Adult People with Hemophilia A Have Low Annualized Bleeding Rate, However the Arthropathy Remains a Burden: A Retrospective Cohort Study

Abstract

Congenital Hemophilia A is a complex disease to treat, especially in places without access to hemophilia treatment centers (HTCs). The primary aim of this study was to analyze the outcomes of a cohort of adult people with congenital hemophilia A in an HTC localized in the Bajio region of Mexico. Observational retrospective study of a cohort of 82 adult people with congenital hemophilia A treated in a tertiary-level hospital in the Bajio region of Mexico, between June 2022 and June 2023. The median age of the patients was 29.5 years, 60.9% with severe hemophilia A, 53.6% were under some factor VIII prophylaxis regimen, and 52.4% had home therapy. The median annualized bleeding rate (ABR) was one bleed/year (IQR 0–3 bleeds/year) including a median of zero joint bleeds/year (IQR 0–3 bleeds/year). The presence of high-response inhibitors was detected in 8.5%, with an overall incidence of inhibitors of 14.6% of the cohort. Univariate analysis showed that inhibitors (OR 21.10; CI 95% 1.20–370.3; P = 0.03) and clinical arthropathy (OR 6.14; CI 95% 2.13–17.68; P = 0.001) were significantly higher in severe hemophilia. Clinically significant arthropathy was found in 71.9% of patients. Ultrasonography of the target joints showed that mainly cartilage degeneration was affected. Blood transfusion-associated viral infections were detected in 10.9% of patients. In our HTC, current treatment with hemostatic agents allows adequate control of ABR with acceptable inhibitor rates. However, we still have joint damage in most patients, which is partly explained by the fact that prophylaxis was introduced only in recent years.

Introduction

Congenital hemophilia A is a recessively inherited factor VIII deficiency disorder X-linked that manifests with a bleeding tendency in patients [1]. The treatment of this disease is complex and requires specialized hemophilia treatment centers (HTCs) [2]. These centers play a significant role in reducing the morbidity of people with hemophilia (PwH) [3].

Prophylactic treatment with replacement factor VIII is the recommended standard of care for the management of hemophilia A. Prophylaxis should ideally be started in childhood as primary or secondary prophylaxis to maintain healthy joint function during adulthood [4]. However, there are significant differences in the treatment of PwH in different regions and countries due to cost and available resources [5, 6].

There are quantitative differences in the administration of deficiency factors, with more patients diagnosed and more factors provided in countries with higher per capita income [7]. In addition, even in high-income countries, there are known barriers to accessing clotting factors, such as financial and logistical barriers, limited availability, and distance to HTCs.

In developing countries, PwH suffer many complications before being evaluated and treated at a specialized HTC [8]. In Mexico, there are discrepancies in the care of PwH, as there are few specialized care centers that focus on the treatment of pediatric hemophilia patients, leaving adult PwH behind. Moreover, these centers are concentrated in the main cities of the country. Consequently, in many regions of the country, these HTCs do not exist [9–11]. A wider distribution of HTCs with sufficient resources throughout Mexico is an unmet need. The present study aimed to analyze the outcomes of a cohort of adult PwH in an HTC localized in the Bajio region of Mexico.

Material and Methods

This HTC is in High-Specialty Medical Unit No. 1 Bajio (UMAE), a decentralized public hospital supported by the Mexican Social Security Institute and is responsible for providing specialized medical care to adult patients with social security in the Bajio region of Mexico. Adult people with congenital hemophilia A are referred from a pediatric hospital of the same health institution.

This HTC has a hemophilia clinic that includes three hematologists, a nurse, an orthopedic surgeon, a social worker, a dentist, and a physical therapist.

Patients and Ethical Considerations

We performed a retrospective study of a cohort of adult patients with hemophilia A. The institutional board ethics and research committees approved this study (register number R 2022-1001-136/153). The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines (STROBE) [12].

Data from 82 adult patients with congenital hemophilia A from the Hemophilia Clinic were collected in a database from June 2022 to June 2023. Information collected included a consecutive number of patients, age, sex, severity, presence of FVIII inhibitors evaluated by Bethesda assay (both high and low titers), type of prophylaxis, home therapy, type of hemostatic agents, annualized bleeding rate (ABR), hemophilic arthropathy, ultrasound classification of hemophilic arthropathy, body mass index (BMI), and blood-borne infections.

Our HTC has two first-generation ultra-pure recombinant factor VIII products (turoctocog alfa and simoctocog alfa), a bispecific monoclonal antibody (emicizumab), two bypassing agents such as activated Prothrombin Complex Concentrate (aPCC) and activated recombinant factor VII (rFVIIa). The decision to receive on demand treatment or prophylaxis was based on the presence of severe hemorrhagic phenotype.

We used the previously published definitions [13]. Briefly, Primary prophylaxis is defined as regular, continuous prophylaxis that begins without documented joint disease. Secondary prophylaxis is defined as regular continuous prophylaxis starting after two or more joint bleeds but before the onset of joint disease. Tertiary prophylaxis is defined as regular continuous prophylaxis starting after the occurrence of documented joint disease. Prophylaxis is classified as continuous (defined as the intention to treat 52 weeks/year and receive an a priori frequency of infusions for at least 45 weeks (85%) of the year under consideration) or intermittent (replacement therapy to prevent bleeding for periods not exceeding 45 weeks per year).

High-dose prophylaxis is defined as 25–40 IU FVIII/kg every two days (> 4,000 UI/kg per year). Intermediate-dose prophylaxis is defined as 15–25 IU FVIII/kg every three days per week (1500–4000 UI/kg per year). Low-dose prophylaxis is defined as 10–15 IU FVIII /kg on 2–3 days per week (100–1500 IU/kg per year).

On-demand treatment involves the use of FVIII to treat bleeds when it is clinically evident. Most patients with severe hemophilia A or the severe phenotype were encouraged to receive home therapy self administered, except in specific situations where this was not possible.

The HEAD-US scoring system [14] was used to assess disease progression and monitor treatment outcomes in this patient cohort.

The clinical study endpoint included a calculated annualized bleeding rate (ABR), defined as the number of episodes of major clinical bleeding in the 1 year before the last follow-up. The annualized bleeding rate (ABR) was reported as the median ABR and their interquartile range. In addition, we evaluated other complications of hemophilia, mainly hemophilic arthropathy and FVIII inhibitors.

Statistical Analysis

Categorical variables were expressed as frequencies and proportions. In contrast, quantitative variables were expressed as mean and standard deviation (SD) or median and interquartile range (IQR), depending on the nature of data distribution. When appropriate, the chi-square test or Fisher’s test was used to assess the association between categorical variables. We calculated odds ratio (OR) and their corresponding 95% confidence intervals (95%CI) by univariate analysis. Statistical analysis was performed using SPSS v20.0. The significance level was set at 5% (p value < 0.05).

Results

We analyzed the outcomes of 82 adult PwH, with a median age of 29.5 years (IQR 22–41); all patients were male. In the entire cohort, 39% had mild to moderate hemophilia and 60.9% had severe hemophilia. The clinical and demographic characteristics of the cohort are shown in Table 1.

Table 1.

Baseline characteristics from the cohort of adult patients with hemophilia A

Characteristic	Total N = 82
Age (years)	29.5 (22–41)
Median (Q1–Q3)
Masculine__n (%)	82 (100)
Severity of hemophilic__ n (%)
Mild	19 (23.2)
Moderate	13 (15.9)
Severe	50 (60.9)
Body Mass Index (Kg/m2)
Mean ± SD	25.7 (5.8)
On-demand treatment___ n (%)	31 (37.8)
Frequency of prophylaxis with VIII__ n (%)
Continuous	43 (52.4)
Intermittent	1 (1.2)
High-responding inhibitors (> 5UIB)
Yes	7 (8.5)
No	75 (91.5)
Emicizumab__ n (%)
Yes	3 (3.7)
No	79 (96.3)
Prophylaxis with FVIII__ n (%)
Primary	1 (1.2)
Secondary	6 (7.3)
Tertiary	37 (45.1)
Intensity of prophylaxis__ n (%)
High dose	29 (35.3)
Intermediate dose	15 (18.3)
Low dose	0
Home therapy___ n (%)	43 (52.4%)
Bypass agent___ n (%)
rFVII	1 (1.2%)
aPCC	3 (3.7%)

Q1: Quartile 1. Q3: Quartile 3

SD Standard deviation

aPCC: activated prothrombin complex concentrate

The presence of inhibitors was detected in 12 (14.6%) patients in the cohort. Of these patients, 7 (8.5%) developed high-responding inhibitors and were treated with on-demand/prophylactic bypassing agents. All patients with FVIII inhibitor development were in the severe hemophilia group.

At the last follow-up, of the 75 patients without high-response inhibitors, 41.3% (31/75) received on-demand treatment in case of bleeding and 58.7% (44/75) were under any prophylaxis with FVIII; of these patients, 34 (77.3%) were treated with turoctocog and 10 (22.7%) with simoctocog. Of the cohort, 52.4% of patients received home therapy.

Bleeding frequency occurred in 42 of the 82 patients (51.2%), with 150 bleeding events, of which 144 were articular and 6 were non-articular. Non-articular bleeding events in our cohort were mucocutaneous bleeding in 4 cases and musculoskeletal bleeding (hematomas of the internal rectus abdominis and femoral) in 2 patients. We report a median ABR of 1 bleeds/year [IQR 0 to 3 bleeds/year] and a median joint bleed ABR of 0 bleeds/year [IQR 0 to 3 joint bleeds/year].

Hemophilic arthropathy was present in 59 of 82 patients (71.9%), and in 15 (25%) of them, more than three joints were affected. The main clinically affected joints in the cohort of adult patients with hemophilia A are listed in Table 2.

Table 2.

Most affected joint in adult patients with Hemophilia A

Joints	N = 129 n (%)
Left ankle	10 (7.7)
Right ankle	11 (8.5)
Left knee	25 (19.3)
Right knee	35 (27.1)
Left elbow	19 (14.7)
Right elbow	20 (15.5)
Left wrist	1 (0.77)
Right wrist	1 (0.77)
Left shoulder	2 (1.5)
Right shoulder	4 (3.1)
Left hip	1 (0.77)
Right hip	0

Data presented as frequency and relative ratio in %

Due to multiple entries (e.g. bilaterally affected joints) the sum is superior to 82

Univariate analysis was performed using the severity of hemophilia as the unit of analysis. This showed that the presence of inhibitors (P = 0.03; OR 21.10; CI 95% 1.20–370.3) and clinical arthropathy were significantly higher in patients with severe hemophilia (P = 0.001; OR 6.14; CI 95% 2.13–17.68). The results of this analysis are shown in Table 3. In addition, a subanalysis of factors associated with clinical arthropathy was performed. It was found that low weight according to BMI (< 18.5 kg/m²) was associated with lower clinical arthropathy (OR 0.16; 95% CI 0.02–0.98; P = 0.04). However, no association was found between the other BMI categories and clinical arthropathy.

Table 3.

Clinical variables associated with hemophilia severity

Characteristic	Non-severe hemophilia (N = 32) n (%)	Severe hemophilia (N = 50) n (%)	OR (CI 95%)	P value
Presence of inhibitor	0	12 (24)	21.10 (1.20–370.3)	0.03 +
Clinical Arthropathy	16 (50)	43 (86)	6.14 (2.13–17.68)	0.001*
Number of clinically affected joints 0–2 3–5  > 6	29 (90) 2 (6) 1 (3)	38 (76) 10 (20) 2 (4)	0.32 (0.08–1.26) 3.75 (0.76–18.39) 1.29 (0.11–14.86)	0.16* 0.11 +  1.00 +
Patients with annual bleeding events	1 (3)	3 (6)	1.97 (0.19–19.89)	0.65 +

Non-severe hemophilia: mild and moderate hemophilia; OR odds ratio, CI confidence interval

*Chi-square test

 + Fisher’s test

Ultrasonography was performed in only 28 patients due to a lack of trained staff. Only one ultrasound radiologist in the department is trained to evaluate HEAD-US. A total of 165 joints were examined by ultrasound using the HEAD-US method. 3 joints could not be examined for various reasons, including left pelvic limb amputation or prosthesis. Clinically, the most affected joint was the right knee; however, the joint with the highest HEAD-US score was the left knee with a mean of 4.19 (standard deviation 2.85), followed by the right knee and left ankle. Comparing the mean scores by joint and severity of hemophilia, higher scores are observed in the group of patients with severe hemophilia in all joints evaluated (Fig. 1). The 66.6% of the joints assessed showed cartilage degeneration, which was the most frequently altered item in the evaluations. Table 4 shows the results of the HEAD-US score.

Fig. 1.

Median HEAD-US total score by joint and hemophilia severity*. *Non-severe hemophilia includes patients with mild and moderate hemophilia. Evaluation of 28 patients and 165 joints by HEAD-US score

Table 4.

Hemophilia early arthropathy detection with ultrasound; the number of joints (%) with a positive score (≥ 1 point) according to each item

HEAD-US items	Elbows (N = 56) n (%)	Knees (N = 54) n (%)	Ankles (N = 55) n (%)	Total (N = 165) n (%)
Synovial hypertrophy	41 (73.2)	29 (53.7)	31 (56.3)	101 (61.2)
Cartilage degeneration	33 (58.9)	35 (64.8)	42 (76.3)	110 (66.6)
Bone irregularities	22 (39.2)	33 (61)	38 (69)	93 (56.3)

Viral infections associated with blood transfusions were found in 9 patients of the cohort (10.9%). A review of records revealed seroconversion of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) in 5 (6.1%) and 6 (7.3%) of patients, respectively.

Discussion

This study is the first report from an HTC for adult PwH in the Bajio region of Mexico. In a total cohort of 82 patients, 60.9% of whom had severe hemophilia A and 53.6% of whom received a prophylaxis scheme, the primary outcome in terms of bleeding events was a median ABR of 1. Recently, a systematic review publication of 67 different patient cohorts with congenital hemophilia [15] reported a mean ABR of 3.4 (IQR 3.0–3.7), noting that ABR was higher in patients older than 12 years [mean ABR 3.9 (IQR 2.2–4.5)]. Our ABR was lower than the other patient cohorts analyzed, underscoring that our cohort focused on an adult patient population and reflects the current efficacy of prophylaxis used at our hemophilia care center.

Home therapy was established in 52.4% of patients, as our center aims to offer factor VIII as home therapy to the majority of patients according to published recommendations [16]. Home therapy has been associated with longer life expectancy and fewer hospitalizations for bleeding. Home therapy has been shown to reduce pain, work absenteeism, and allow patients greater independence and lower costs [17], underscoring the benefits of this treatment. We believe that the proportion of home therapy should be increased in our center. However, this requires the training and education of patients and caregivers [18].

Regarding inhibitor development, the percentage of inhibitors in our cohort was 14.6%, of which 58.3% (7/12) were high-responders. It is worth noting that all patients who developed inhibitors had severe hemophilia. The rate observed in our study is within the range reported by other national and international cohorts, in which the presence of inhibitors in severe hemophilia ranges from 9.7 to 24.5% [19]. However, comparisons between different cohorts of hemophilia patients are difficult because the prevalence of inhibitors varies from center to center. This may be due to specific differences in population, therapeutic strategies, and inhibitor detection protocols [19–21]. The development of inhibitors has a negative impact on treatment response and quality of life, highlighting the need for continuous monitoring of their development. This would allow us to predict the cost of hemostatic agents needed to treat these patients during bleeding events.

We found clinically evident hemophilic arthropathy in 71.9% of patients, with the knees being the most affected joints. Compared with other patient cohorts worldwide, we found a high incidence of joint damage [22–24]. This finding may be since prophylaxis with factor VIII was only introduced in our center in 2018, as there was no previous access to prophylaxis. In contrast, in high-income countries, advances in replacement therapy were made as early as the 1970s [25]. In addition, most of our patients are on tertiary prophylaxis, reflecting the delay in diagnosis, timely care, and limited access to treatment in our setting.

Regarding the use of the HEAD-US scoring system, in our patient cohort, knees were identified as the target joints with the highest joint damage scores, while ankles were the most affected joint in up to 76.3% of ultrasound evaluations. It is worth noting that subclinical bleeding in target joints can be detected by ultrasonography. The implementation of this method in our center is recent and has been performed in only one-third of hemophilia patients. In several countries, the HEAD-US system is already part of the routine assessment of hemophilia patients [26, 27].

In addition to appropriate treatment and follow-up to prevent clinical arthropathy in patients with hemophilia, other risk factors such as obesity and overweight should also be considered. In our subanalysis of factors associated with clinical arthropathy, a body mass index (BMI) < 18 kg/m² was found to be statistically associated with a lower rate of arthropathy. In contrast, another study has reported that hemophilic arthropathy is more common in obese patients with hemophilia and a corresponding decrease in joint range of motion correlates with higher BMI [28]. On the contrary, obesity may lead to joint and muscle overload in hemophilic patients, making them more vulnerable to joint bleeding and resulting in joint damage [29]. We believe that the lack of association between obesity and arthropathy in our cohort is due to the fact that we obtained a mean BMI of 25.6, suggesting that most of the included patients were of normal weight. Further studies should focus on the impact of obesity and other comorbidities in patients with hemophilia.

Of note, blood transfusion-associated infections were present at 7.3% for HIV and 6.1% for HCV. These data indicate that plasma-derived products still pose a potential risk for the transmission of these blood-borne viral infections in some centers [30, 31].

The federal government administers our public health care system, and it is funded primarily by federal general revenues and taxes. Consequently, the economic burden remains a challenge in treating these patients, with prophylaxis being the cornerstone of treatment and the most costly approach. Typical dosing regimens rely on weight-based calculations. However, dosing based on individual pharmacokinetic response is more effective in predicting clotting factor levels that protect against bleeding [32, 33]. Pharmacokinetics for personalized dosing of patients with severe hemophilia A significantly reduces ABR and spontaneous bleeding, improves patient quality of life, and reduces costs to the health care system [33]. This strategy can potentially optimize the clinical effectiveness of these expensive therapies, so future studies should focus on this topic.

Study Limitations

The retrospective nature of the study was its main limitation. Prospective, and multicenter regional studies are necessary.

Conclusion

Despite good bleeding control through evaluation of ABR, we recognize that hemophilic arthropathy is still a frequent problem due to the generational gap in treatment in our setting. However, with the recent introduction of prophylaxis in pediatric patients, a lower incidence of joint damage is expected in the coming years.

This study demonstrates the impact of delayed prophylaxis in hemophilia patients, a reality in many areas of the country with limited access to hemophilia centers. Understanding and analyzing our current landscape is the first step towards improving future care for PwH through appropriate management of available resources for hemorrhage prevention and treatment, monitoring, and appropriate inhibitor treatment. By following up with the cohort, we can enhance their quality of life and establish new areas of research for adult PwH treated in our center.

Abbreviations

PwH

People with hemophilia

HTCs

Hemophilia Treatment Centers

STROBE

Strengthening the reporting of observational studies in epidemiology guidelines

ABR

Annualized bleeding rate

BMI

Body mass index

aPCC

Activated prothrombin complex concentrate

rFVIIa

Activated recombinant factor VII

SD

Standard deviation

IQR

Interquartile range

OR

Odds ratio

HCV

Hepatitis C virus

HIV

Human immunodeficiency virus

Authors’ Contribution

EPZ, LFAM contributed to the conception and design of the study. CVO and KESB collected patients’ information and data. BOMO, OMV analyzed and interpreted patients’ data. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Declarations

Conflict of interest

The author(s) of the manuscript declare(s) that none of the participants have any financial or personal relationships with other individuals or organizations that could inappropriately influence their work or lead to any other conflict of interest. It is further affirmed that this is an original article not currently under review by another journal and that neither the text nor the data reported have been previously published.

Ethics Approval

The author(s) of the manuscript entitled “Adult people with Hemophilia A have low annualized bleeding rate, however the arthropathy remains a burden: A Retrospective Cohort Study.” declare(s) that our research was performed in accordance with the Declaration of Helsinki. The present study was approved by the ethics and research committee of the High-Specialty Medical Unit No. 1 Bajio (registration number R 2022-1001-136/153). The ethics committee approval was granted for an observational study and the need for patient consent was waived. This study was conducted based on the guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE).