Keywords
haemophilia - von Willebrand disease - socioeconomic status - quality of life - outcomes
Schlüsselwörter
hämophilie - von-willebrand-syndrom - sozioökonomischer status - lebensqualität -
ergebnisse
The impact of inherited bleeding disorders such as haemophilia and von Willebrand
disease (VWD) on the socioeconomic status (SES) of affected individuals has not been
sufficiently addressed. Major problems in haemophilia are repeated joint bleeds, which
may lead to haemophilic arthropathy with significant impact on school education and
professional career. Before modern factor replacement therapy, the possibility of
enjoying a full social life was limited.[1] With prophylaxis, younger haemophiliacs have less joint damage,[2] but it is not clear how this influences their social status.
On the one hand, social status can be determined by an individual's own achievements.
On the other hand, social status is influenced by the inherited position of an individual
– called ascribed status.[3]
[4] SES is often measured as a combination of education, income, and occupation. Socioeconomic
factors and social class are fundamental determinants of human functioning, including
development, well-being, and physical and mental health.[5] Different methods have been suggested to measure SES.[6]
Studies assessing social status in adults with haemophilia have evaluated marital,
educational, and occupational status;[7] those in children and adolescents have focused on academic achievements[8]
[9] and perceived placement within the school community.[10] More recent studies involving haemophilia patients still showed a higher rate of
unemployment and occupational disability compared to the general male population in
the Netherlands[11] or to matched controls in Austria.[7]
Patients born after the broad availability of prophylaxis showed better results,[11]
[12] a finding also supported by a Scandinavian study.[13] This effect is particularly evident in the educational achievements of a North American
haemophilia cohort.[14] So far, no comparative data has been published involving German Haemophilia patients.
In a previous study, we have explored the impact of social factors on treatment outcomes
in patients with bleeding disorders (PWBD).[15] The specific aim of the current study was to compare the SES of PWBD with that of
an age- and gender-matched control group comprised of patients with thrombophilia
or a thrombotic event (PWT) from the same German treatment centre and living in the
same region of Northern Germany.
Study Design and Methods
This study was conducted at the Haemophilia Treatment Centre (HTC) of the University
Medical Centre Hamburg-Eppendorf, Germany. Patients ≥ 18 years with congenital bleeding
disorders (i.e. haemophilia A or B or VWD type 3) visiting the centre for routine
check-up were invited to participate in the study. A control group of PWT, matched
for gender and age, was chosen to avoid selection bias regarding social status. As
a control group, we aimed to recruit patients who had not been affected by a disease
from early childhood on, but who visited our outpatient clinic.
Since patients visiting the HTC in Hamburg are coming from different counties in Northern
Germany (i.e. Hamburg, Schleswig-Holstein, Niedersachsen, and Mecklenburg-Vorpommern),
it was inappropriate to compare their SES with that reported for the normal population
of the county of Hamburg. The study was approved by the local ethics committee (reference
number, PV3783).
All participants provided written informed consent in accordance with the Declaration
of Helsinki. Patients were recruited from August 2011 through May 2013.
All participants were asked to complete questions including the following aspects:
-
socio-demographic characteristics (e.g. marital status, employment status, school
education, income, partnership, children),
-
HRQoL,
-
life satisfaction,
-
perceived impact of the disease on the patient's life,
-
physical activity,
-
pain, and
-
concomitant diseases.
In addition, clinical data were collected from patient charts (PWBD: e.g. type and
severity of haemophilia, annual bleeding rate, joint status; PWT: type of thrombophilia
or thrombotic event and whether patients received anticoagulants).
HRQoL was assessed using the generic SF-36 questionnaire. The SF-36 quantifies physical
and social functioning and the ability of individuals to fulfil their physical and
emotional roles[16] and consists of 36 items pertaining to 8 domains, which can be summarized to a physical
component score (PCS) and a mental component score (MCS).[17] High values imply a good HRQoL (range 0–100).
Life satisfaction was assessed by a five-point Likert scaled general question ranging
from „not at all satisfied“[1] to „very satisfied“.[5]
SES was determined by the following socio-demographic characteristics as described
before:[15]
A social status index was created using the following formula based on which three
groups of social status could be categorised (low, medium, and high):
Social Status Index =
The impact of the disease on patients' lives was classified as high or low based on
the number of different aspects affected as has been previously described.[15] Patients were asked to state for 6 different aspects (i.e. school and professional
education, childhood, choice of job, career, social contacts, and leisure activities)
whether they have been affected by the disease. According to the median split, high
impact was classified by more than one and low impact by one or less impacted aspects
of their lives.
Pain in the previous three months was evaluated on a visual analogue scale (VAS) ranging
from 0 (no pain) to 10 (worst imaginable pain).[18]
Physicians examined the orthopaedic joint status only in PWBD using the World Federation
of Haemophilia (WFH) Orthopaedic Joint Score (OJS)[19] with higher values implying higher impairments.
Statistical Analysis
All statistical analyses were conducted using SPSS version 23 (SPSS Inc. Chicago,
IL, USA). Continuous variables were presented as mean ± standard deviation (SD), if
normally distributed, or as median and range, if not normally distributed. Data were
tested for normal distribution with the Kolmogorov-Smirnov test. Differences between
groups were examined by Student's t-test or ANOVA (normal distribution) or by Mann-Whitney
U-test or Kruskal-Wallis-test (no normal distribution). Categorical variables were
analysed using the Pearsońs chi-squared test. A p value of < 0.05 was considered
significant.
Results
Description of Study Groups
Socio-demographic characteristics, general clinical data, and health behaviour of
PWBD and PWT are shown in [Table 1]. In total, 58 PWBD were recruited.[15] Of these, 45 (77.6 %) were evaluable for a comparative analysis with the age- and
gender-matched control group of PWT; all participants were male. The main reason for
not being able to analyse all PWBD was the lack of proper controls, because male PWT
visiting the treatment centre were generally older than PWBD. None of the screened
PWBD or PWT refused study participation.
Table 1
Socio-demographic characteristics, clinical data, and health behaviour of patients
with bleeding disorders (PWBD) and patients with thrombophilia or a thrombotic event
(PWT)
|
Parameter
|
PWBD (n = 45)
|
PWT (n = 45)
|
p-value
|
|
Mean ± SD
|
Mean ± SD
|
|
|
Age (years)
|
42.3 ± 15.0
|
43.6 ± 13.9
|
n. s.
|
|
n (%)
|
n (%)
|
|
|
Age distribution
|
18–29 years
|
12 (26.7)
|
8 (17.8)
|
n. s.
|
|
30–44 years
|
13 (28.9)
|
15 (33.3)
|
|
45–64 years
|
15 (33.3)
|
17 (37.8)
|
|
≥ 65 years
|
5 (11.1)
|
5 (11.1)
|
|
Mean ± SD
|
Mean ± SD
|
|
|
BMI (kg/m2)
|
23.8 ± 2.9
|
25.7 ± 5.4
|
n. s.
|
|
Chronic pain intensity (VAS)
|
4.9 ± 2.1
|
3.8 ± 2.1
|
0.027
|
|
n
(%)
|
n
(%)
|
|
|
Pain localisation
[*]
|
Joints
|
20 (57.1)
|
8 (25)
|
0.001
|
|
Back
|
1 (2.9)
|
6 (18.8)
|
|
Head
|
0 (0)
|
1 (3.1)
|
|
Joint/back/head
|
14 (40)
|
7 (21.9)
|
|
Other
|
0 (0)
|
10 (31.3)
|
|
Co-morbidities
|
Hypertension
|
11 (25.0)
|
4 (9.1)
|
0.043
|
|
Coronary heart disease
|
2 (4.5)
|
0 (0)
|
n. s.
|
|
Stroke
|
0 (0)
|
1 (2.4)
|
n. s.
|
|
Malignant tumour
|
0 (0)
|
1 (2.4)
|
n. s.
|
|
Diabetes
|
3 (6.8)
|
2 (4.7)
|
n. s.
|
|
Health behaviour
|
Smoking
|
21 (47.7)
|
12 (26.7)
|
|
|
Alcohol intake
|
32 (72.7)
|
39 (86.7)
|
n. s.
|
|
Drug abuse
|
4 (9.0)
|
1 (2.2)
|
n. s.
|
|
Sport activities
[**]
|
No
|
28 (63.6)
|
12 (26.7)
|
0.001
|
|
Yes (no impact[1])
|
13 (29.6)
|
22 (48.9)
|
|
Yes (impact[2])
|
3 (6.6)
|
11 (24.4)
|
* Two patients with missing data in the group of PWT
** One patient with missing data in the group of PWBD
1 Swimming, bicycling, gymnastic
2 Contact or team sport.
PWBD and PWT were from the county of Hamburg (19 vs. 22), Schleswig-Holstein (19 vs.
16), Niedersachsen (6 vs. 7), or Mecklenburg-Vorpommern (1 vs. 0) so that regional
background was comparable.
Prevalence of pain during the preceding 3 months was not different between the two
groups, with 78 % of PWBD and 76 % of PWT reporting pain. However, PWBD reported significantly
worse pain intensity than PWT (mean VAS, 4.9 ± 2.1 vs. 3.8 ± 2.1; p = 0.027). With
regard to pain localisation, PWBD reported to have pain mainly in joints (57.1 %),
while 31 % of PWT had pain in locations other than joints, back or head (p < 0.001).
Interestingly, one quarter of PWBD suffered from hypertension compared to only 9.1 %
of PWT (p = 0.043). Concerning the health behaviour of study subjects, PWBD were more frequently
smoking (p = 0.033) and were doing less frequently sports than PWT (p = 0.001); no difference was found with regard to alcohol intake or drug abuse.
According to their self-reported general health status 23.8 % of PWBD reported a bad
health status compared to 9.1 % of PWT (not significant).
Clinical Patient Characteristics
A severe form of the bleeding disorder (plasma FVIII/IX activity < 1 %) was present
in 73.7 % and 50 % of patients with haemophilia A and B, respectively ([Table 2a]). One patient had VWD type 3. First documented bleeding episode was in median at
the age of 3 years (range, 0–22 years); data were only available from 31 PWBD. The
majority of all PWBD (60 %) received on-demand treatment, while only 8.9 % were on
continuous primary prophylaxis. Of the 32 patients with a severe form of the bleeding
disorder, 17 (53 %) received primary (n = 4) or secondary prophylaxis (n = 13).
Table 2a
Clinical patient characteristics of patients with bleeding disorders (PWBD) (n = 45)
|
Parameter
|
n (%)
|
|
Bleeding disorder (
n = 45)
|
Haemophilia A
|
38 (84.4)
|
|
Haemophilia B
|
6 (13.3)
|
|
Von Willebrand disease
|
1 (2.2)
|
|
Haemophilia A (
n = 38)
|
Severe (FVIII < 1%)
|
28 (73.7)
|
|
Moderate (FVIII 1–5%)
|
3 (7.9)
|
|
Mild (FVIII 5–40%)
|
7 (18.4)
|
|
Haemophilia B (
n = 6)
|
Severe (FIX < 1%)
|
3 (50.0)
|
|
Moderate (FIX 1–5%)
|
2 (33.3)
|
|
Mild (FIX 5–40%)
|
1 (16.7)
|
|
Von Willebrand disease (
n = 1)
|
Type 3 (severe)
|
1 (100)
|
|
Type of treatment (
n = 45)
|
Trimary prophylaxis
|
4 (8.9)
|
|
Secondary prophylaxis
|
13 (28.9)
|
|
Intermittent prophylaxis
|
1 (2.2)
|
|
On-demand treatment
|
27 (60.0)
|
|
History of inhibitor
|
Yes
|
4 (7.0)
|
|
viral infections
|
HIV+
|
7 (15.6)
|
|
HCV+
|
28 (62.2)
|
|
Target joints
|
Yes
|
12 (27.9)
|
|
Orthopaedic surgery
|
Joint replacement
|
7 (15.5)
|
|
Arthrodesis
|
4 (8.9)
|
|
Parameter
|
Median (range)
|
|
No. of annual bleeds
|
All bleeds
|
3 (0–34)
|
|
Joint bleeds
|
2 (0–27)
|
|
Orthopaedic joint score
|
|
8 (0–38)
|
|
No. of target joints
|
|
0 (0–3)
|
|
Age at first documented bleeding episode
|
|
3 (0–22)
|
Of the 45 PWT, 27 (60 %) had inherited or acquired thrombophilia (i.e. factor V gene
mutation Leiden, prothrombin gene mutation G20210A, antithrombin, protein C or protein
S deficiency or antiphospholipid syndrome). Forty-two patients (93 %) had previously
suffered at least one thromboembolic event with the first event at a median age of
43 years (16–75). Twenty-eight patients (62.2 %) were on anticoagulant treatment at
the time of the questionnaire ([Table 2b]).
Table 2b
Clinical patient characteristics of patients with thrombophilia or a thrombotic event
(PWT) (n = 45)
|
Parameter
|
n (%)
|
|
Type of thrombophilia
|
Factor V gene mutation Leiden heterozygous
|
9 (20)
|
|
Factor V gene mutation Leiden homozygous
|
1 (2.2)
|
|
Prothrombin gene mutation G20210A heterozygous
|
3 (6.7)
|
|
Antithrombin deficiency
|
0
|
|
Protein C deficiency
|
1 (2.2)
|
|
Protein S deficiency
|
1 (2.2)
|
|
Antiphospholipid syndrome
|
12 (26.6)
|
|
No inherited or acquired thrombophilia
|
18 (40)
|
|
Site of VTE
|
No VTE
|
3 (6.7)
|
|
Distal DVT
|
5 (11.1)
|
|
Proximal risk-associated DVT
|
3 (6.7)
|
|
Proximal idiopathic DVT
|
5 (11.1)
|
|
Pulmonary embolism
|
7 (15.5)
|
|
Pulmonary embolism and DVT
|
9 (20)
|
|
Recurrent VTE
|
13 (28.8)
|
|
Anticoagulation
|
Currently on anticoagulation
|
28 (62.2)
|
|
Previously on anticoagulation
|
14 (31.1)
|
|
Never anticoagulation
|
3 (6.7)
|
|
PTS
|
No PTS
|
21 (46.7)
|
|
PTS present
|
8 (17.7)
|
|
No information available
|
16 (35.5)
|
|
Parameter
|
Median (range)
|
|
Age at first thrombosis (years)
|
|
43 (16–75)
|
|
Time since diagnosis of first VTE (months)
|
|
19 (2–252)
|
VTE: venous thromboembolism; DVT: deep vein thrombosis; PTS: post-thrombotic syndrome.
Comparison of SES Between PWBD and PWT
PWBD of all types of severity were included, but in general, no significant differences
were found between the severity groups with regard to the following outcomes: SES,
HRQoL, impact of the disease on patientś lives, life satisfaction; the only difference
was seen for the impact of the bleeding disorder on patientś careers (p < 0.007), with severe patients (42.9 %) reporting more frequently that their disease
had an impact on their careers than mild/moderate patients (7.7 %). Nevertheless,
since this was the only difference, we decided to report the following results for
the entire PWBD.
Marital status, partnership and number of children were not different between PWBD
and PWT. There was also no significant difference with regard to school and professional
education, but a trend towards a higher graduation in PWT. A significant difference
was found regarding occupational status (p = 0.047): 66 % of PWBD were working compared to 84 % of PWT. There was no difference
with regard to working hours (full- or half-time) or type of occupation. Similar proportions
of PWBD and PWT were retired due to age, while only PWBD were retired due to their
disease (n = 6) or unemployed (n = 3). Monthly income was lower in PWBD (p = 0.029, [Fig. 1]).
Fig. 1 Differences in monthly net-income (€) between PWBD and PWT. Tested for significance
using the Pearson's Chi-squared test (p = 0.029).
As a potential confounder for socioeconomic achievements, we also explored the educational
status of the study subjects' parents, which showed no significant difference regarding
school graduation: 37 % and 36 % of mothers of PWBD and PWT, respectively, had no
or the lowest formal qualification; fathers of PWT had a slightly higher graduation
than fathers of PWBD (26 vs. 19 % with entry requirements for university and 33 vs.
45 % with no or the lowest formal qualification).
According to the project-specific SES index, no significant difference was found between
the groups ([Table 3]).
Table 3
Socioeconomic status of patients with bleeding disorders (PWBD) and patients with
thrombophilia or a thrombotic event (PWT) according to age groups
|
Age groups
|
Socioeconomic status
|
PWBDn (%)
|
PWTn (%)
|
|
18–29 years
|
Low
|
3 (27.3)
|
3 (37.5)
|
|
Medium
|
5 (45.5)
|
3 (37.5)
|
|
High
|
3 (27.3)
|
2 (25)
|
|
30–44 years
|
Low
|
2 (15.4)
|
1 (6.7)
|
|
Medium
|
7 (53.8)
|
5 (33.3)
|
|
High
|
4 (30.8)
|
9 (60)
|
|
45–64 years
|
Low
|
2 (13.3)
|
1 (5.9)
|
|
Medium
|
10 (66.7)
|
10 (58.8)
|
|
High
|
3 (20)
|
6 (35.3)
|
|
> 65 years
|
Low
|
2 (40)
|
1 (20)
|
|
Medium
|
3 (60)
|
3 (60)
|
|
High
|
–
|
1 (20)
|
|
All
|
Low
|
9 (20.5)
|
6 (13.3)
|
|
Medium
|
25 (56.8)
|
21 (46.7)
|
|
High
|
10 (22.7)
|
18 (40)
|
Comparing psychosocial parameters of the SF-36 ([Fig. 2]), PWBD reported worse values in the dimensions ‘“physical functioning“, „bodily
pain“, and „general health perception“ than PWT. The ‘physical summary component score’
(PCS) was also significantly worse in PWBD (41.2 ± 11.5) compared to PWT (50.5 ± 8.6;
p < 0.001).
Fig. 2 Differences in health-related quality of life (SF-36) between PWBD and PWT. Differences
between groups were analysed by Student's t-test.
The self-reported impact of the disease on different aspects of the patients' lives
showed significant differences between PWBD and PWT ([Fig. 3]), with more impact on „childhood“ (p < 0.001), „career“ (p = 0.014), „social contacts“ (p = 0.002), and „leisure activities“ (p < 0.001) in PWBD. 57 % of the PWBD reported an influence of the disease on their
school education, and 51 % felt an impact on the choice of their profession. One third
of patients perceived to have less career opportunities, mainly because of actual
or suspected days lost from work. Based on the classification of high and low impact
of the disease on patients' lives, there was a significant difference between PWBD
(69.9 %) and PWT (33.3 %; p < 0.001).
Fig. 3 Impact of the disease on different aspects of the patients’ lifes in PWBD and PWT.
Tested for significance using the Pearson's Chi-squared test.
Asked for general life satisfaction, 81.4 % of PWBD reported to be „rather“ or „very
satisfied“ with their lives compared to 86.4 % of PWT, which was not significantly
different (mean answer on the 5-point Likert scaled question, 4.02 ± 0.9 vs. 4.25 ± 0.75,
PWBD vs. PWT; p = 0.216).
Discussion
In this comparative study of PWBD and PWT, we observed a significant difference in
occupational status, with less PWBD working than PWT. Only PWBD were unemployed or
retired due to their disease, and monthly net-income was lower in PWBD. No differences
were found with regard to the social status itself (as defined by our social status
index), marital status, partnership, and number of children as well as school and
professional education with a trend towards higher achievements in PWT. PWBD reported
a stronger impact of the disease on their lives than PWT and showed more significant
impairments in the physical aspects of their HRQoL. However, no significant difference
was found regarding life satisfaction.
Previous studies from Austria and the Netherlands reported similar findings, with
a higher rate of unemployment and early retirement in haemophilia patients compared
to controls.[7]
[11] Patients with severe haemophilia from the Netherlands were less frequently fulltime
working than the general population.[11] In this regard, no differences were found between PWBD and PWT in our study. In
contrast to these studies, a more recent publication comparing the Swedish high-dose
with the Dutch intermediate-dose prophylactic regimen in younger patients with severe
haemophilia (median age 24 years) showed that, compared to the general population,
fewer haemophilia patients from both countries achieved a university degree,[20] which is in line with our results. In our cohort, rates of unemployment and early
retirement were higher than in controls, while in the above study, unemployment rates
were similar (Netherlands) or lower (Sweden) compared to the normal population. These
encouraging results might be due to the fact that in this study all patients were
on continuous primary prophylaxis compared to only 12.5 % of patients with severe
haemophilia in our cohort.
A positive effect of prophylaxis on rates of unemployment and early retirement is
confirmed by another Scandinavian study that compared Swedish patients on early prophylaxis
with Norwegian patients treated on-demand.[13]
More than 50 % of the patients in our cohort reported an impact of their bleeding
disorder on several aspects of their lives, including an influence on school education,
choice of profession, and career. This is in contrast to Scandinavian data, according
to which 86 % of patients reported to have the same opportunities as someone without
haemophilia. In that cohort, 79 % of patients were on prophylaxis.[21] Results comparable to those of our study revealed an Iranian study involving 100
haemophilia patients aged 16–67 years (mean age 28 ± 9 years), in which 49 % reported
that haemophilia had a negative impact on education.[22]
In our cohort, with one third of patients being < 35 years old, hypertension was more
prevalent than in controls, but lower (25 %) compared to the Canadian ARCHER study
in haemophilia patients ≥ 35 years (31.3 %)[23] and an Italian study in patients with severe haemophilia ≥ 65 years (71.8 %).[24] One possible explanation could be that patients with haemophilia are less active
in sports, which has been shown in our cohort and it could be confounded by the high
rate of smoking in that group. That PWBD were more often smoking than PWT which could
be due to a perceived protection against cardiovascular disease in PWBD and a higher
thrombosis risk of smoking in PWT. By contrast, the body mass index (BMI) was not
different between the two groups.
The current study suffers from the relatively small number of enrolled patients (n = 45),
which is a common limitation of single-centre studies in haemophilia and additionally
due to the fact that not all registered patients appeared to their annual routine
visits. Additionally, it was difficult to recruit appropriate PWT in the age range
of our patient cohort, since these patients are normally older. We considered male
patients with (rather mild) thrombophilia or a thrombotic event (PWT) „healthy enough“
to serve as an appropriate control group that is matched not only for age and gender,
but also for the region of residence in Germany from which the patients with haemophilia
were recruited. By choosing PWT as a control group, we wanted to avoid selection bias
with regard to social status (as would have been the case when choosing, for example,
the patients' peers, hospital personnel, or even healthy blood donors). Our assumption
was confirmed by the fact that median age of first manifestation of the disease was
43 years (range, 16–75 years) for PWT compared to 3 years (range, 0–22 years) for
PWBD. Other potential control groups like the patient's peers would probably have
had a similar social background. Moreover, these controls would have been difficult
to approach, since older haemophilia patients in general do not want to speak about
their disease with others which, on the other hand, would have been necessary for
the recruitment of their peers.
We have chosen a comparison group which was easily accessible and which came from
the same region of Northern Germany. Thus, one might argue that the findings of our
study cannot be extrapolated to the entire country. However, there is a well-known
South-North slope with regard to the SES in our country, and we therefore think that
our data are sufficiently representative for the Northern part of Germany.[25]
[26] In contrast, a comparison to socioeconomic data of the whole German population does
not seem appropriate. Such a comparison would require a multi-centre setting including
patients from all regions of the country.
Conclusion
PWBD showed a negative perceived and measured impact of the bleeding disorder on their
lives: PWBD
-
were more frequently unemployed or retired due to their disease,
-
had lower monthly income, and
-
showed a trend towards lower educational achievements than PWT.
This finding might be due to a low proportion of patients receiving prophylactic factor
replacement therapy, emphasising the need for implementation of early and continuous
prophylaxis. Future studies involving German PWBD on early prophylaxis are needed
to prove the effect of prophylaxis on socioeconomic achievements as a meaningful long-term
outcome parameter in haemophilia treatment.
