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. 2023 Jan 12;7(1):100005. doi: 10.1016/j.rpth.2022.100005

Long-term impact of primary prophylaxis on joint status in patients with severe hemophilia A

María del Mar Meijón Ortigueira 1,∗, María Teresa Álvarez-Román 2, Hortensia De La Corte Rodríguez 3, Nora Butta Coll 2, Víctor Jiménez-Yuste 4
PMCID: PMC9986103  PMID: 36891521

Abstract

Background

Primary prophylaxis with factor VIII concentrates is the therapeutic gold standard for severe hemophilia A. Although this approach will change substantially with the use of nonsubstitutive therapies, the long-term effects of primary prophylaxis remain unclear. We present information on joint health with tailored primary prophylaxis in a consecutive series at a single center.

Methods

We retrospectively analyzed 60 patients who did not develop early inhibitors. The annual bleeding rate and annual joint bleeding rate, prophylaxis characteristics, physical activity, adherence, and development of inhibitors were compared between those with and without joint involvement at the end of follow-up. Joint involvement was defined as a Hemophilia Joint Health Score or Hemophilia Early Arthropathy Detection with an ultrasound score ≥1.

Results

Among 60 patients with median follow-up of 113 ± 6 months after starting prophylaxis, 76.7% had no joint involvement at the end of the follow-up. Those without joint involvement started prophylaxis at a younger median age (1 [IQR 1-1] year vs 3 [IQR 2-4.3] years). They also had lower annual joint bleeding rate (0.0 [IQR 0-0.2] vs 0.2 [IQR 0.1-0.5]), were more often physically active (70% vs 50%), and had lower trough factor VIII levels. Adherence to treatment was not significantly different between groups.

Conclusion

Initiation of primary prophylaxis at a younger age was the main factor associated with long-term preservation of joint status in patients with severe hemophilia A.

KeyWords: hemophilia A, factor VIII, joint, prophylaxis, age

Essentials

  • •

    Primary prophylaxis is the gold standard for treatment of hemophilia.

  • •

    Long-term data on tailored prophylaxis in patients with severe hemophilia A is needed.

  • •

    Starting prophylaxis before 2 years of age could further reduce joint involvement in these patients.

  • •

    Tailored prophylaxis could help optimize management with nonsubstitutive therapies.

1. Introduction

Primary prophylaxis with factor VIII (FVIII) concentrates has been the gold standard for treating patients with severe hemophilia A (SHA). It was defined by the European Pediatric Network for Hemophilia Management as the regular and continuous administration of FVIII to prevent spontaneous bleeding and the development of arthropathy associated with hemophilia. The early initiation of FVIII is one of the most important variables affecting the outcomes of such patients. However, the age at initiation has changed in the definition of primary prophylaxis established by various working groups (Table 1) [[1], [2], [3]]. Although the use of FVIII is widely accepted [[3], [4], [5]], there is no universal regimen, and protocols with differing dosages have been published [[6], [7], [8], [9], [10], [11], [12], [13]]. Nevertheless, due to the complexity of administering this treatment regularly, especially in children, the weak association between the hemorrhagic phenotype and FVIII levels in certain patients, and the increase in physical activity; significant heterogeneity has been generated in the treatment regimen selected by individualizing the therapy based on various parameters [[14], [15], [16], [17]].

Table 1.

Definitions of primary prophylaxis.

European Paediatric Network for Haemophilia Management, 1999 Primary prophylaxis determined by age Long-term continuousa treatment started before the age of 2 years and prior to any clinically evident joint bleeding.
Primary prophylaxis determined by first bleed Long-term continuousa treatment started prior to the onset of joint involvement (presumptively defined as having had no more than one joint bleed), irrespective of age.
European Paediatric Network for Haemophilia Management, 2006 Regular continuous treatment started after the first joint bleed and before the age of 2 years.
International Society on Thrombosis and Haemostasis, 2014 Regular continuousb replacement therapy started in the absence of documented joint disease, determined by physical examination and/or imaging studies, and before the second clinically evident joint bleed and age 3 years.
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a

With the intent of treating 52 weeks/year up to adulthood and receiving treatment a minimum of 46 weeks/year.

b

Continuous is defined as the intent to treat for 52 weeks/year and receiving a minimum of an a priori defined frequency of infusions for at least 45 weeks (85%) of the year under consideration.

Despite its typical early start, primary prophylaxis cannot completely prevent the development of some degree of joint involvement [18] The effects of joint involvement, triggered by breakthrough bleeding, can be underestimated even with the use of scores commonly employed in clinical practice, such as the Gilbert score and the Hemophilia Joint Health Score (HJHS) 2.1 [19]. The importance of early detection of joint involvement has led to the development of the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score [20], an ultrasound–based method that can identify early changes in the synovium, cartilage, and bone of the most frequently affected joints (elbows, knees, and ankles) for the subsequent performance of specific imaging studies.

The advent of new nonsubstitutive therapies, such as emicizumab, is undoubtedly transforming the current and future landscape of prophylaxis. Given the proposed definition of prophylaxis recently published in the World Federation of Hemophilia guidelines [21], which prioritizes outcomes over product regimens, there is a need for reliable, homogeneous data on the achievements of classical primary prophylaxis regimens with FVIII and their long-term outcomes to establish the goals for treating these patients.

In this study, we retrospectively analyzed the protection level of primary prophylaxis in patients with SHA under follow-up at La Paz University Hospital, Madrid, Spain, with emphasis on joint status after 20 years of follow-up.

2. Methods

2.1. Design

We retrospectively analyzed patients with SHA (FVIII <1%) without inhibitor at the start of primary prophylaxis, who were consecutively diagnosed from January 2000 to December 2019. Variables were collected throughout the analysis period as follows. The data were collected and analyzed between March 2020 and March 2021.

This study was approved by the Research Ethics Committee on Medicines of La Paz University Hospital. The data were treated confidentially under Spanish regulations.

2.2. Variables

2.2.1. Definition of primary prophylaxis, regimen, and FVIII trough levels

Patients who started prophylaxis before 2014 were treated following the definition of prophylaxis established by the European Pediatric Network for Hemophilia Management during that period [1], [2]. Patients included after the update of the definition of primary prophylaxis by the International Society on Thrombosis and Hemostasis in 2014 were treated according to the updated criteria [3].

We started patients on prophylaxis with FVIII concentrates at a dosage of 25 to 40 IU/kg weekly for the first year of life until a balance between exposure days, trough levels of FVIII, physical activity, and annual bleeding rate (ABR) was achieved. The dosage was subsequently increased according to the hemorrhagic phenotype and physical activity. For each person, we sought to personalize FVIII trough levels according to their clinical evolution without establishing fixed target levels [22].

We analyzed FVIII trough levels monthly at the start of prophylaxis, prior to each treatment adjustment, and at least twice a year in patients with stable prophylaxis treatment patterns and absence of spontaneous bleeding or synovitis detection. We performed a pharmacokinetic study prior to switching from standard half-life FVIII concentrates to extended half-life concentrates.

To perform FVIII analysis, the chromogenic method was used (FVIII chromogenic assay, Siemens, IU/dL) in a BCS-XP analyzer (Siemens). We had previously used other analyzers but with no changes in the method during the follow-up. Pharmacokinetic studies were performed using the myPKFiT and WAPPS-HEMO applications.

2.2.2. Joint status

We analyzed joint status using the HJHS 2.1 score on an annual basis. Since 2014, we likewise performed an annual assessment using the HEAD-US score for each person. Joint involvement in our patients was defined as an HJHS or HEAD-US score of ≥1.

2.2.3. Hemorrhagic episodes

La Paz University Hospital is a reference center for patients with congenital coagulopathies in Madrid. Madrid has approximately 5 million inhabitants, and the longest distance to our center is approximately 50 km; however, 90% of the population lives in the surrounding area. Throughout their follow-up, patients were educated on the warning signs that they should recognize when they come to the hospital for assistance. Once at the hospital, patients were evaluated by the hematology specialists, who asked the radiology service to perform confirmatory imaging tests in cases of suspected hemarthrosis or muscle bleeding, the most frequently performed tests being musculoskeletal ultrasound or computed tomography.

Data were collected from medical record data, written patient–reported data, and more recently through electronic systems. We documented the ABR and the annual joint bleeding rate (AJBR). Joint bleeds were confirmed by imaging tests, mainly musculoskeletal ultrasound. The following formula was employed to calculate ABR and AJBR: (number of bleeding episodes/duration of the study in days) × 365.25. The overall results were expressed as means.

2.2.4. Physical activity

Physical activity performed by each person was recorded in the clinical history at each medical checkup. For their evaluation, we used the Activity Ratings Chart (Playing It Safe, National Hemophilia Foundation) [23] Two groups were differentiated according to the score obtained (<2 for low- or low-to-moderate-risk activities and ≥2 for moderate-, moderate-to-high-, or high-risk activities).

2.2.5. Adherence

The definition of adherence was established according to the criteria established by Schrijvers et al. [24], who sought to reach a consensus on adherence from a clinical point of view using the Delphi methodology, considering changes in dosage, frequency of prophylaxis administration, and loss of infusions. Patients who took ≥85% of the prescribed doses (ratio of the number of doses administered to the prescribed doses) were considered treatment compliant. Adherence was calculated from the computerized records of the Pharmacy Department.

2.2.6. Inhibitor development

Patients who developed persistent inhibitors in the early exposure days and needed to switch to immune tolerance induction regimens were excluded from the analysis. The development of inhibitors during follow-up was documented using the Bethesda method (>0.6 BU/dL in 2 successive determinations) and the number of exposures at the time of inhibitor development.

2.2.7. Statistical analysis

Qualitative data were described as absolute frequencies and percentages, and quantitative data as medians and IQRs. The association between the qualitative variables was analyzed using the chi-squared test or Fisher’s exact test. To compare qualitative and quantitative data, we used the Mann–Whitney U test as a nonparametric test. In all statistical tests, P values < .05 were considered bilateral and significant. Data were analyzed with the SAS 9.3 statistical program (SAS Institute).

3. Results

We retrospectively studied 64 European patients diagnosed with SHA on primary prophylaxis under follow-up at La Paz University Hospital between January 2000 and December 2019. Patients who developed persistent inhibitors in the early exposure days and required changes in the prophylaxis regimen during follow-up, needing immunotolerance, were excluded from the analysis (n = 4) (Figure 1).

FIGURE 1.

FIGURE 1

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follow-up and analysis (433 × 215 mm [300 × 300 DPI])

The median follow-up time for the 60 patients analyzed was 10 (8-16) years. The mean age at the end of the follow-up was 10.7 ± 5.5 years, and the follow-up time for prophylaxis was 113 ± 6 months. Joint involvement was observed only in 23.3% (n = 14) of the series at the end of the follow-up period (Table 2).

Table 2.

HEAD-US and HJHS 2.1 scores.

Patients without joint involvement (n = 46) Patients with joint involvement (n = 14)
Score n (%) Score n (%) Score (range)
HJHS 2.1 0 46 (100) ≥1 6 (42.9) 1 to 10
HEAD-US S (synovial) 0 46 (100) ≥1 9 (64.3) 1
HEAD-US C (cartilage) 0 46 (100) ≥1 8 (50.0) 1 to 4
HEAD-US H (bone) 0 46 (100) ≥1 2 (14.3) 1
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HEAD-US, Hemophilia Early Arthropathy Detection with Ultrasound; HJHS, Hemophilia Joint Health Score.

In patients without joint involvement at the end of follow-up, the median age at initiation of prophylaxis was 1 (1-1) year compared with those with joint involvement (3 years, [2-4.3]). The median age of joint involvement onset was 12 (3-18) years. The results are summarized in Table 3.

Table 3.

Patient characteristics.

Patients without joint involvement (n = 46) Patients with joint involvement (n = 14) P
Race/Ethnicity European (n = 60)
Country of origin Spain (n = 60)
Age at the end of follow-up, y 8.5 (6-14) 18 (12-19) 0.003
Age at start of prophylaxis, y 1 (1-1) 3 (2-4.3) <0.001
 <3 y, n 46
 <2 y, n 42 8
 ≥3 y, n 0 06
Age at onset of joint involvement, years (HJHS 2.1 or HEAD-US ≥1) - 12 (3-18)
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Note: Values are listed as median (IQR) unless otherwise specified.

When comparing the variables FVIII trough levels and treatment received, we observed that the patients who developed joint involvement received more IU/kg/year (6622 [6,153-10,410] vs 6080 [5,090-7,561], P = .052) and had higher FVIII trough levels (2.4 UI/dL [0.9-4.7] vs 0.9 UI/dL [0.4-1.8], P = .026). The primary type of FVIII concentrate used was standard half-life recombinant FVIII, switching to extended half-life FVIII concentrates in 15 cases, 9 based on the increase in ABR over the previous year and the degree of physical activity performed, and 6 to facilitate adherence by reducing the number of annual infusions (Table 4). Adherence was ≥85% in both groups, with no statistically significant differences (P = .167). Central venous access was placed in 38 (63.3%) patients, with a median usage time of 83 (1-228) months.

Table 4.

Prophylaxis characteristics.

Patients without joint involvement (n = 46) Patients with joint involvement (n = 14) P value
Median (IQR) duration of prophylaxis, months 96 (65-149) 152 (102-203) .042
Median (IQR) FVIII trough levels, UI/dL 0.9 (0.4-1.8) 2.4 (0.9-4.7) .026
Total number of FVIII assays analyzed (n) 362 107
Median (IQR) dosage, IU/kg/year 6080 (5,090-7,561) 6622 (6,153-10,410) .052
Adherence, % 96 (87-102) 88 (80-101) .167
Standard half-life FVIII products
 
  • •

    Plasma–derived FVIII concentrates, %

 - 28.6
 
  • •

    Recombinant FVIII concentrates, %

 100 71.4
Switch to extended half-life FVIII products, (n), % 14 (30.4) 1 (7.1)
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FVIII, factor VIII.

Patients with joint involvement had a higher number of joint bleeds (AJBR 0.2 [0.1-0.5] vs 0.0 [0-0.2], P = .013), with a median ABR similar to that of patients without joint involvement (0.6 [0.4-1.0] vs 0.7 [0.2-0.9], P = .630). Approximately 70% of patients without joint involvement were physically active, mainly with low or low-to-moderate risk (score <2). The time spent in physical activity was similar in both groups. The results are shown in Table 5.

Table 5.

Hemorrhagic episodes and physical activity.

Patients without joint involvement (n = 46) Patients with joint involvement (n = 14) P value
ABR 0.7 (0.2-0.9) 0.6 (0.4-1.0) .630
AJBR 0.0 (0-0.2) 0.2 (0.1-0.5) .013
Other bleedings 0.5 (0.2-0.8) 0.4 (0.2-0.5) .426
Physical activity (n, %) 32 (70) 7 (50) .145
- NHF risk score <2 (n) 20 1
- NHF risk score ≥2 (n) 12 6
Duration, y 4 (3-6) 4 (2-6) .552
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Note: Values are listed as median (IQR) unless otherwise specified.

ABR, annualized bleeding rate; AJBR, annualized joint bleeding rate.

The correlation analysis between the variables to be considered in prophylaxis (Spearman’s ρ) showed that starting prophylaxis at ≥2 years of age presented a higher degree of correlation with the appearance of joint involvement than the rest of the variables (ρ = 0.68, P < .001). Results are shown in Figure 2. When evaluating the impact of the age at prophylaxis initiation on the other variables in patients who did not develop joint involvement, we found that delayed initiation of treatment was associated with higher rates of total and joint bleeds, as well as with higher FVIII trough levels (Figure 3).

FIGURE 2.

FIGURE 2

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Correlation of the different variables of primary prophylaxis with the development of joint involvement (479 × 384 mm [600 × 600 DPI])

FIGURE 3.

FIGURE 3

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Correlation of the different variables of primary prophylaxis with the age of treatment initiation in patients without joint involvement (554 × 361 mm [300 × 300 DPI])

The occurrence of inhibitors during prophylaxis was documented in 6 (10%) cases, 5 of which were in the group of patients who did not develop joint involvement, with a mean of 14 (6-20) exposures; 83.3% were low titer (n = 5), and 16.7% were >5 BU/mL (n = 1). In all cases, they were transient inhibitors, without requiring specific treatment.

4. Discussion

The advent of new extended half-life FVIII concentrates, and especially the introduction of nonsubstitutive therapies, such as emicizumab, has led to a progressive change in managing patients with SHA. Although these new therapies offer excellent results in reducing ABR, more research is needed to assess their long-term effectiveness in joint health protection in future prophylaxis regimens. The coming innovations in both the nature of therapy and the objective of prophylaxis following the World Federation of Hemophilia’s new definitions require a global and uniform evaluation of the impact of the current protocols used for primary prophylaxis in SHA. This evaluation would guide the principles for future treatment lines and obtain a benchmark for evaluating their long-term impact. In this study, we retrospectively studied the effects of a homogeneous primary prophylaxis protocol on joint protection with FVIII concentrates in 60 patients analyzed over 20 years of follow-up. We conducted an exhaustive analysis of the variables, including age at start of primary prophylaxis, pharmacokinetic parameters, ABR, physical activity, therapeutic adherence, and assessment of joint status by physical and ultrasound examinations.

Three years is currently considered the age limit for starting primary prophylaxis. The importance of an early start has been supported by several studies [[25], [26], [27], [28], [29], [30]]. However, the various protocols show significant variability in terms of age at start of primary prophylaxis and the length of follow-up. No subanalyses have been performed within the accepted age criteria to assess whether there is better joint protection status at specific age intervals for starting primary prophylaxis. Various studies around the world have supported the primary prophylaxis scheme, including Nilsson et al. (1992, Sweden) [31], Kreuz et al. (1998, Germany) [32], van der Berg et al. (2001, Netherlands) [33], Yee et al. (2002, United Kingdom) [34], and Panicker et al. (2003, United States) [35]. These studies have reported on cohorts consisting of 11 to 70 patients, with starting age ranging from 0.5 to 16 years.

The onset of arthropathy depends mainly on the AJBR. Various studies have documented that patients on prophylactic treatment can experience delayed development of joint disease compared with patients receiving on-demand treatment, although prophylaxis does not eliminate its onset. The Joint Outcome Study published by Manco-Johnson et al. [36] compared the occurrence of joint involvement in both groups, documenting the development of damage by MRI after a mean participation period of 49 months in 45% of patients receiving episodic treatment versus 7% of patients on prophylaxis. The occurrence of joint involvement under the Swedish and Dutch prophylaxis regimens was also compared by Fischer et al. [12], with a median HJHS of 4 (IQR 2-6.8) in the first group and 9 (IQR 2-18) in the second. Therefore, the results of our study, over a 20-year follow-up period, suggest the benefits of individualized prophylaxis schemes over conventional regimens as a protective factor in preventing the occurrence of joint involvement. In contrast, the subanalysis performed on the 37 patients included in the Joint Outcome Continuation Study (JOS-C) [37] established the protective role of early prophylaxis (median age, 1.3 years; n = 15) vs later onset (median age, 7.6 years; n = 18), finding wide variability in age between the cohorts. This fact is confirmed in our study, in which a greater correlation was observed between the initiation of prophylaxis in patients ≥2 years of age and the development of joint involvement, even though the initiation of primary prophylaxis could have been performed up to 3 years of age.

Although prophylaxis protocols have classically recommended FVIII trough levels >1%, there is heterogeneity in these patients’ hemorrhagic phenotype and its variable correlation with FVIII levels in certain events, with 3 to 10% of patients not experiencing their first bleeding episode at an early age [[38], [39], [40], [41], [42], [43], [44], [45]]. In our series, lower FVIII trough levels in patients without joint involvement did not result in an increase in total bleeding events. In patients who developed joint involvement, median FVIII trough levels >1% were not associated with decreased AJBR. These data highlight the importance of individualization according to the patient’s bleeding phenotype vs the conventional need to maintain certain target FVIII trough levels during follow-up. In addition, the correlation between physical activity and trough levels to reduce the associated breakthrough bleeding in tailored prophylaxis has not yet been standardized [46]. In our study, 32 patients were physically active, mainly at low or low-to-moderate risk, with a median FVIII trough level of <1%, with no joint involvement at the end of follow-up or a significant increase in bleeding events. Regarding the form of prophylaxis administration, adherence is favored in the initial phase after the implantation of a central venous catheter. In our series, the significant variability in the catheter maintenance time was because, despite the existence of learning programs to promote their withdrawal and avoid the potential complications derived from their continuous use, the convenience offered to caregivers meant that, in many cases, their use was extended over time.

Due to the importance of the periodic characterization of the articular status of the patients with hemophilia when adjusting prophylaxis, various scores have been developed to evaluate synovitis. Ultrasound and magnetic resonance imaging are the tests of choice for hemophilia diagnosis and evolutionary control, and their importance lies in the fact that the involvement of the synovial membrane and the chondrocyte constitute the first step toward the development of arthropathy associated with hemophilia. The HEAD-US score evaluates the posterior longitudinal section of the posterior olecranial recess at the elbow, the central longitudinal section of the suprapatellar recess at the knee, and the longitudinal section of the anterior tibio-astragalic recess in line with the extensor tendon of the first toe at the ankle by ultrasound, with a score of 0 corresponding to a normal joint status. Its implementation in clinical practice has also made possible the evolutionary control of acute hemarthrosis. According to the conventional HJHS 2.1 functional assessment score (n = 54), several patients in this study who had no evident joint involvement experienced changes according to their HEAD-US score (3 cases of synovitis, 5 cases of chondral involvement, and 1 case of subchondral involvement). According to the HEAD-US score, a study [47] had observed that approximately 14% of their patients presented changes compatible with incipient arthropathy in apparently healthy joints observed during physical examination. Our results highlight the advantages of using ultrasound assessment scores in routine clinical practice. Likewise, in patients with established joint involvement, reflected in both scores, the study has been completed by means of specific imaging tests relevant to each case and by performing a multidisciplinary follow-up with the traumatology and rehabilitation services.

There are several limitations to our study, such as its retrospective nature and the collection of patient–reported ABR and AJBR data, with its possible inaccuracies. Nonetheless, given the implementation of the HEAD-US score in clinical practice in 2014, the existence of incipient joint involvement undetectable by conventional functional scores in patients at younger ages at the end of the follow-up period cannot be ruled out. However, the HEAD-US score has been used as a surrogate outcome of joint status, allowing us to assess our cohort’s situation and uniformly evaluate the effect of primary prophylaxis. The correlation between the different prophylaxis variables, including follow-up time, has shown that, despite the limitations of our study previously described, the age at the start of treatment was the factor most associated with the development of joint involvement. Another strength of our study is the homogeneous management of the cohort by a multidisciplinary team over this period with standard criteria over time.

Of all the factors to be considered in prophylaxis regimens, we suggest that early initiation of prophylaxis, preferably in children younger than 2 years of age, together with periodic monitoring of joint status using tools to detect incipient involvement, are the most relevant factors when evaluating the efficacy of treatment in these patients. In a complementary manner, tailoring the treatment based on ABR evaluations, along with proper analytical monitoring, could result in a low incidence of arthropathy. While we await the results of long-term prophylaxis using the new nonreplacement therapies, our data illustrate the importance of starting treatment early and serve as a basis for establishing a solid long-term comparison of the specific variables that influence the treatment of these patients.

Acknowledgments

Funding

This study was supported by ISCIII-Fondos Feder (PI19/00631).

Author Contributions

M.d.M.M. and M.T.Á.-R. designed the research and wrote the manuscript; N.B.C., H.D.L.C.R., and V.J.-Y. reviewed the manuscript.

Relationship Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study.

Footnotes

Funding information ISCIII-Fondos Feder, Grant/Award Number: PI19/00631.

Handling Editor: Dr Pantep Angchaisuksiri

María del Mar Meijón and María Teresa Álvarez-Román contributed equally to the study.

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