith away from dogma rooted in the coagulation lab test results.
While it is clear that bleeding is driving the impact on HR-QoL, until recently this connection was thought to be mainly due to secondary IDA. However, Gilbert et al. noted that women with haemophilia A/carriers also experience subclinical joint bleeding leading to structural joint damage akin to affected men. 64 This was demonstrated by soft tissue and osteochondral changes on joint magnetic resonance imaging (MRI). 64 Also, women with factor VIII deficiency also seem to have reduced joint range of motion even in those with factor activity levels above 40%. 64 All of this data suggests that women with haemophilia experience musculoskeletal bleeding and sequelae related to this, including diminished bone density and structural bone health.
In male haemophilia patients, many studies have identified a high prevalence of low bone mineral density (BMD) and increased risk for osteoporosis. [75][76][77][78] The pathophysiology of low BMD in haemophilia has yet to be elucidated. It may be possible that factor VIII itself is responsible for the maintenance of bone integrity. 79 However, the underlying mechanism is likely multifactorial as recurrent musculoskeletal bleeding leads to chronic inflammation, structural changes and secondary functional impairments. 75,78

CONCLUSION
It is clear that implementation of the recently proposed nomenclature for haemophilia carriers will be useful in facilitating communication amongst providers, patients and community members fostering respect and improving shared-decision making. Acknowledging the patient journey of these patients is crucial as well as accepting the reported bleeding tendency. The proposal is simply a start of the conversation and we hope it is a living document.
A nomenclature system can help assist the provider and patients in diagnosis but certainly it will take a change of provider attitudes to improve the relationship between the same providers and carriers.
Moving forward we should demand carrier inclusion in more industry sponsored drug studies and developing studies focused on the nonsevere state.
Appropriate identification and management of HMB, as well as the iron deficiency associated with it, is crucial to the care of WGH.
Education around normal menses and normalization of discussion of this topic may help identify issues earlier and improve quality of life.
The health-related consequences of haemophilia have been extensively studied in men and we are beginning to evaluate the multifaceted impact of haemophilia-related bleeding among women as well.
Additional observational data is needed to evaluate for objective evidence of musculoskeletal bleeding as it seems that the culture shift towards improving the care of carriers is slow to turn. An example of an important knowledge gap is whether carriers are at increased risk of diminished bone density. This is important because osteoporosis is associated with future risk of fracture and premature mortality.
We are currently conducting a prospective Canadian cohort study to compare bone mineral density in adult perimenopausal symptomatic haemophilia A carriers with age and body mass index-matched controls via dual-energy X-ray absorptiometry. Our hypothesis is that carriers will have lower bone mass relative to control women of similar age and if we are right, the connection between carriership and impaired musculoskeletal health will be indisputably confirmed which should help change the paradigm of clinical care offered to these women.
Although considerable advances have been made in the care of women and girls with bleeding disorders, much work is left to be done.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.