Hemophilia refers to a rare congenital bleeding disorder (1) mainly affecting men (2). It is characterized by a coagulation factor deficiency of factor VIII (FVIII; hemophilia A, HA) or factor IX (FIX; hemophilia B, HB) (1).

Normal factor (FVIII or FIX) activity ranges from 50 to 150% (3) Residual factor activity in a patient’s plasma is used to differentiate three severity degrees of hemophilia: mild with a relatively broad range of >5 to <40%, moderate with 1 to 5%, and severe with <1% of normal factor activity. Those with the normal factor activity ranging from 40 to 50% are not yet classified (4) Mild hemophilia with its wide range shows a varying phenotype. Some patients may present with a bleeding phenotype overlapping with severe hemophilia, possibly requiring prophylactic treatment (5), highlighting the importance of an individualized treatment strategy (1, 6).

Unlike severe hemophilia, mild phenotypes are often diagnosed later in life (5, 7), usually as a result of extended bleeding episodes provoked by injury or medical interventions; however, recurrent spontaneous bleeding episodes are rare in mild hemophilia. Recently, patient age was reported to correlate with arthropathy, a most relevant factor negatively affecting the quality of life (QoL) (7).

In mild HA, the development of FVIII neutralizing antibodies (inhibitors) is usually due to intensive exposure to factor concentrates (7, 8); the risk of inhibitor development may be associated with certain F8 mutations (8). While occurring less frequently in patients with mild or moderate HA compared to the severe form, these conditions pose a lifelong risk (8). Inhibitors can increase the severity of bleeding episodes (7) and may even shift a mild phenotype to a severe one (9), thereby complicating the treatment (10). FIX inhibitors are rare (1.5 to 3% of patients) and are almost exclusively found in patients with severe HB (1, 11), for whom an HB-specific formal clinical guidance may be lacking due the rarity of their condition (12). FIX inhibitor formation is unrelated to the type of FIX clotting factor concentrate (CFC) and is considered a most serious complication as anaphylaxis and nephrotic syndrome may occur (11).

Exact numbers of patients with (mild) hemophilia are unknown (1) due to various reasons (2, 7), and the number of undiagnosed patients is likely to far exceed (1) than those reported (2): in 2020, 4,518 patients with HA (mild type: 738 patients) and 860 patients with HB (mild type: 152 patients) were newly registered in the German Hemophilia Registry (13).

In patients with mild HA without medical contraindications, desmopressin is recommended for minor bleeding episodes, surgeries, and other invasive procedures (1). Desmopressin, a synthetic vasopressin analog, induces von Willebrand factor release from endothelial organelles and simultaneously increases FVIII levels by two- to six-fold (7, 14, 15). Factor replacement therapy may be required upon serious trauma or surgical procedures. Anti-fibrinolytic therapy with or without desmopressin can be used for the treatment of mucosal bleeding or invasive dental procedures. The use of desmopressin is cheaper than CFCs, avoids exposure to FVIII concentrates, and reduces the risk of inhibitor development (1, 16). It is ineffective in patients with HB (1, 7).

Patients with mild hemophilia or their families may initially lack awareness of the disease (9), leading to a delay in diagnosis (7). Suspicion may only be raised upon severe symptom development or complications, such as prolonged bleeding episodes after medical interventions, resulting from inadequate management. The literature on mild hemophilia including diagnosis and management is limited (7), and mild hemophilia may be underdiagnosed and undertreated compared to severe hemophilia (7, 17).

The current treatment of severe hemophilia aims to change its phenotype to that of moderate-to-mild hemophilia (1, 18) by prophylaxis (1). However, for patients with mild-to-moderate hemophilia, unmet needs (18), such as recommendations for physical activity (19), remain.

This survey aimed to investigate the care reality and QoL of patients with mild hemophilia, as daily problems and restraints may remain largely neglected (7).

This cross-sectional survey was conducted to collect information on the care reality and the QoL of patients aged ≥12 years in Germany, diagnosed with mild HA or HB. The main objectives of this study were to assess the patient satisfaction with the therapy and support provided by hemophilia centers, the impact of hemophilia on daily life, QoL [EQ-5D-5L questionnaire (20)], and medical treatments. The web-based survey collected anonymous data directly from patients in a single session using standardized electronic questionnaires filled out in the AMS-ePRO^® tool, a validated electronic patient-reported outcome system. Consequently, the captured data were encrypted.

Various medical specialists, hemophilia centers, patient organizations, and support groups across Germany distributed invitations. Distribution and individualized one-time QR codes on invitations were not tracked, thereby ensuring anonymity. To minimize the selection bias, invitations were handed out to all eligible patients. Patients accessed the survey using their own smartphones/tablets by scanning the QR code. Internet connection via a standard web browser was secured by hypertext transfer protocol secure, and the database server was hosted under controlled conditions in an off-site facility.

Easy-to-complete lay language questions focused on demographics, diagnosis, and main objectives discussed earlier. It is important to note that drug-related adverse events were not collected, and there were no free-text fields. However, respondents were able to skip questions, and while logged in, questions could be answered in any order and ticked answers could be amended. Data capture could end prematurely, and re-entry was not possible. Logic and plausibility checks were implemented to ensure data quality and to minimize data inconsistencies.

Based on the number of patients and demographics in Germany, 150–200 patients were expected to participate. The sample size was based on the estimated number of suitable patients and was not formally calculated, as this was an exploratory survey without formal hypothesis testing. Statistical analyses were conducted using SAS^® (v9.4 or later; SAS Institute Inc., Cary, NC, United States). The analysis set included all eligible patients who answered at least one question. All results were reported descriptively. Continuous variables were represented using mean, standard deviation, median, quartiles (Q1 and Q3), range (minimum/maximum), and the number of missing values. Categorical variables were represented as absolute and percentage frequencies of answers. All available data were included in the analyses and summarized as far as possible. Unless otherwise specified, missing data were not replaced. The survey started in September 2021 and ended in July 2022.

This survey aimed to shed light on the reality of care for patients with mild hemophilia, as daily problems and restrains may remain largely neglected (7).

The proportion of hemophilia types in our patient population examined (HA: 87.5% and HB: 12.5%; 40 answers) was in line with that of the population affected (HA: 80 to 85% and HB: 15 to 20%) (1). The median age at diagnosis reported here (6.0 years) was similar to other publications (2.4 to 6.5 years), (9, 10, 21, 22), and the median factor activity at diagnosis (14%) was also in line with other findings (15%) (21). One patient indicated FVIII levels within the lower limit of normal (4), and medical history suggested a possible coagulopathy. Due to limited data, we can only speculate if this was due to temporarily elevated FVIII activity, or artifacts in applied assays (1), reporting an error or a misunderstanding by the patient. The two latter reasons or false low values (1) may be causal for the factor levels below the limit of “mild” (4), which were detected by coincidence in another patient with FVIII deficiency. Both patients were included in the analysis as local laboratory standards on categorization levels for hemophilia slightly differ.

The main reasons for diagnosis in this survey, such as familial predisposition, bleeding episodes during/after a surgery or dental treatment, and increased hematoma frequency or intensity, were also reported by other publications (7, 21). The diagnosis of mild hemophilia is often delayed compared to that of more severe phenotypes (7, 9, 18) and this delay is highly dependent on a country’s economic status (2, 9). Patients unaware of their condition may neglect symptoms until late (7, 9). The main reason for a late(r) diagnosis is the late(r) onset of bleeds as patients with a mild phenotype often do not have spontaneous bleeds and require “adequate” trauma (7).

In our survey, most patients (84.2%) had previously received the factor concentrate for the treatment of hemophilia. Other studies report lower proportions to treat bleedings (51 to 75%) (16, 21) or joint bleeds (40%) (21); an exact comparison of the results is limited as, due to limited data, we cannot report the exact specification of the CFC use. Generally, the use of CFCs bears the risk of inhibitor development, which may eventually complicate treatment (10, 23). The age at first FVIII treatment largely depends on the level of the baseline factor activity. In addition, patients with mild HA may receive their first CFC dose at 4.4 years. A known family history of HA may lead to an earlier treatment (3.9 years), while a negative family history can lead to a delay in therapy (6.4 years). Patients with mild HA and a negative familial history tended to be older if factor activities ranged between 10 and 15% (7.2 years) and 25 and 40% (12.1 years) (24). This is approximately in line with our cohort: The familial predisposition was known by less than half of the patients (46.3%), and they initiated the CFC treatment at a median age of 10.0 years, with a median factor activity at diagnosis of 14.0% (12.0–25.0%). The patients in our survey used factor concentrates mainly to treat joint bleeding and/or in a perioperative setting, as recommended (1).

Most patients (69.2%) received the factor concentrate on-demand as a current treatment option, which was lower than that reported in the DYNAMO study (98%), an international multicenter study including men aged 12 to 55 years with non-severe hemophilia (residual FVIII/IX activity: 2 to 35%) (21). Other patients (59.0%) chose non-medicinal treatment or no medication for the treatment of bleeding episodes and used plasters or dressings or other medications except the factor concentrate (25.6%; see below).

We observed a higher prophylaxis rate (10.3%) than the DYNAMO study (1.7% prophylaxis/intermittent prophylaxis), which included patients with a lower factor activity range (2 to 35%) determined by the central laboratory upon inclusion (21), while we report a patient-reported factor activity at diagnosis. The prophylaxis rate in our study was similar to the PROBE study (11.8% of men with mild hemophilia with regular/intermittent prophylaxis [n = 12] and 2.63% of women [n = 1] with regular prophylaxis) (25); however, we did not overtly offer the prophylaxis subcategories “regular/intermittent” (4) and did not ask for the participants’ sex. Knowledge on the benefits of prophylaxis is scarce (18). Patients with mild hemophilia may receive prophylaxis for the treatment of acute bleeding episodes or before invasive procedures (7, 25), potentially at a later stage than patients with severe hemophilia (5). There may be patients with mild hemophilia, who would benefit from prophylaxis, fostering “adequate” hemostasis and protection from the consequences of the diseases (5).

Factor concentrates with an extended half-life were rarely used by patients using “factor concentrate if required” and/or “on current prophylaxis”, and most patients (63%) were unsure if they are treated with those concentrates. FVIII concentrates with extended half-life, non-replacement, or gene therapy may even raise target trough levels (26). Gene therapy, non-replacement, or novel concentrates might be a future option, at least for some carefully selected patients (1, 27).

Less than half of the patients (43.6%) had received desmopressin in the past, and one-quarter of the patients (25.6%) used medications other than factor concentrates such as tranexamic acid or desmopressin as a current treatment option. Desmopressin is recommended for most patients with mild hemophilia A (28). The majority of the patients will reach adequate peak FVIII levels (≥30%) post-desmopressin and almost all if treatment decisions are adapted to desmopressin response testing results (16). However, FVIII levels >50% are considered safe for major surgery may not be reached (29). Desmopressin, recommended for patients with mild (and moderate) HA (1), was used by the patients in our survey for medical procedures, surgery, or accidents. Spontaneous or joint bleeding was less frequently treated with desmopressin, which is similar to the DYNAMO study. In the DYNAMO study, desmopressin was most commonly used for the treatment of minor wounds, oral cavity bleeds, and soft-tissue/(sub)cutaneous bleeds (16).

Approximately 60% of patients chose non-medicinal treatment or no medication for the treatment of bleeding episodes as compressions, a procedure applied by others for small bleeds or cuts, that is following the standard RICE (rest, ice, compression, and elevate) principle (30).

Half of the patients (50.0%) experienced complications due to untreated bleeding episodes in the past, which was lower than the percentage reported in the DYNAMO study (75%) (21). The treatment of mild hemophilia may be suboptimal regarding joint outcomes (25, 31). Increasing factor levels do not automatically correspond to a less severe phenotype (32); for individuals with HA, it is necessary to maintain factor levels of ≥15% (33) or > 20% (34) to prevent all spontaneous joint hemorrhages. Regression models of a longitudinal study (34) predicted 1.4 and 0.6 bleeds/year for patients with hemophilia A and B and factor levels of 15%, which seemed unlikely to prevent all joint bleeds. This may highlight the importance of adequate prophylaxis to avoid loss of joint range-of-motion and final hemophilic arthropathy after infrequent but ongoing bleeding episodes over time (35). Patients with mild HA may experience destruction of cartilage or mild-to-moderate synovitis (17). Repeated (limited or subclinical) or even single joint bleeding may lead to joint arthropathy, resulting in pain and decreased mobility of affected joints (1, 17, 18, 26). A large proportion of patients with non-severe hemophilia may therefore be at risk of long-term sequelae if not receiving more intensive treatment (31). Therefore, early detection of signs of joint damage (26), and patient education on prevention and early recognition of joint bleeding (21) are crucial (36).

Approximately, half of our patients (55.3%) visited the hemophilia center only when needed. Those patients requiring regular visits (44.7%) had to visit either once in every six months (52.9%) or only about once a year (41.2%). Patients with mild or mild-to-moderate hemophilia should visit a hemophilia treatment−/−comprehensive care center at least every two years (37). In daily routine, visits to hemophilia centers may be much more frequent with every 6 to 12 months, while the mean frequency could be even higher (19).

The generally (very) high satisfaction of the patients in our survey with the support from their hemophilia center and the treatment of bleeding episodes was also reported in another, yet small, survey from the United Kingdom, (30) and a larger study from the United States comprised patients with all severities (mild 32.8%), females patients with hemophilia, and patients with other bleeding disorders, such as von Willebrand disease (38).

In our survey, patients perceived hemophilia sometimes (43.2%) a burden during their daily life, and one-third (35.1%) of patients seldom had this feeling. This is slightly less than reported by other publications (26, 39). Mild hemophilia may negatively impact employment (19, 39) and have a moderate (59%) or large (53%) impact on education or work (39). Interestingly, the impact on education and work may be lower for patients with severe hemophilia, suggesting a better care reality for these patients (39). QoL data in mild hemophilia and comparisons to healthy controls are rare (26) indicating an unaddressed unmet need.

Most patients (73.0%) always/usually needed support from the hemophilia center, indicating the need for adequate treatment (10). However, patients may choose a wait-and-see approach before seeking healthcare services, depending on the severity of bleeding episodes and pain (30). Improved patient education may lead to earlier intervention and, thereby, timely treatment (7, 9).

Most patients had no problems in all five EQ-5D-5L dimensions (“mobility”, “self-care”, “usual activities”, “pain/discomfort”, and “anxiety/depression”), with the only exception of pain/discomfort. In this dimension, approximately similar proportions of patients experienced either no (41.2%) or a slight (47.1%) impairment. The patients experienced slight problems with mobility (21.6%) and usual activities (14.7%), and 26.5% of patients had slight symptoms of anxiety/depression. Our findings was similar to that of the B-Natural study HB cohort (31). The QoL was found to be affected in our study as well as in other studies (26). Patients with mild hemophilia may experience pain and long-term disabilities typically associated with severe hemophilia (40). Here, the percentage of slight/moderate pain/discomfort and no severe pain was lower than that in the B-HERO-S study, which included adult patients and caregivers of children with HB of all grades (19, 41). Patients with mild (and moderate) hemophilia reported higher acute and chronic pain levels than people without bleeding disorder, suggesting suboptimal treatment of joint disease (25), which again negatively impacts QoL (25, 31), strengthening the need for regular, close surveillance (17).

In this study, the median patient self-rated health, as reported by the EQ-VAS scale, was 80.0, ranging from 30 to 100, with a score of 100 equaling “best imaginable health”. This score was higher than that in the B-HERO-S study (41) and was similar to the P-FiQ study, which included both patients with HA and HB (19).

The definition “mild” based on the residual factor activity may not result in an actual perception of a mild disease by the affected patients. Mild hemophilia can be easily overlooked, leading to inadequate patient management, especially regarding joint problems/hemophilic arthropathy and lowering the patients’ QoL. Further research, such as longitudinal studies to track the progression of clinical outcomes or a study to determine whether individuals with higher factor activity have fewer emergency visits or scheduled appointments, might be useful in this patient population. Increased awareness of mild hemophilia is needed to improve diagnosis and treatment for these patients.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

RA: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing, Resources. GG: Resources, Writing – review & editing. SH: Resources, Writing – review & editing. KH: Resources, Writing – review & editing. CK: Investigation, Resources, Writing – review & editing. WM: Investigation, Resources, Writing – review & editing. CP: Resources, Supervision, Writing – review & editing. MO: Investigation, Supervision, Writing – review & editing.