Hemophilia in Germany (Year 2002/2003 Survey)
H. Krebs, and W. Schramm, on behalf of the participating German Hemophilia Centers
Introduction
The annually survey »HIV Infection and Causes of Death in Patients with Hemophilia in Germany« already goes along with a fine tradition. Already in the late 1970s Professor Landbeck began to survey annually hemophiliacs living at that time in West Germany for causes of death and the prevalence of diseases. This was carried on till today, so that our actual insights rest upon a broad database. However data quality could be much more improved in future.
Patients and Methods
Questionnaires called »Todesursachenstatistik 2002/2003« were sent to all establis- hed hemophilia centers in Germany. Prompted was information about patients with hemophilia A, B and von Willebrand disease. In particular, anonymous data con- cerning the last 12 months about the number of treated patients, type and severity of illness, HIV-status and causes of death was inquired. This data was merged with existing data returning to 1982 and analyzed statistically. In the 2001/2002 survey, a total number of 8070 patients (including possible double registrations) have been reported from the participating centers.
Results
Participating Centers
Since the first survey the number of participating centers has increased every year with a particular rise in 1991 when the hemophilia treatment centers of the former East Germany joined in. Today these centers contribute a significant portion of the overall data (Fig. 1). In this year’s survey the number of reporting hemophilia cen- ters slightly decreases from 75 centers last year to 71 centers this year (Table 1).
Thereby the total number of patients (including patients with von Willebrand disea- se) reported from all centers remained relatively constant and added up to 8070 patients compared to 7759 patients in last year’s survey (Table 2).
I. Scharrer/W. Schramm (Ed.)
34
thHemophilia Symposium Hamburg 2003
” Springer-Verlag Berlin Heidelberg 2005
Table 1. Numbers of participating hemophilia centers
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
East 47 62 79
West 18 18 24
Totals 65 80 103 111 119 119 71 75 93 87 72 75 71
Patients
The distribution of patients with hemophilia A (48.31%), B (8.41%) and patients with von Willebrand disease (43.27%) is given in Table 2. Compared to the data of the previous surveys these are relative consistent findings. When severity of disea- se is analyzed with a cut-off of 2% factor activity, the distribution between the two subgroups, i.e. below 2% and above 2%, is almost similar in patients with hemophi- lia A and B as shown in Table 2. 18.36% of patients with von Willebrand disease sho- wed ristocetin co-factor levels below 30%.
Inhibitors
In 4.46% (174) of the patients with hemophilia A and in 2.21% [15] of the patients with hemophilia B an inhibitor was found (see Fig. 2 and Table 2). These findings correspond to international large-scale prevalence studies and registry data indica- ting that the prevalence of inhibitors in the hemophilia A population overall is be- tween 5% and 7% [10].
Fig. 1a, b. Participating hemophilia centers
Table 2. Cumulative data from 71 centers as of 2002/2003
Hemophilia A Hemophilia B von Willebrand Total disease
N % N % N % N
Total 3899 48.3% 679 8.41% 3492 43.27% 8070
Factor activity = 2% 1978 50.73% 326 48.01% — — 2304
Factor activity > 2% 1921 49.27% 353 51.99% — — 2274
Ristocetin Cofactor = 30% — — — — 641 18.36% 641
Ristocetin Cofactor > 30% — — — — 2851 81.64% 2851
Inhibitor (low responders) 46 1.18% 7 1.03% — — 53
Inhibitor (high responders) 128 3.28% 8 1.18% — — 136
Total HIV negative 3238 — 571 — 2951 — 6760
Total HIV positive 583 — 89 — 7 — 679
HIV positive, no AIDS 273 — 47 — 5 — 325
HIV positive, CD4<200 cells/µl 59 — 13 — 1 — 73
HIV positive, full blown AIDS 35 — 3 — 0 — 38
HIV positive, no comment 216 — 26 — 1 — 243
HIV Status
Of all reported patients a total of 679 were infected with HIV. Analyzed for HIV dis- tribution in subgroups nearly 15% of all patients with hemophilia A, 13% of all patients with hemophilia B, and 0.2% of all patients with von Willebrand disease were HIV-infected (Fig. 3). A total of 38 patients (5.6% of all HIV positive patients) has reached the stage of full-blown AIDS, compared to 325 patients (47.9% of all
No inhibitor
95,54%
3725 1,18%
46
3,28%
128
Hemophilia A
Inhibitor
쮿No inhibitor
쮿Low responder
쮿High responder
No inhibitor 97,79%
664 1,03%
7
1,18%
8
Hemophilia B
Fig. 2. Distribution of inhibitors in patients with hemophilia A and hemophilia B
HIV positive patients) that have up to now not shown severe symptoms of the immune disease (Tab. 3). Unfortunately 243 HIV positive patients with no further details concerning stadium were reported. As this bates data quality considerable further investigation is needed to fill in the missing information.
Tab. 3. HIV status
HIV status Hem. A Hem. B von Willebrand disease Total
HIV negative 3238 571 2951 6760
HIV positive, no AIDS 273 47 5 325
HIV positive, CD4+ < 200 cell/µ 59 13 1 73
HIV positive, full-blown AIDS 35 3 0 38
HIV positive, no comment 216 26 1 243
Total HIV positive 583 89 7 679
Mortality from all Cases
In the 2002/2003 period a total of 16 patients were reported dead with the distribu- tion of causes of death given in Table 4. Since the beginning of the survey in 1982 a total of nearly 800 patients have been reported dead. The development of mortality and causes of death since 82/83 are depicted in Fig. 6 to Fig. 8. In this year’s survey liver disease (38%) and cancer (19%) have been the main causes of death while AIDS (6%) loses ground anymore (see Fig. 7a). Up to 1995 the number of AIDS-rela- ted deaths increased continuously with decline taking place since then. As at present more than half of the primary HIV-infected patients with hemophilia are still alive (679), the main reason for this development can probably be attributed to improved antiretroviral therapies as described by many authors [1, 3, 6]. In contrast liver
0 1000 2000 3000
von Willebrand disease
Hemophilia B
Hemophilia A
Number of patients
HIV-Status
❚
HIV negative
❚
HIV positive, no AIDS
❚
HIV positive, CD4 <200 cells/ µl
❚
HIV positive, full blown AIDS
❚
HIV positive, no comment
Fig. 3. Distribution of HIV-infected patients
disease showed a sharp increase from 14% last year except for 38% this year. No patient died of a bleeding. Cancer as a cause of death remained relatively constant still staying on an alarming high level (19%). Overall annual mortality in patients with bleeding disorders in the 2002/2003 survey adds up to 0.2% per year. No indi- cations for Creutzfeld-Jakob disease in our patient collective has been reported since 1978. Once again mentionable is the low portion of reported deaths with no comment, improving data quality clearly.
Table 4. Distribution of death causes
Patients N %
AIDS 1 6
Liver disease 6 38
Bleeding 0 0
Cancer 3 19
Other diseases 3 19
No comment 3 19
Total 16 100
Arranging data for greater periods of time one can see these changes obviously (see Fig. 4 b, d, f). Clustered data for the years 1982 to 1994 and 1994 to 2003 gives us a statistically significant difference between these periods concerning all important causes of death as HIV (p < 0.022), liver disease (p < 0.023) and cancer (p < 0.001).
The same numerical picture shows the HIV/liver disease/cancer deaths expressed as percentage of all deaths per year (see Fig. 5 a–c).
Mortality from Liver Disease
Therewith in this year’s survey the increase of liver disease as a cause of death has reached statistical significance the first time, suggesting a further increase in future (see Fig. 4 d). The obvious reason for this probably can be attributed to the increasing number of deaths induced by liver cirrhosis and hepatocellular carcinoma due to chronic HCV [7]. As we did not discriminate type of cancer in our surveys up to now there might be a relevant portion of patients in this group having died of primary hepatocellular carcinoma induced by chronic HCV intensifying the impact of liver disease on causes of death in patients with hemophilia even more.
Clustered data analyzed for HIV negative and positive patients for the period
1999 to 2003 only indicates a slight difference in mortality (45 vs. 53 deceased pati-
ents), not reaching statistical significance. However the same data separated for cau-
ses of death (liver disease and cancer) shows a clear difference in the percentage of
total number of deaths between the two subgroups (see Fig. 9). These findings har-
den the suspicion that the combination of HIV/HCV coinfection accelerate pro-
gression of liver disease [4, 9, 11].
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 10
20 30 40 50
Anzahl Todesfälle
(a)
1994-2003 1982-1994
Anzahl Todesfälle
60
50
40
30
20
10
0
52
(b)
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
4 8 12
Anzahl Todesfälle
(c)
1994-2003 1982-1994
Anzahl Todesfälle
14
12 10
8 6
4
2 0
78
(d)
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 1
2 3 4 5
Anzahl Todesfälle
(e)
1994-2003 1982-1994
Anzahl Todesfälle
6
5
4
3
2
1
0 -1
(f)
total number of deaths per year (HIV) total number of deaths per year (liver disease) total number of deaths per year (HIV)
total number of deaths per year (liver disease) total number of deaths per year (cancer) total number of deaths per year (cancer)
p < 0.001 p < 0.023
p < 0.022 HIV
Liver disease
Cancer
Fig. 4a–f. Comparison total number of deaths of HIV, liver disease and cancer (a – f)
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
25 50 75 100
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
25 50 75 100
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
25 50 75 100
HIV Liver disease
Cance r
% of total number of deaths per year
(a) (b)
(c)
Fig. 5. Comparison % of total number of deaths of HIV, liver disease and cancer (a–c)
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
20 40
60
Causes of death
쮿
Other
쮿Bleeding
쮿HIV
쮿Liver disease
쮿Cancer
쮿No comment
쮿Accident, suicide,
murder, drugs
period
total number of deaths per year
Fig 6. Causes of death since the beginning of the survey
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
10 20 30 40 50
82/83 84/85
85/86 86/87
87/88 88/89
89/90 90/91
91/92 92/93
93/94 94/95
95/96 96/97
97/98 98/99
99/00 00/01
01/02 02/03 0
25 50 75 100
Causes of death
쮿Other
쮿
Bleeding
쮿HIV
쮿
Liver disease
쮿Cancer
쮿No comment
쮿Accident, suicide,
murder, drugs
% of total number of deaths per year total number of deaths per year
(a)
(b)
Fig. 7. Chart of deceased patients per year, separated for causes of death
Causes of death 쮿 Other
쮿 Bleeding 쮿 HIV
쮿 Liver disease
쮿 Cancer 쮿 No comment
쮿 Accident, suicide,
murder, drugs
0 1 / 0 2 9 9 /0 0 9 7 /9 8 9 5 /9 6 9 3 /9 4 9 1 /9 2 8 9 /9 0 8 7 /8 8 8 5 /8 6 8 2 /8 3 8 0 0
6 0 0
4 0 0
2 0 0
0
Causes of death 쮿 Other
쮿 Bleeding 쮿 HIV
쮿 Liver disease
쮿 Cancer 쮿 No comment
쮿 Accident, suicide, murder, drugs
total number of deaths per year (cumulated)
Fig. 8. Cumulative chart of deceased patients, separated for causes of death
50
40
30
20
10
0
13 13
(a)
50
40
30
20
10
0
26 36
(b)
% of total number of deaths 1999 – 2003
1999 – 2003 HIV negative 1999 – 2003 HIV positive
Liver disease Cancer Liver disease Cancer
