Turning severe into moderate haemophilia by prophylaxis: are we reaching our goal?

Abstract

Background

Since the introduction of prophylaxis, physicians have tried to convert the clinical phenotype of severe haemophilia (SH) into that of moderate haemophilia (MH), but the outcome of patients with SH has never been compared to that of patients with MH.

Material and methods

The outcome of 80 patients with SH on long-term, intermediate dose prophylaxis was compared to that of 40 patients with MH in a single-centre study. Data on treatment history, activities (assessed by the IPAQ and HAL), quality of life (assessed by the SF-36 and EQ5D), and 5-year bleeding and clotting factor consumption were collected for patients born between 1970–1995.

Results

The median age of the patients was 24 years (IQR 18–30). All patients with SH received long-term prophylaxis, which was started at a median age of 4.8 years (IQR 3.2–6.2). Among the patients with MH, ten (25%) received prophylaxis, starting at a median age of 10.8 years (IQR 3.8–13.8). The annual number of bleeds, including joint bleeds, was significantly higher in patients with SH (median 2.0 joint bleeds/year, IQR =0.8–3.7) than in patients with MH (median 0.8 joint bleeds/year, IQR =0–1.2). Due to greater use of prophylaxis, the annual clotting factor consumption of SH patients (median 2,120 IU/kg; IQR 1,514–2,768), was higher than that of MH patients (median 133 IU/kg; IQR 49–468). Patients with SH showed slightly but significantly more loss of clinical function (assessed by the Haemophilia Joint Health Score): a median of 8 points (IQR 3–15) vs a median of 2 points, IQR 0–6). Quality of life, as measured by the SF-36, EQ5D and physical activity, was similar between patients with disease of different severity, as well as compared to that of the general population.

Discussion

When comparing unselected cohorts, the bleeding pattern of patients with SH does not appear to be fully converted to that of the milder bleeding pattern of MH by long-term, intermediate-dose prophylaxis, although activities and quality of life were similar.

Introduction

Haemophilia is classified according to a patients’ residual factor activity level. Patients with severe haemophilia have a residual factor activity level of <1 IU/dL and can bleed spontaneously into joints, muscles and other soft tissues. Patients with moderate haemophilia have factor activity levels between 1 IU/dL - 5 IU/dL and these patients mostly bleed only after trauma and surgery. Patients with mild haemophilia have factor activity levels of >5 IU/dL and hardly bleed at all, apart from after surgery. Haemophilia can be treated with replacement clotting factor, which has been available since 1965¹. In the 1970s prophylactic treatment was introduced with the aim of convert the severe bleeding phenotype into the bleeding pattern of patients with moderate haemophilia². The goal of prophylaxis is to prevent bleeding, especially into joints, thus preventing arthropathy and consequent loss of quality of life³.

Prophylaxis is a regular infusion of clotting factor concentrate to replace the deficient clotting factor in the plasma of haemophiliacs. This treatment is only available through intravenous administration. Given the short half-life of replacement factor, patients have to inject at least three times a week on a prophylactic regimen⁴, which poses a considerable burden, especially in young children.

Traditionally, target trough levels of prophylaxis⁵ have been set at 1–3 IU/dL^6,7, the residual factor activity levels present in patients with moderate haemophilia. In theory, the outcome of patients with severe haemophilia on long-term prophylaxis should, therefore, be comparable to that of patients with moderate haemophilia. However, in The Netherlands an intermediate dose of prophylaxis is provided, which is more tailored to the patients’ clinical outcome than to trough levels⁸. In this single-centre, cohort study, bleeding rates, orthopaedic outcome and quality of life of patients with severe haemophilia on long-term prophylaxis were compared to those of patients with moderate haemophilia.

Materials and methods

All patients with severe haemophilia (<1 IU/dL factor VIII/factor IX activity) on long-term, intermediate-dose prophylaxis and with moderate haemophilia (1–5 IU/dL factor VIII/factor IX activity), born between 1970 and 1995, treated at the van Creveldkliniek, Utrecht, The Netherlands, were included in this retrospective study. Patients who had ever had inhibitors >0.6 BU (19 patients) and those who did not have access to haemophilia care in their childhood were excluded (6 patients). Two patients did not want to participate in the study.

Questionnaires on quality of life (SF 36, EQ5D), daily activities (HAL) and sports activities (IPAQ and a self-designed sports-list specifying type of participation in sports during the preceding year) were administered to all patients aged >17 years. Prophylaxis was defined as at least one regular infusion per week for at least 45 weeks per year. Long-term prophylaxis for severe haemophilia was defined as treatment with prophylaxis for at least 30% of the time between diagnosis and last evaluation, with a minimum of 7 years. Joint bleeds were defined as complaints in ankles, knees, elbows, hips, wrists, or shoulders requiring treatment with concentrate at least once.

Weekly physical activity was measured by the International Physical Activity Questionnaire (IPAQ), which allows for the computation of metabolic equivalence estimates (MET)⁹. To compare activity with the general population (controls), patients received an extra questionnaire to be filled in by a friend or colleague within a 5-year age range of the patient. This questionnaire contained the IPAQ and a sports-list. All sports activities were categorised into medium-risk activities, such as swimming and cycling, or high-risk activities, such as football, skiing and hockey¹⁰. The outcome of the patients with severe haemophilia was compared to that of the patients with moderate haemophilia. The patients’ scores in the short-form 26 (SF-36) and a EuroQoL health-related quality of life questionnaire (EQ5D) were compared to those of the male population in The Netherlands^11,12.

Statistical testing was performed using the Kruskal-Wallis test, a non-parametric test for continuous variables and Fisher’s exact test for categorical variables. Statistical analyses were performed with Stata SE11 (Statacorp, Texas, United States of America).

Results

The treatment history and bleeding details of 80 patients with severe haemophilia and 40 patients with moderate haemophilia were collected. Table I shows the patients’ characteristics according to haemophilia severity. The median age at last evaluation was 24 years (range, 12 to 37 years in patients with severe haemophilia and 13 to 38 years in patients with moderate haemophilia). Haemophilia A was diagnosed in 105 of the 120 patients (88%). Most patients were diagnosed before the age of 1 year (median 0.6 years, interquartile range [IQR] 0.3–1.2 years). Patients with severe haemophilia had a factor activity of <1 IU/dL; patients with moderate haemophilia had a median factor activity of 2 IU/dL (range, 1–5 IU/dL).

Table I.

Characteristics, bleeding and treatment of patients with severe or moderate haemophilia.

	Severe	Moderate	P-value
Patients’ characteristics
Number	80	40
Age in 2007 (years)	24 (18–30)	24 (19–32)	0.56
Haemophilia A	72 (90%)	33 (83%)	0.24
Age at diagnosis (years)	0.7 (0.18–1.0)	0.5 (0–2.0)	0.90
Factor activity (IU/dL)	<1	2 (2–3)	<0.001
Bleeding
Age at 1st joint bleed (years)	2.0 (1.1–3.0)	4.8 (3.0–8.5)	<0.001
Annual n. of bleeds	3.9 (1.9–6.1)	2.2 (0.8–3.1)	<0.001
Annual n. of joint bleeds	2.0 (0.8–3.7)	0.8 (0–1.2)	<0.001
No joint bleed in preceding 5 years	7 (9%)	10 (25%)	0.02
Treatment
Age at starting prophylaxis (years)	4.8 (3.2–6.2)	10.4 (2.8–13.8)	0.05
History of long-term prophylaxis	80 (100%)	10 (25%)	<0.001
Weekly dose of prophylaxis (IU/kg)	47 (35–55)	29 (17–54)	0.16
Home treatment	80 (100%)	21 (53%)	<0.001
No treatment in preceding 5 years	0	1 (3%)	0.33
Annual factor consumption in 5 years (IU/kg/year)	2,120 (1,514–2,768)	133 (49–468)	<0.001

Legend Values are median (IQR) or n. (%)

Bleeding and treatment

Bleeding and treatment characteristics are presented in Table I. Patients with severe haemophilia suffered their first joint bleed at a median age of 2.0 years (IQR 1.1–3.0 years), which was much earlier than patients with moderate haemophilia who had onset of joint bleeding at a median age of 4.8 years (IQR 3.0–8.5 years). The frequency of bleeding was higher in patients with severe haemophilia on long-term prophylaxis than in patients with moderate haemophilia (P <0.001). Patients with severe haemophilia had a median 3.9 bleeds/year, including 2.0 joint bleeds (IQR 0.8–3.7 joint bleeds/year), while those with moderate haemophilia had a median of 2.2 bleeds, including 0.8 joint bleeds (IQR 0–1.2 joint bleeds/year). In the preceding 5 years, seven patients with severe haemophilia (9%) and ten with moderate haemophilia (25%) had not suffered any joint bleeds.

All patients with severe haemophilia had used long-term prophylaxis for a median of 18 years (range, 7.8–36.7 years). Patients with severe haemophilia started prophylaxis at a median age of 4.8 years(IQR 3.2–6.2 years). The median weekly dose at last evaluation was 47 IU/kg (IQR 35–55 IU/kg). Twelve patients with severe haemophilia (15%) stopped prophylaxis completely during the study period at a median age of 21 years (IQR 16–22 years). The bleeding frequency in these patients remained low with a median of 1.0 joint bleed/year (IQR 0.3–4.0 joint bleeds/year) which was comparable to the frequency in patients with moderate haemophilia (P =0.4). Seven patients with severe haemophilia tried to stop prophylaxis, but had to restart it within a year, because of high bleeding frequencies (median 3.6 joint bleeds/year, IQR 0.6–6.3 joint bleeds/year).

Ten patients with moderate haemophilia (25%) also used prophylaxis during the study period. These patients used a median weekly dose of 29 IU/kg (IQR 17–54 IU/kg). Patients with moderate haemophilia started prophylaxis later (P <0.05), at a median of 10.4 years (IQR 2.8–13.8 years), compared to those with severe haemophilia.

All patients on prophylaxis used home treatment and an additional 11 patients with moderate haemophilia also used home treatment. Patients treated with prophylaxis all had factor activity levels ≤3 IU/dL (median 2 IU/dL, range 1–3 IU/dL), while patients treated on demand had slightly higher factor activity levels (median 3 IU/dL (IQR 2–4 IU/dL).

Patients treated on demand had significantly lower bleeding rates (P <0.01) and better joint outcome (P <0.01) than patients with either severe or moderate haemophilia treated with prophylaxis. Patients treated on demand suffered a median of 0.5 joint bleeds/year (IQR 0–1 joint bleeds/year), while patients with moderate haemophilia treated with prophylaxis suffered a median of 1.1 joint bleeds/year (IQR 0.4–2.9 joint bleeds/year) and those with severe haemophilia had a median of 2.0 joint bleeds/year (IQR 0.8–3.7 joint bleeds/year).

Given the greater use of prophylaxis, factor consumption was much higher (P <0.001) in patients with severe haemophilia than in those with moderate haemophilia. Sixteen patients with severe haemophilia (12%) needed a central venous access device at some point in their lives, whereas none of the patients with moderate haemophilia ever did.

Joint outcome and quality of life

Joint outcome and quality of life of the patients divided according to disease severity and compared to the general population are shown in Table II. Although clinical loss of function, as measured by the Haemophilia Joint Health Score (HJHS), varied widely for both severities, scores were slightly, but significantly higher in patients with severe haemophilia. Overall, joint damage appeared only mild: 44 patients with severe haemophilia (55%) and 29 patients with moderate haemophilia (73%) had HJHS scores <10 points. The proportion of patients with a history of orthopaedic surgery was similar in both groups, 12 patients with severe haemophilia (15%) and 3 with moderate disease (8%) had a history of orthopaedic surgery (p =0.38). Most of these patients (9 with severe and 2 with moderate haemophilia), underwent at least one major orthopaedic procedure; the others had only had minor surgery.

Table II.

Joint outcome and quality of life according to disease severity, compared to the same factors in the general population (unaffected controls).

	Severe haemophilia	Moderate haemophilia	Unaffected controls	P-value*
Number	60	34	105
Age (years)	27 (21–31)	25 (20–33)	24 (20–31)	0.56
Joint outcome
Loss of function (HJHS, max 128 points)	8 (3–15)	2 (0–6)	-	<0.001
History of orthopaedic surgery	12 (15%)	3 (8%)	-	0.38
Quality of life
Utility (EQ5D)	0.80 (0.72–1)	0.92 (0.72–1)	0.87 (0.84–1.0)	0.66
Physical activity (MET)	4,294 (1,554–10,480)	2,240 (880–5,118)	3,023 (1,493–6,936)	0.26
Participation in sports	47(59%)	28 (70%)	92 (88%)	<0.01
Participation in high-risk sports	27 (34%)	20 (50%)	64 (61%)	<0.01

Legend Values are median (IQR) or n. (%)

^*P-values for comparison between patients with severe or moderate haemophilia.

Of 120 patients sent the questionnaires, 94 patients (78%) returned them, whereas 105 questionnaires were received from unaffected controls. Quality of life was similar across all groups. Patients with haemophilia, either severe or moderate, reported equal quality of life as measured by the SF-36 (Figure 1) or EQ5D (Table II). Patients were also just as active as their peers, with median activity being 3,276 MET (IQR 960–8,640) in patients and 3,023 MET (IQR 1,493–6,936) in peers.

Figure 1.

SF-36 scores of patients with severe or moderate haemophilia compared to the score in the genera, malel population. The solid black line represents the male population in The Netherlands.

Patients with severe haemophilia reported a higher activity level (median 4294 MET; IQR 1,554–10,480 MET) than patients with moderate haemophilia (median 2,484 MET; IQR 942–5,660 MET). More than half of all haemophiliacs were involved in at least one sports activity. The majority of people in the control group (61%) participated in at least one high-risk sport. Haemophilia patients were more cautious, 50% of patients with moderate haemophilia and 34% of those with severe haemophilia also participated in high risk sports, with these rates being significantly lower than the rate in controls (Table II).

Discussion

The goal of prophylaxis is to convert the bleeding pattern of patients with severe haemophilia into that of patients with moderate haemophilia. This study showed that, despite early prophylaxis, bleeding frequencies and joint function scores were slightly higher in patients with severe haemophilia treated with long-term, intermediate-dose prophylaxis. A significant variation in bleeding phenotype was observed in both patients with severe and moderate haemophilia. The bleeding rates of patients with moderate haemophilia who needed prophylaxis were comparable to those of patients with severe haemophilia on intermediate-dose prophylaxis but higher than those receiving on demand treatment, suggesting that the tailored dose of prophylaxis does not completely change a severe bleeding phenotype in a moderate bleeding phenotype. Activity and quality of life were, however, comparable across all groups.

When comparing disease severities, the effects of the 15% of patients with severe haemophilia who discontinued prophylaxis and the 25% of patients with moderate haemophilia who required long-term prophylaxis who were included could not be quantified separately. It may seem odd that patients with moderate haemophilia treated with prophylaxis were included in the analyses. Excluding these patients with moderate haemophilia on prophylaxis would have introduced confounding by indication; leaving out patients with moderate haemophilia with a high bleeding frequency; for a similar reason, patients with severe haemophilia who discontinued prophylaxis, but had received long-term prophylaxis in their childhood, were also included in the comparison. Moderate haemophilia may be considered a “natural experiment” for trough levels in prophylaxis of severe haemophilia. Patients with moderate haemophilia treated with prophylaxis reported higher bleeding frequencies than those treated on demand. Without medical intervention, these patients would not have received prophylaxis and the outcome of patients with severe haemophilia would probably have been very close or similar to that of those with moderate haemophilia.

Quality of life and physical activity were similar in all groups as well as compared to the general population, which implies that the goal of prophylaxis to let patients be as active as their peers without haemophilia was reached. Evidently, one or two extra joint bleeds per year, if treated quickly and sufficiently, will not tremendously influence clinical function and quality of life. Surprisingly, patients with severe haemophilia reported the highest levels of activity. One third even participated in high-risk sports. Most of these patients infuse just before activities, to profit from the high level of factor activity enabling them to participate in all kinds of (high-risk) sports without bleeding.

However, quality of life may have been overestimated due to coping effects. It has been shown that patients with a chronic disease rate their quality of life higher than the general population¹², and haemophilia is certainly a chronic condition. Patients suffered their first joint bleeds young, at a median age of 2.0 years in those with severe disease and 4.8 years in those with moderate haemophilia. They learned to cope with their condition and the invasive treatment in their childhood, which may no longer be perceived as intrusive, but as a habit.

Patients on long-term prophylaxis spend a large part of their life with more than 5 IU/dL factor activity¹³. In effect they may be expected to have a better outcome than patients with moderate haemophilia, who spend most of their lives with <5 IU/dL factor activity. This study showed that their bleeding and outcome were slightly worse than in moderate haemophilia. In 2009, Collins et al.¹⁴ modelled time with factor activity below 1 IU/dL and the association with joint bleeding. They predicted an increased number of joint bleeds when a patient spends more time per week with factor activity <1 IU/dL, which may account for the worse outcome in severe haemophilia. At the Van Creveldkliniek, prophylaxis is targeted at bleeding pattern, rather than through levels, hence relatively low dosages were used, the median weekly dose being 47 IU/kg over three infusions. Even though a dose of 1,000 IU every other day will keep an average adult male with a factor level above 1% all the time, this is not the case for all patients¹⁴. In order for the prophylactic regimen to work, patients need to adhere to the prescribed treatment. In a recent European study adherence to therapy was 80–87% in haemophiliacs¹⁵. Lack of compliance to prophylaxis can lead to an increased time spent with factor activity <1 IU/dL and increased bleeding. As the Dutch regime targets clinical symptoms more than trough levels, hardly any trough levels were available for this study.

Severe haemophilia could perhaps be converted to moderate haemophilia by using a higher dose of prophylaxis. Fischer et al. compared the effect of intermediate-dose prophylaxis in Dutch patients and high-dose prophylaxis in Swedish patients⁸. Compared to the Swedish patients, Dutch patients had a higher bleeding rate and showed a trend towards more abnormalities on radiography.

The future of prophylactic treatment for severe haemophilia should be focused on retaining at least the current clinical outcome and quality of life. It is clear that residual clotting factor activity is associated with better outcome, but it is not the only determinant of bleeding: patients with moderate haemophilia also showed considerable variation in bleeding, independently of factor activity.

Compared to patients with moderate haemophilia, increased bleeding in young adults with severe haemophilia on an intermediate dose of prophylaxis was associated with a slightly increased loss of joint function and less participation in (high-risk) sports, but normal physical activity levels and only minimal changes in quality of life. Future studies should investigate the benefits of more stringent bleeding control as used, for example, in Sweden⁸. Apparently, the goal set by Inga-Marie Nillsson in the 1950s¹⁶ of turning severe haemophilia into moderate haemophilia is not reached entirely with intermediate-dose prophylaxis. The goal of letting haemophilia patients be as active as their peers is, however, reached for both patients with moderate and severe haemophilia.