Introduction

Hemophilia A and hemophilia B are coagulation disorders related to the deficiency of factors VIII and IX, respectively. Hemophilia A and B are rare diseases worldwide, since their prevalence is approximately 1 case per 5,000 people [1, 2]. Patients with severe hemophilia are those with less than 1 IU/dL of the deficient factor [3, 4]; patients with levels between 1 and 5 IU/dL and between 5 IU/dL and 40 IU/dL are classified as moderate and mild, respectively [4]. The most severe forms of hemophilia are characterized by spontaneous bleeding in the joints and muscles [3]. Repeated bleeding in the same locations can lead to hemophilic arthropathy [5].

Quality care for these conditions, especially severe cases, requires the intervention of a multidisciplinary team focused on the prevention of bleeding and joint damage, the management of bleeding episodes, rehabilitation, pain management, psychosocial intervention and education [4, 6]. Through such efforts, joint damage is prevented or delayed, the patient’s quality of life is preserved [7], and risk factors that negatively modify the evolution of the condition are mitigated [4]. In severe cases, prophylaxis serves as a pharmacological strategy focused on the prevention of bleeding, which can be primary, secondary or tertiary depending on the history of bleeding and joint damage [4, 8].

The complications related to treatment with clotting factor replacement that has the greatest impact is the development of inhibitors, since they affect the effectiveness of coagulation factors and increase the risks of morbidity and mortality and the costs to the health system [3, 4, 9, 10]. Real-world studies allow the evaluation of the clinical outcomes of patients under routine conditions. These findings provide decision-makers with information related to the effectiveness and safety of pharmacological technologies and consider scenarios that cannot always be evaluated in clinical studies. Additionally, they can complement available information to provide data on how doctors and patients choose treatments, dosages and regimens and on the frequency of use of health services and technologies and their effectiveness [5, 11].

Currently, in Colombia, there are no studies regarding the follow-up, treatment and outcomes of patients with hemophilia A and B; therefore, it is important to expand knowledge regarding this population. This need has led to the objective of evaluating the incidence of adverse outcomes in a cohort of patients diagnosed with hemophilia A and hemophilia B at a health care institution (Institución Prestadora de Servicios Especializada: IPS-E) of Audifarma SA) in Colombia. The IPS-E is a health institution dedicated to the care of patients affiliated with the Health System with high-cost diseases such as hemophilia, rheumatoid arthritis, among others, providing transdisciplinary care, the safe administration of health technologies, including medicines, aimed at restoring health and improving the quality of life.

Materials and methods

This was a retrospective study of a dynamic cohort of patients diagnosed with hemophilia A and hemophilia B who entered the Coagulopathies Program of IPS-E for replacement therapy between January 2012 and July 2019. Given the descriptive nature of the study, the evolution of the treatment and the patients’ clinical results were evaluated during the follow-up period. The index date was defined as the date of admission to the IPS-E Coagulopathies Program and the initiation of some recombinant or plasma-derived clotting factor replacement within a prophylaxis regimen. The follow-up time began from the index date to inhibitors development, ≥0.6 Bethesda units/milliliters (BU/ml), death, loss to follow-up, abandonment of the Program or July 2019, whichever came first.

Inclusion criteria were male patients diagnosed with hemophilia A or B, who had been registered with the Specialized Coagulopathies Program of IPS-E for 6 or more months and were undergoing prophylactic treatment with recombinant or plasma-derived factors. Those who presented inhibitors upon entering the program or who were participating in a clinical trial were excluded. Sample size estimation was not performed due to the design of the study; therefore, all of the patients in the Program who met the inclusion criteria were included in the cohort.

All clinical, treatment and outcome information were obtained from the patients’ medical records, which were reviewed by two trained physicians, and all information was recorded in an electronic collection format. The following groups of variables were collected:

1. Sociodemographic: age, sex, city of residence, weight, height, family history of hemophilia and development of inhibitors.
2. Clinical: type of hemophilia, date of diagnosis, presence of arthropathy, history of bleeding and previous treatment.
3. Pharmacological: type of prophylaxis (primary, secondary, tertiary), type of factor, dose, administration interval, switches in coagulation factors, interruptions, and their causes.
4. Adverse events: bleeding, site of bleeding, trauma, surgeries, hospitalizations, development of inhibitors (BU), anaphylactic reactions or nephrotic syndrome. Finally, patients who developed inhibitors were followed.

The main outcomes were the development of inhibitors, severity of bleeding, trauma, hospitalizations, and anaphylactic reactions. These outcomes were determined by the information available in the medical records. Additionally, data related to treatments performed in the 6 months prior to admission to the Specialized HCP Coagulopathies Program were taken into account. In those patients who developed inhibitors, a descriptive follow-up against complications and management was carried out from the medical records.

Results

A total of 207 patients undergoing prophylactic treatment were identified. Of these, 40 already had inhibitors before entering the program, five who were not in the program for at least 6 months, two who did not have a complete medical record, and one who was participating in a clinical trial were excluded. Finally, 159 subjects met the inclusion criteria. They were followed for an average of 5.9±2.3 years and had an average age at admission of 23.6±16.1 years. The majority of patients were classified in the severe hemophilia A group. The patients were distributed mainly in the cities of Bogotá/Cundinamarca (n = 87; 54.7%), Cali/Valle del Cauca (n = 28; 17.6%) and Medellín/Antioquia (n = 10; 6.3%., and the rest (n = 34; 21.4%) were from 11 other departments in Colombia. Fifty-three 53 patients had some family history of hemophilia (Table 1).

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Table 1. Demographic and clinical characteristics of hemophilia A and B patients on prophylaxis prior to follow up; in Colombia, 2012–2019.

https://doi.org/10.1371/journal.pone.0286187.t001

In the cohort, 47 patients (29.6%) had some associated comorbidities, the most frequent were arterial hypertension (n = 12; 7.5%), non-ulcer dyspepsia (n = 3; 1.9%), type 2 diabetes mellitus (n = 1; 0.6%) and chronic obstructive pulmonary disease (COPD) (n = 1; 0.6%). However, they also had other infections, such as hepatitis C virus (HCV) infection (n = 24; 15.1%), human immunodeficiency virus (HIV) (n = 2; 1.2%) and hepatitis B virus (HBV) (n = 2; 1.2%). Patients had these infections for more than 10 years on average, in total, at the time of admission to the program and had an average of 39.9 years old.

Prior to admission to the cohort, 121 (76.1%) patients were receiving prophylaxis (Previously Treated Patients–PTPs), and none of these had low or high response inhibitors. Table 1 shows the proportions of patients according to the type of hemophilia, severity, age at the time of diagnosis, family history, complications prior to admission (especially arthropathy) and previous management.

The most frequent type of management was secondary prophylaxis (n = 71; 44.7%), followed by tertiary prophylaxis (Table 2). The most frequently used coagulation factor was recombinant (n = 84, 52.8% of all patients); in 68 patients (80.9%), there was no clinical record of the reason for its use, while in 8 (9.5%) cases, the reported reason was previous hypersensitivity to the plasma derivative. Table 2 also shows the distribution of patients according to the type of prophylaxis, the factors used, the weekly doses of substitution therapy and other reasons for switches or modifications of treatment (in 42 cases, 26.4%) during the follow-up period, in addition to the frequency and causes of discontinuation/interruption of treatment (36 cases, 22.6%), with loss of affiliation with the insurance health company (Entidad Promotora de Salud- EPS) being the most frequent (n = 11; 6.9%).). The median time of discontinuation of treatment was 3 months, mainly due to loss of affiliation and administrative problems with the EPS.

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Table 2. The frequencies of treatment-related variables among hemophilia A and B patients on prophylaxis in Colombia.

https://doi.org/10.1371/journal.pone.0286187.t002

Out of the 159 studied patients; 28 (17.6%) have been switched from one substitution therapy to another., the majority of the switches between the different coagulation factors used was the transition from plasma derivatives to recombinant treatment in both the hemophilia A and hemophilia B patients. Table 3 shows the frequency of switches between the types of coagulation factors used.

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Table 3. The frequencies and types of treatment switching among hemophilia A and B patients on prophylaxis in Colombia.

https://doi.org/10.1371/journal.pone.0286187.t003

Regarding complications and events in the patients with hemophilia who were receiving prophylaxis, the vast majority of the patients had suffered some type of trauma, almost one-third had undergone some type of surgical intervention, and almost one-fifth had to be hospitalized during the follow-up period. More than 90% had been some type of hemorrhage, most commonly articular and of traumatic origin; of these patients, the majority required the administration of substitution therapy. Only 2 (1.2%) patients had experienced anaphylactic reactions (Table 4).

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Table 4. The frequencies of different complications reported among hemophilia A and B patients during the follow-up period on prophylaxis in Colombia.

https://doi.org/10.1371/journal.pone.0286187.t004

Discussion

Based on the information for the cohort of patients with hemophilia A and B receiving prophylactic management at a IPS-E, it was possible to identify the sociodemographic and clinical characteristics and clinical outcomes of interest, such as the frequency of bleeding, trauma and inhibitor development during follow-up, in addition to the drugs used, their doses and any switches. The evaluation of these results allows the continuous improvement of the health system [11, 12]. Additionally, the information collected could contribute to the development of mechanisms to guide therapeutic strategies, access to pharmacological treatments and the generation of knowledge based on real-world evidence of patients with hemophilia in Colombia.

Within the selected cohort of patients with severe hemophilia, more than half (56%) were diagnosed in the first 12 months of life, and the remaining cases for whom this data were available were diagnosed between 12 and 60 months of age (22%); this finding is consistent with the reports of epidemiological studies in which patients with severe forms of the disease were diagnosed during the first years of life [3, 13]. This behavior may be related to the adoption of a regulatory framework that promotes comprehensive and timely access to orphan diseases [2]. In addition, patients who entered the follow-up cohort during the observation period had an average age of approximately 24 years, which implies a long evolution of the disease and complications prior to admission to the Coagulopathies Program, as is evident in the study. A high proportion of patients with arthropathy at admission (approximately 80%) had two affected joints, a situation to which clinicians responsible for their care and attention should be alert given its impact on the burden of the disease, quality of life and the need for tertiary prevention. Studies conducted in Austria with patients with severe hemophilia show comparable proportions of arthropathy (76.7%) [11], a complication that can be reduced in these patients with adequate prophylaxis, as reported by Manco-Johnson et al. [12] and as recommended by the World Federation of Hemophilia [2].

The standard of treatment for severe cases is the regular replacement of factor through prophylaxis with clotting factor replacement or other hemostatic products to prevent bleeding; it is recommended that such prophylaxis be started at an early age to avoid musculoskeletal complications [4, 14]. However, the present study shows that only 17% of the cohort were receiving primary prophylaxis; this explains the high number of patients who had complications prior to inclusion in the cohort, as many of them were receiving secondary and tertiary prophylaxis [15]. This situation is consistent with studies conducted in the United States showing that between 1999 and 2010, the proportion of patients receiving prophylaxis increased from 40% to 80%, which had an impact on the reduction of new bleeding [12].

In the present study, the frequency of recombinant factor use increased from 36% prior to admission to the cohort to 47.8%, a finding that was associated with hypersensitivity and inadequate response to previous therapies. The most frequent change was from plasma derivatives to recombinants. Similar findings were reported in other studies, such as that of Ay et al., which reported that as of 2020, up to 74.5% of patients with severe forms of the disease were using recombinants [11] and indicated that 3 administrations per week of factor VIII was the most frequent interval [11, 12].

The interruption or discontinuation of prophylaxis for at least one week in almost a quarter of patients throughout the follow-up period was one of the most relevant problems and was often associated with administrative problems with the EPS and loss of insurance status, a situation that can cause the patient to miss check-up visits and increases the probability of negative outcomes. The adherence report by Tencer et al. showed a median adherence of 76% in the United States [16]; additionally, Khair K et al. in a multicenter study in the United States, Canada, United Kingdom and Sweden, found a median adherence rate of 58.8% [17], and a similar study identified barriers to adherence to prophylaxis, including issues associated with health systems and others related to the patient and his family [18].

According to the patients’ clinical records, 90.6% of the patients had at least one bleeding event during the follow-up period. This finding is consistent with reports of other series of patients with hemophilia A and B, which indicated that between 92.0% and 94.2.% of patients experienced a bleeding event from 1997 to 2003 [19]. However, a finding comparable to 9.4% of the patients did not experience bleeding with prophylaxis over an average of almost 6 years of follow-up is comparable to reports from developed countries of rates between 5.7% and 41% [5, 11]. Considering that the majority of the patients in the present study were in secondary and tertiary prophylaxis, the incidence of 19.2 bleeds per 1000 patients per year (1.9 mean bleeds per year per patient) represents a lower mean annual bleeding rate than that reported for hemophilia A study in the United States by Yan S et al.; who reported that between 2.5 and 3.9 bleeds per patient per year [20]. The differences reported between different countries can be attributed to the dose, the type of mutation and the type of clinical follow-up, as well as patient differences in adherence and behavior [3, 11, 21].

In the evaluated group, the low frequency of development of inhibitors of coagulation factors, and even the recognition that most cases reflected a low response that later became negative, can be explained by the appropriate follow-up of the patients in this program. However, additional studies are required to confirm this association, given the low number of patients in this study who developed inhibitors. Another study reported that a history of not knowing the type of factor a patient used before entering a hemophilia treatment cohort may be associated with an increased risk of inhibitor development [22].

Some limitations should be recognized, such as the fact that data were obtained from outpatient clinical records; however, the care process was detailed in the medical records, which allowed the collection of complete and high-quality information. Other limitations include the small number of patients with severe/moderate hemophilia who met the inclusion criteria and therefore the low frequency of some outcomes, which did not allow statistical analysis. Finally, there was significant heterogeneity in the identified patients as a result of the long evolution of the disease prior to admission to the follow-up cohort, which led to a high frequency of complications and a lack of information about the follow-up and treatments that the patients had received in previous years. In addition, strengths of the study are recognized, such as the complete follow-up of each of the patients for a long period and the description of their treatments and outcomes, which resulted in the complete collection and analysis of the data, and the inclusion of a larger sample of patients than has not previously been reported in Colombia.

Conclusion

These findings show that in this cohort of patients with hemophilia A and B undergoing prophylactic management, especially those undergoing secondary and tertiary, the use of recombinant coagulation factors led to bleeding rates similar to those reported by high-income countries and a frequency of complications comparable to the reports in the published literature, which are mainly based on the experiences of developed countries.