Hemophilia A (HA) and hemophilia B (HB) are a rare group of X-linked recessive hemorrhagic diseases, being characterized by a deficiency or abnormality in the clotting factors VIII and IX, respectively. HA and HB are marked by bleeding manifestations, including spontaneous bleeding episodes commonly into muscles and joints. Joint bleeding usually affects weight-bearing joints, such as knees or ankles, which can lead to the development of disabling hemophilic arthropathy.1 In addition, people with hemophilia (PwH) are also at risk for life-threatening bleeding, including intracranial hemorrhage.1

Advancements in hemophilia treatment have markedly shifted the disease from being a life-threatening condition to a chronically manageable one. Central to this progress is the institution of prophylactic treatment, which entails routine administration of clotting factor concentrates (CFCs) to avert bleeding episodes. Specifically, factor VIII is utilized for HA, and factor IX for HB. Prophylactic therapy mitigates the risks of joint damage and other complications stemming from recurrent bleeding, thereby enabling the PwH to have a more active lifestyle. Prophylactic therapy also leads to fewer hospitalization episodes and a decrease in school or work absenteeism, thus considerably reducing the disease's burden on both the PwH and their families.2

In Brazil, the public health system provides access to therapies in addition to CFCs, including immune tolerance induction, bypass agents (recombinant factor VIIa) and emicizumab, which are particularly relevant for treating the PwH who develop inhibitors.3,4 Extended half-life products have the potential to enhance the landscape of prophylactic treatment in hemophilia, due to less frequent dosing and tailored treatment regimens, although this modality of treatment is partially available in the public health system or Unified Health System in Brazil. Despite the available therapies, hemophilia places a significant burden on patients/caregivers, payers and society. It results in direct costs from hospitalizations, outpatient visits and drug treatments, as well as in indirect costs from diminished work productivity and absenteeism. Hemophilia also presents intangible costs, including impaired quality of life, pain and suffering of the inflicted and their families and the emotional and physical impact on them and their caregivers.2

According to the 2020 Annual Global Survey of the World Federation of Hemophilia,5 Brazil is one of the countries with the largest population of PwH. Despite the high prevalence and burden of hemophilia in Brazil, little information is available regarding certain aspects, such as the burden of disease and determinants for the access to healthcare resources. Our scoping review is deliberately designed to explore and elucidate the unique landscape of hemophilia care in Brazil. The primary objective is to gain a comprehensive understanding of the national context, encompassing epidemiological trends, burden of the disease, patient journey and unmet needs of the PwH. This focused approach allows us to identify specific areas of concern and potential opportunities for improvement in research, education and healthcare management tailored to the Brazilian setting. By focusing our review specifically on Brazil from the outset, we aim to provide readers with a clear perspective of the existing gaps and particularities in hemophilia care in the national context, which is a crucial aspect in our research outcomes.

This study was conducted following the JBI methodology for scoping reviews,6 following a protocol defined a priori7. The report was structured in compliance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (Appendix I).

We identified 909 references; 145 of these were selected according to titles and abstracts. After the full-text review, 92 references (25 thesis and 67 papers) met the inclusion criteria. The PRISMA flow diagram (Figure 1) outlines the screening and selection process of these articles.

Figure 1.

Flow diagram of the literature search. BDTD: Biblioteca Digital Brasileira de Teses e Dissertações; LILACS: Literatura Latino-americana e do Caribe em Ciências da Saúde; MEDLINE: Medical Literature Analysis and Retrieval System Online.

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Most studies (n = 60) included populations with HA and HB, six did not specify the hemophilia subtype and 15 included only the HA population. Regarding the context, most studies (n = 76) were in reference to the public healthcare system. Domiciliary care and schools were the setting of interest in one and two studies, respectively, while the context was not informed in 13 studies. Most studies were performed in southeastern and southern Brazil (Figure 2). The number of studies regarding the nine questions is described in Figure 3.

Figure 2.

Granulation map of the study performed in Brazil.

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Figure 3.

Evidence map: number of studies on the concepts “Clinical-epidemiological profile”, “Burden of disease” and “Patient journey and unmet needs” and on each respective research question.

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The main findings are reported in Tables 1, 2 and 3 and described according to each concept in this section.

The current scoping review investigated epidemiological issues, burden of disease, patient journey and unmet needs for the PwH in Brazil. Ninety-two studies were included and addressed all research questions except the Main outcomes of interest in hemophilia, from the perspective of patients and managers in healthcare (question 2.3). The distribution of the Brazilian studies is not even in the country, studies conducted in the states of São Paulo and Minas Gerais are more frequent in the literature.

Although some studies provided data on the prevalence of HA and HB, none of them were developed specifically to investigate the prevalence and incidence of these coagulopathies in Brazil. Therefore, information on this epidemiological aspect comes almost exclusively from the Ministry of Health through the Hemovida Web Coagulopatias system implemented in 2009 or through a periodical report. Despite it being estimated that almost 100 % of the PhW in Brazil are registered the in Hemovida Web Coagulopatias, this system has limitations in identifying patients who may not use the public health system, as well as in identifying duplicate patients, aside from the possible incompleteness of the information.

There are also few studies that specifically aimed to investigate the prevalence of inhibitors or the relationship between the prevalence of inhibitors and other aspects of the disease (severity, complications, QoL or mortality). The findings of the current review on the prevalence of inhibitors are quite divergent, since we found a great heterogeneity in the study designs and population (e.g., severe hemophilia or individuals carrying certain genetic mutations).

Most of the studies found reported the seroprevalence of viral infections, such as HIV, HCV and HBV. Viral infections are the most common complications of the hemophilia treatment, especially in those PwH born before the mid-1980′s, when effective methods of viral inactivation of CFCs were introduced. It has been estimated that after the implementation of viral inactivation methods and screening for viral infection in blood donors, the risk of viral infections resulting from the hemophilia treatment has been reduced in Brazil. However, the current scoping review found no studies on this topic.

Regarding the complications of hemophilia itself, osteoarticular complications and pain emerged in the current review as the most impacting elements on the physical functioning and QoL of the Brazilian PwH. This finding corroborates the current evidence that chronic arthropathy, which is often associated with deformity and instability, flexion contractures, muscle atrophy and pain, is a major determinant of the health-related QoL in the PwH and the general impairment of physical dimensions results in lower levels of QoL,33 not only for those with severe hemophilia, but also for non-severe hemophilia, despite low joint bleeding rates.34 Furthermore, the restricted access to physiotherapy and rehabilitation was found as an unmet need for the PwH in Brazil. Data on the number of days lost from work/school each year and its association with the physical functioning limitation, as well as with osteoarticular complications, have not yet been studied in the Brazilian population. Moreover, the investigation of the employment status of the PwH is restricted.

The latest advances in hemophilia treatment led to a change in the aim of treatment from increasing life expectancy to preventing joint damage and protecting against joint bleeding and hemophilic arthropathy.35 Therefore, adherence to the treatment is important in the maintenance of the health status. However, logistical difficulties in reaching the hemophilia treatment center were raised as the main barrier of the PwH in Brazil and adherence to the prophylactic treatment rates were shown to vary from 25 % to 72 %, which is in line with results obtained in a previous study applying analysis for the global and US PwH populations.36 In this context, the HDP seems a promising strategy to overcome logistical barriers and to reduce abstention from work/school. However, the Brazilian PwH may feel a lack of confidence in the dosage to be used, fear of possible reactions or may face difficulties in storing the medication at home.31,32 Controversially, receiving treatment at a hemophilia treatment center proved to be a positive factor associated with the adherence to the treatment27 and adolescents who underwent auto-infusion presented poor adherence to the treatment.12 Still, research on the factors associated with adherence to home and outpatient treatment is necessary to improve the screening of candidates for each type of treatment setting.

Although no study has addressed the main outcomes of interest in hemophilia, from the perspective of patients and managers in healthcare, a report from the Ministry of Health14 mentions the need for epidemiological surveillance of inhibitors, infections, osteoarticular complications and chronic diseases and mortality. This report also mentions those records in the Hemovida Web Coagulopatias system as fundamental in the correct monitoring of this population, giving it a longer life, and the initiation of the presentation of chronic degenerative diseases that are characteristic of the general population, encouraging the implementation of policies aimed at improving the quality of care provided to patients.

To our knowledge, this is the first scoping review aiming to map the Brazilian publications on hemophilia referring to these three concepts: (i) clinical-epidemiological profile; (ii) burden of the disease, and; (iii) patient journey and unmet needs. As a limitation, the great heterogeneity of study designs and samples hinders the interpretation of data, a common issue observed in scoping reviews of clinical conditions. Still, the aim of this scoping review was to investigate and gather what is known about HA and HB in Brazil and guide future research and support for the implementation of health policies for the PwH and not to answer the framed questions.

The evidence provided by this scoping review shows results for the three concepts established, the clinical-epidemiological profile, burden of the disease and patient journey and unmet needs. Hemophilia still poses a considerable burden on the PwH, despite the available modalities of treatment. There are remaining medical and social unmet needs that should be addressed by researchers and policymakers in the future, such as the low rates of adherence, disease complications, and unemployment. Only one question related to main outcomes of interest in hemophilia could not be answered. This exposes a gap in the literature and offers opportunities for future studies.