Introduction
Haemophilia A and B (HA and HB) are rare hereditary bleeding disorders characterized
by the deficiency or complete absence of clotting factor VIII (FVIII) or IX (FIX)
leading to spontaneous bleeds into muscles and joints. The severity of the disease
is determined by the residual factor activity,[1 ] but the clinical manifestation may vary.[2 ] For patients with severe haemophilia (PWSHs), standard of care is prophylactic substitution
of factor concentrates as prophylaxis reduces joint bleedings and improves joint status.[3 ]
[4 ]
[5 ] Beside this, it is known that in children early prophylaxis results in a better
joint status.[6 ] In addition, patients still benefit from prophylaxis when it is started later in
life,[5 ] making prophylaxis the standard of care in all PWSHs. There are two approaches of
prophylaxis with a fixed regimen depending on body weight (BW) and tailored regimens
taking into account bleeding phenotype and pharmacokinetic properties.
As prophylaxis is nowadays considered standard of care in haemophilia treatment, changes
in treatment strategies and factor consumption over time are of special interest.
In Germany, the annual factor consumption of patients with haemophilia (PWHs) is usually
reported to the Paul Ehrlich Institute as a collective report. Some clinicians also
report individual data to the German Haemophilia Registry, but in 2015 only in 38.6%
of all PWSHs individual data were announced.[7 ] As a result there is a lack of comprehensive data reflecting changes in factor consumption
and different treatment strategies in Germany over time.
The Kompetenznetzwerk Hämorrhagische Diathese Ost (KHDO) is an association of clinicians
dedicated to “supporting clinical and scientific research in the field of haemophilia
and severe coagulation disorders and improving clinical care for these patients” in
the eastern part of Germany. The KHDO published epidemiologic data based on the reports
submitted to the Paul Ehrlich Institute regarding treatment strategies, factor consumption
and infections in PWHs in eastern Germany in 2005.[8 ]
The aim of this study was to collect current epidemiologic data including patient
characteristics, bleeding rates, weight classification and infectious diseases. Comparing
these data with our previously published data from 2005, we intended to document changes
in haemophilia treatment over the last decade in eastern Germany.
Methods
Retrospective data of the year 2015 from patients with HA and HB were provided from
12 haemophilia centres in eastern Germany. Data were collected from patient diaries
and medical records regarding age, height, BW, blood group, dosing regimen, factor
consumption, documented bleeds and inhibitory antibodies. Severity of haemophilia,
bleeding events and inhibitor status were documented according to the current International
Society of Thrombosis and Haemostasis (ISTH) guideline.[9 ] All patients with HA or HB who had a complete patient diary for 2015 with documented
bleeds and factor consumption were eligible. In addition, we included three patients
with available data on virology but without completed patient diary. Data were analysed
in the haemophilia centres and the treating physicians were consulted for clarification
in case of conspicuities.
Bleeds were measured as documented by the patients and treating physicians. As annualized
bleeding rate (ABR) all documented bleeds were summarized, while the annualized joint
bleeding rate (AJBR) only refers to documented joint bleeds. In addition, major bleedings
were defined as non-joint bleedings that were life-threatening or led to hospital
admission or required transfusion of red blood cells. As minor bleedings all other
haemorrhages with documented bleeding sites were counted. Additional substitutions
without further information in patient diaries or medical records and bleedings without
specified bleeding site were counted as unclear substitutions and summarized as bleedings
in the total ABR.
In addition, results from human immunodeficiency virus (HIV) antibodies, anti-HBs,
HB-antigen, anti-hepatitis C virus (anti-HCV) and HCV-polymerised chain reaction (PCR)
measurements were obtained in patients with available data.
Body mass index (BMI) was calculated using the formula: BMI = weight [kg]/size [m2 ] = [kg/m2 ]. For adults (≥18 years), BMI was classified according to the World Health Organization
guideline. Overweight is therefore defined as BMI of 25 to 29 kg/m2 and obesity as a BMI of ≥30 kg/m2 .[10 ] In children (<18 years), the percentile curves according to Kromeyer-Hauschild were
used for classification. Overweight is here referred to as BMI between 90th and 97th
percentiles, obesity between 97th and 99.5th percentiles and extreme obesity as ≥99.5th
percentiles.[11 ]
[12 ]
For the calculation of factor consumption, 5 patients (2 children, 3 adults) with
inhibitory FVIII or FIX antibodies and 2 patients (1 child, 1 adult) with a negative
Bethesda test but a remaining shortened half-life after immune tolerance induction
were excluded.
Results
We screened 417 patients and excluded four patients due to inconsistent data in patients'
diaries and medical records. In total, we collected data of 413 patients (115 children
and 298 adults) with HA or HB. The median age in the whole cohort was 32 years, in
the paediatric group 9 years and in the adult cohort 44 years. Most patients had severe
haemophilia (83 children [72.2%] and 203 adults [68.1%]). In total, 96 (83.5%) children
and 249 (83.6%) adults suffered from HA. Patients' characteristics are summarized
in [Table 1 ].
Table 1
Characteristics of 413 patients included in the study
Children
Adults
Age (y)
n ; median (range)
115; 9 (1–17)
298; 43.5 (18-83)
Body weight (kg)
n ; median (range)
115; 30 (8-111)
292; 81.1 (46-130)
BMI (kg/m2 )
n ; median (range)
112; 17.6 (6.7-34)
281; 26 (17.9-42.6)
Haemophilia A
Severe
n , (%)
74 (64.4%)
176 (59.0%)
Moderate
n , (%)
7 (6.1%)
22 (7.4%)
Mild
n , (%)
15 (13%)
51 (17.1%)
Haemophilia B
Severe
n , (%)
9 (7.8%)
27 (9.1%)
Moderate
n , (%)
4 (3.5%)
16 (5.4%)
Mild
n , (%)
6 (5.2%)
6 (2%)
Therapeutic regimen
Prophylaxis
n , (%)
90 (78.3%)
171 (57.4%)
On-demand
n , (%)
25 (21.7%)
127 (42.6%)
Inhibitor status
Active inhibitor
n , (%)
2 (1.7%)
3 (1%)
History of an inhibitor
n , (%)
10 (8.7%)
9 (3%)
Abbreviation: BMI, body mass index.
Note: The numbers are given for patients with available data.
Therapeutic Regimen
Almost all children (98.8%) with severe haemophilia were treated prophylactically.
Because of the young age, one infant born in 2015 with severe haemophilia had an on-demand
treatment with 500 IU. He started prophylaxis in early 2016. In the adult cohort,
162 (80.2%) PWSHs had a prophylactic treatment in 2015. In patients with moderate
haemophilia, more children had a prophylaxis compared with adults (54.5 vs. 18.4%).
Five (71.4%) children with moderate HA but only one (25%) child with moderate HB were
on prophylaxis. In seven (31.8%) adults with moderate HA but not in adults with moderate
HB, a prophylactic factor substitution was prescribed.
In 2005 only 90% of the children with severe haemophilia and 64% of the adults were
on prophylaxis.[8 ] Change in therapeutic regimen is shown in [Fig. 1 ].
Fig. 1 Therapeutic regimen in patients with severe haemophilia: (a ) children in 2005; (b ) children in 2015; (c ) adults in 2005; (d ) adults in 2015.
In total, 67.2% of children with severe HA on prophylaxis were treated with doses
ranging from 20 to 39 IU/kg BW FVIII or FIX, while 79.4% of the adults with severe
HA on prophylaxis were treated with ≤29 IU/kg BW FVIII or FIX. In addition, more children
had a dose ≥40 IU/kg BW compared to adults (HA 11.5 vs. 4.4%; HB 22.2 vs. 0%). Prophylaxis
was administered in patients with severe HA three times per week in 51 (83.6%) children
but only in 76 (55.9%) adults. Prophylaxis regimens in children and adults are summarized
in [Tables 2 ] and [3 ].
Table 2
Prophylaxis regimens in 70 children with severe haemophilia without inhibitors
Children
Haemophilia A, n = 61
Haemophilia B, n = 9
≤19 IU/kg
20–29 IU/kg
30–39 IU/kg
≥40 IU/kg
≤19 IU/kg
20–29 IU/kg
30–39 IU/kg
≥40
IU/kg
1 ×/d
0
0
0
0
0
0
0
0
3 ×/wk
10
18
17
6
0
0
0
0
2 ×/wk
3
3
2
0
0
2
2
1
1 ×/wk
0
0
1
1
0
2
1
1
Total
13
(21.3%)
21
(34.4%)
20
(32.8%)
7
(11.5%)
0
(0.0%)
4
(44.5%)
3
(33.3%)
2
(22.2%)
Table 3
Prophylaxis regimens in 153 adults with severe haemophilia without inhibitors
Adults
Haemophilia A, n = 136
Haemophilia B, n = 17
≤19 IU/kg
20–29 IU/kg
30–39 IU/kg
≥40 IU/kg
≤19 IU/kg
20–29 IU/kg
30–39 IU/kg
≥40 IU/kg
1 ×/d
0
0
0
1
1
0
0
0
3 ×/wk
35
26
12
3
2
1
0
0
2 ×/wk
12
25
9
2
4
4
0
0
1 ×/wk
5
5
1
0
2
2
1
0
Total
52
(38.2%)
56
(41.2%)
22
(16.2%)
6
(4.4%)
9
(52.6%)
8
(42.1%)
1
(5.3%)
0
(0.0%)
In 2015 a total of 48 (42.1%) children and 124 (41.6%) adults were treated with recombinant
factor concentrates. In the group of PWSHs, more adults (n = 106; 52.5%) than children (n = 37; 44.6%) were treated with a recombinant factor. In contrast, in 2005 only 19%
of the children and 24% of the adults were on recombinant factor concentrates ([Fig. 2 ]).
Fig. 2 Use of factor concentrates in patients with haemophilia in 2005 and 2015.
Factor Consumption
Median annual factor consumption in PWSHs was 125,400 (84,438–202,000) IU in children
(n = 80) and 183,500 (94,500–279,000) IU in adults (n = 196). Children with severe HA had a trend toward higher median factor consumption
compared with children with severe HB (129,000 [90,000–209,000] vs. 80,400 [68,700–138,300]
IU; p = 0.074), reaching significance in adult patients (186,000 [116,750–289,000] vs.
116,400 [43,200–247,000] IU; p = 0.047). When factor consumption was adjusted to BW, children with severe HA had
a significantly higher consumption than children with severe HB (4,700 [2,902–6,272]
vs. 2,062 [1,468–4,075] IU/kg; p < 0.01). This difference was also seen in adult patients (2,288 [1,503–3,645] vs.
1,940 [575–2,942] IU/kg; p = 0.040). Remarkably, children with moderate HA had a median annual factor consumption
of 144,000 (9,000–195,000) IU while adults with moderate HA used only 34,500 (6,750–161,250)
IU (p = 0.53). Patients with moderate HA used significantly more factor concentrates than
patients with moderate HB (children: 144,000 [9,000–195,000] vs. 7,800 [1,650–41,625]
IU, p < 0.01; adults: 34,500 [6,750–161,250] vs. 1,200 [0–6,000] IU, p < 0.01).
In relation to their BW, children with severe haemophilia used more factor concentrates
than adults. Median annual consumption in children with severe HA was 4,700 [2,902–6,272]
IU/kg and for adults 2,288 [1,503–3,645] IU/kg (p < 0.01). This difference was still significant when patients with on-demand therapy
were excluded (4,727 [3,042–6,281] vs. 2,529 [1,741–3,848] IU/kg, p < 0.01). In HB patients no statistical significance was observed (2,062 [1,468–4,075]
vs. 1,940 [575–2,942] IU/kg, p = 0.607)
Compared with 2005, mean factor consumption increased in children with severe HA and
HB by around 50,000 IU and adults by around 65,000 IU. We were not able to conduct
adequate and detailed statistical comparison between our results and those for 2005
because we did not have the individual factor consumption for patients in 2005. Mean
factor consumption is summarized in [Table 4 ].
Table 4
Mean annual factor consumption in patients with haemophilia in 2005 and 2015
Children
Adults
2015
2005
2015
2005
Haemophilia A
Severe
151,489
n = 71
98,894
n = 81
217,151
n = 169
151,394
n = 246
Moderate
106,429
n = 7
65,486
n = 29
75,682
n = 22
49,603
n = 96
Mild
16,200
n = 15
26,524
n = 60
13,804
n = 51
3,631
n = 158
Haemophilia B
Severe
105,200
n = 9
64,256
n = 20
159,185
n = 27
85,295
n = 51
Moderate
17,025
n = 4
22,967
n = 3
3,520
n = 15
13,900
n = 30
Mild
167
n = 6
8,500
n = 8
9,200
n = 5
6,393
n = 46
Bleeding Rates
Children with severe haemophilia on prophylaxis had a mean ABR of 4.2 (median 2, IQR
1–6) and a mean documented AJBR of 1.1 (median 0, IQR 0–1). Adults with severe haemophilia
on prophylaxis had a mean ABR of 5.1 (median 3, IQR 1–7) and a mean documented AJBR
of 1.9 (median 0, IQR 0–2.8). Major bleeds were rare in adults (n = 8, mean 0.05) and there was no documented major bleeding in children with severe
haemophilia. However, substitutions for unclear reasons were frequent: in children
100 and in adults 398 substitutions of unknown reason were documented. In PWSHs, children
and adults had 82 and 316 unclear substitutions, respectively. Bleeding rates in PWSHs
on prophylaxis are displayed in [Table 5 ].
Table 5
Bleeding rates in patients with severe haemophilia on prophylaxis without inhibitor
Total number of documented bleeds/substitutions, n
Mean
Median
IQR
Children, n = 79
ABR
331
4.2
2
1–6
AJBR
75
1.1
0
0–1
Major bleeds
0
0
0
0–0
Minor bleeds
174
2.2
1
0–3
Unclear substitutions
82
1.0
0
0–1
Adults, n = 148
ABR
749
5.1
3
1–7
AJBR
289
1.9
0
0–2.8
Major bleeds
8
0.05
0
0–0
Minor bleeds
136
0.92
0
0–1
Unclear substitutions
316
2.2
0
0–2
Abbreviations: ABR, annualized bleeding rate; AJBR, annualized joint bleeding rate;
IQR, interquartile range.
Mean ABR in adult PWSHs on prophylaxis was 5.1 versus 10.2 in patients with on-demand
therapy (p = 0.19). Mean AJBR was significantly lower in patients on prophylaxis (1.9 vs. 5.5,
p < 0.01).
Influence of Body Weight and BMI on Factor Consumption and Bleeding Rates
According to the classification of Kromeyer-Hauschild in 112 children with available
data, 85 (75%) had a normal BW, 7 (6.2%) were overweight, 11 (9.7%) underweight and
9 (8.0%) patients were obese. Children with severe haemophilia showed the same distribution
(underweight 10%, normal weight 73.3%, overweight 6.3%, obese 10%).
In 281 adult patients with available data, 118 (42.0%) had a normal BW, 96 (34.2%)
were overweight, 47 (16.7%) had obesity grade 1 and 15 (5.4%) obesity grade 2 or 3,
while only 5 (1.8%) were underweight, showing the same distribution in adults with
severe haemophilia.
Overweight and obese children with severe haemophilia without inhibitors on prophylaxis
had lower factor consumption per kg BW than children with normal weight or underweight.
In adults this difference did not reach statistical significance. In addition, bleeding
rates in children and adults with and without overweight were not statistically different
([Table 6 ]).
Table 6
Factor consumption and bleeding rates in patients with severe haemophilia without
inhibitors on prophylaxis according to body weight and BMI
Children
Adults
≤ Normal weight
≥ Overweight
p
BMI < 30
BMI ≥ 30
p
Annual factor use (IU)
Median (Q25–Q75)
124,800
(88,500–211,000)
n = 65
140,750
(103,350–171,625)
n = 12
0.844
197,200
(144,000–299,750)
n = 122
245,750
(201,250–337,750)
n = 28
0.111
Annual factor use/kg BW (IU/kg)
Median (Q25-–Q75)
4,755
(3,365–6,123)
n = 65
2,242
(2,034–4,384)
n = 12
0.045
2,543
(1,730–3,927)
n = 122
2,284
(1,721–3,112)
n = 28
0.235
Annual factor use/BMI (IU/BMI)
Median (Q25–Q75)
8,102
(5,553–11,572)
n = 65
5 703
(4,115–7,193)
n = 12
0.074
7,851
(5,745–11,833)
n = 121
6,936
(5,762–9,335)
n = 28
0.125
ABR
Median (Q25–Q75)
3 (1–6)
n = 65
2 (0–4)
n = 12
0.269
3 (0.25–7)
n = 114
2 (1–3.5)
n = 28
0.333
AJBR
Median (Q25–Q75)
0 (0–1)
n = 65
0 (0–0)
n = 12
0.187
0 (0–3)
n = 114
0 (0–1)
n = 28
0.199
Abbreviations: ABR, annualized bleeding rate; AJBR, annualized joint bleeding rate;
BMI, body mass index; IQR, interquartile range.
Inhibitors
Among the 115 children, only two (1.7%) had an active inhibitor against FVIII, revealed
by a positive Bethesda test at the time of the survey. Both had an inhibitor titer > 5
Bethesda units (BU). Another 10 children (8.7%) had a history of an inhibitor but
a negative Bethesda test at the time of our survey. The historical titer was >5 BU
in five (50%) children.
Among the 298 adults, three (1.0%) had an active inhibitor (one low titer and two
high titers). Another 8 patients had a history of an inhibitor (2 low titer, 3 high
titer and 3 with unknown titer).
Virology
All children with available data were negative for HIV, HCV-PCR and HBs-antigen. There
was one anti-HCV-positive child and another anti-HBc positive child. Of the 112 children
with available laboratory findings or vaccination records, 105 (93.8%) had a detectable
anti-HBs titer. Seven adults with haemophilia (2.3%) and six adults with severe haemophilia
(3.2%) were carriers of the HBs-antigen. The prevalence of anti-HBc-positive patients
was 34.2% in the whole cohort of adult patients and 47.3% in adults with severe haemophilia.
In the whole adult population, we found 112 (37.6%) anti-HCV-positive patients, most
of them had severe haemophilia (n = 101; 53.2%). However, only 13 (6.8%) PWSHs were HCV-PCR positive.
In 2005, 149 patients were documented as being anti-HCV positive. Of these 149 patients,
95 (63.8%) were HCV-PCR positive. In 2015 this rate decreased to 12.9%. Available
data about virology are summarized in [Table 7 ].
Table 7
Prevalence of viral infections in children and adults with haemophilia
Children, n (%)
Children with severe haemophilia, n (%)
Adults, n (%)
Adults with severe haemophilia, n (%)
HIV positive
0, (0%)
n = 113
0, (0%)
n = 81
9, (3%)
n = 277
5, (2.7%)
n = 188
Anti-HCV positive
1, (0.9%)
n = 113
1, (1.2%)
n = 81
112, (37.6%)
n = 279
101, (53.2%)
n = 190
HCV-PCR positive
0, (0%)
n = 114
0, (0%)
n = 82
14, (4.7%)
n = 279
13, (6.8%)
n = 190
HBs-Ag positive
0, (0%)
n = 112
0, (0%)
n = 80
7, (2.3%)
n = 275
6, (3.2%)
n = 186
Anti-HBc positive
1, (0.9%)
n = 112
1, (1.3%)
n = 80
102, (34.2%)
n = 268
86, (47.3%)
n = 182
Abbreviations: HBs-Ag; hepatitis B virus surface antigen; HCV, hepatitis C virus;
HCV-PCR, hepatitis C virus-polymerised chain reaction; HIV, human immunodeficiency
virus.
Discussion
The aim of this retrospective study was to demonstrate changes in haemophilia care
in East Germany and to compare the data obtained in 2015 with those from the previous
study of the KHDO one decade ago.[8 ] We collected data from 413 PWHs from 12 haemophilia treatment centres in 2015 and
evaluated them with regard to patients' characteristics, factor consumption, bleeding
rates and infectious diseases.
We found a stronger adherence to the prophylactic regimen in 2015 compared with 2005.
Almost all children and 80% of the adult PWSHs received prophylactic substitution.
As a result, factor consumption increased within the last decade but still remains
moderate. Other studies found the annual factor consumption in adults on prophylaxis
to be 4,102 IU/kg BW (median) in severe HA[5 ] and 4,945 IU/kg BW (mean) in severe HB.[14 ] In our cohort adults with severe HA and HB on prophylaxis only used 2,288 IU/kg
BW (median) and 1,845 IU/kg BW (mean), respectively.
The median annual, BW-related consumption in prophylactically treated children with
severe HA was significantly higher compared with adults receiving prophylaxis (4,727
[3,042–6,281] vs. 2,529 [1,741–3,848] IU/kg, p < 0.01). Compared with 2005, mean factor consumption in 2015 increased in children
with severe HA and HB by approximately 50,000 IU.
This moderate increase in factor consumption can be further explained with a change
in treatment strategies in PWHs. As described in the literature and performed in many
haemophilia centres, the treatment strategy has changed in the last decade from a
regimen based on BW and fixed time intervals to a more personalized prophylactic regimen
based on individual factor pharmacokinetics, trough levels and bleeding rates with
the aim of zero bleeds for all haemophilia patients.[15 ]
[16 ]
[17 ]
[18 ] To achieve this aim, higher trough levels were aspired which might have resulted
in the increase in factor consumption. The variety of treatment regimens in our patients
in 2015 and the low bleeding rate show that personalized prophylaxis results in low
bleeding rates with a comparably low factor consumption. However, due to the lack
of individual data from 2005, we cannot exclude that other factors like an increase
in BW might be the cause for the increased factor consumption, making it difficult
to draw final conclusions.
Apart from this, we document a shift from the use of plasma-derived to recombinant
factor concentrates. As all plasma-derived factor concentrates currently licensed
in Germany are safe in terms of transmission of infections, this change is more likely
due to the fact that recombinant factors are easier in handling and storage.[19 ] In addition, switching patients from plasma-derived to recombinant factor concentrates
is not related to inhibitor development in previously treated patients (PTP),[20 ]
[21 ]
[22 ] which might have encouraged patients and physicians to prefer recombinant factors.
Interestingly, the shift to recombinant factors is seen not only in children but also
in adults. A recently published study reported a higher incidence of inhibitor development
following treatment with recombinant factor concentrates in previously untreatetd
patients (PUPs).[23 ] It will be interesting to see how these data will influence the factor use especially
in children in the future.
The prevalence of obesity in our patients was 8% in children and 10% in adults. Other
studies reveal a much higher prevalence in other cohorts.[24 ] As fatty tissue has lower blood volume, PWHs with obesity have an increased in vivo
recovery when dosed per BW, resulting in higher trough levels.[25 ]
[26 ]
[27 ] Our data reveal lower factor consumption in obese children with haemophilia when
calculated per BW without an increased bleeding tendency. The same effect is seen
in adults without reaching statistical significance. The reason for this finding might
be the fact that physicians rather treat patients according to their bleeding tendency
and trough levels than with a fixed dose per BW. When interpreting these data, it
has to be taken into account that obese patients tend to have less physical activity
that might lead to a lower bleeding rate as well. However, another study in adult
patients with HA obese patients showed identical bleeding rates and factor consumption
per BW compared with non-obese patients.[27 ]
Our data show a comparably low inhibitor rate of approximately 10% in children and
even lower in adults. The reasons for the low inhibitor rate might be the high amount
of patients being treated with plasma-derived factor concentrates which are known
to be associated with a lower inhibitor risk in PUPs.[23 ]
Our data regarding infections are very encouraging. No child with haemophilia had
an active infection with HCV, HBV or HIV. Already in 2005 no child with haemophilia
had an active infection with HCV or HIV. Moreover, in the adult cohort we were able
to document a dramatic reduction in the rate of patients with active hepatitis C infection.
This is clearly the effect of the progress in treatment options in the last few years.
