J. Oldenburg, A. Pavlova, J. Schröder, H.-H. Brackmann, W. Effenberger, R. Zimmermann, A. Huth-Kühne, I. Scharrer, R. Grossmann, E. Seifried and C. Seidl
Introduction
Acquired hemophilia A is a rare but serious coagulopathy affecting 1 in about 1,000,000 inhabitants/year. Mainly the elderly, persons with autoimmune disorders and infrequently, women in the immediate postpartum period are exhibiting this condition, that results in bleeding into the skin, muscles, gastrointestinal and geni- tourinary tracts. It is due to autoantibodies directed against specific domains of the factor VIII molecule [1]. The pathogenesis if this disorder is only partly understood.
Only in 50% of the patients an underlying disease can be diagnosed, the other 50%
of the patients are idiopathic.
Results and Discussion
In order to investigate whether specific HLA alleles increase the risk of developing acquired haemophilia A we determined the HLA profile in 45 patients with acqui- red hemophilia A that were diagnosed during the last 6 years in Bonn, Frankfurt, Heidelberg and Würzburg. In the HLA-A, -B and -C systems small relative risk figures were found for A2 (1.6), A3 (0.4), B7 (0.5), respectively (Fig 1). However,
I. Scharrer/W. Schramm (Ed.)
34
thHemophilia Symposium Hamburg 2003
” Springer Medizin Verlag Heidelberg 2005
Table 1. Evaluation of the relative risk in different HLA alleles with respect to inhibitor forma- tion in acquired hemophilia, normal Caucasians and hemophilia patients with and without inhibitors
Ac HA vs N Inh HA vs Non- Inh. HA
Higher Risk RR Lower Risk RR
A2 1.5 A2 0.5
DQB 0502 9.9 DQB 0502 1.1
DR13 1.9 DR13 0.1
DR16 9.9 DR16 1.5
Lower Risk Higher Risk
A3 0.4 A3 2.2
B7 0.5 B7 4.0
DQB0602 0.3 DQB0602 3.7
Dr15 0.6 DR 2.2
0
5 10
15
20
25
30
w C 1
w C 2
w C 3
w C 4
w C 5
w C 6
w C 7
w C 8
w C 12
w C 14
w C 15
w C 16
w C 17
HLA-C 0, 0
5, 0
10, 0
15, 0
20, 0
25, 0
30, 0
35, 0
40, 0
45, 0 A 2 A 1 A 3 A11 A23 A24 A26 A28 A29 A30 A31 A32 A68
1.6 0.4
HLA-A 0 2 4 6 8
10
12
14
16 B7 B8 B1 3 B 1 4 B1 5 B 1 8 B2 7 B 3 5 B3 7 B 3 8 B3 9 B 4 0 B4 1 B 4 2 B4 4 B 5 0 B5 1 B 5 2 B5 5 B 5 6 B5 7 B 5 8 B7 8
0.5 HLA-B
A B Acquired Hemophilia Normal (Caucasians) Acquired Hemophilia Normal (Caucasians)
Acquired Hemophilia Normal (Caucasians) C Fi g .1 .C o m p ar is o n o f HLA class I an ti gen dist ri b u tio n in p at ien ts w ith ac q uir ed hemo p h ilia and Ca ucasian po pula tio n. (A: HLA -lo cus A; B: HLA -lo cus B; C: HLA -lo cus C)
0.3
0,00 2,00 4,00 6,00 8,00 10,00 12,00 14,00 16,00 18,00
DR1 DR3 DR4 DR7 DR8 DR10 DR11 DR12 DR13 DR14 DR15 DR16 Acquired Hemophilia Normal cauc.
0.6
9.9
Fig. 2. Comparison of HLA class II - DR anti- gen distribution in patients with acquired hemophilia and Caucasian population
0,00 2,00 4,00 6,00 8,00 10,00 12,00
DQ5011 DQ5021 DQ531
Acquired Hemophilia Normal
0,00 2,00 4,00 6,00 8,00 10,00 12,00 14,00 16,00 18,00
D Q 06011 D Q 0602 D Q 0603 D Q 0604
A cquired He mophlia N orma l
A
B
Fig. 3. Comparison of HLA class II - DQ5 (A) and DQ6 (B) subclass distribution in patients
with acquired hemophilia and Caucasian population
DR16 and DQB0502 showed a substantial increase of frequency in acquired in- hibitor patients compared to normal population (10% vs 1%), resulting in a rela- tive risk of 9.9, while DR15 and DQB0602 showed decreased relative risks of 0.6 and 0.3 (Fig 2, 3 and 4) [2, 3]. This finding may be of special interest because HLA alleles with higher risk figures in acquired HA have lower risk figures in inhibitors with inherited HA and vice versa (Table 1). Thus in the presence of endogenous FVIII other HLA alleles may promote immune response than in the absence of endogenous FVIII [4, 5]. Moreover, it has been reported by Chicz et al. (1993) that a FVIII peptide comprising amino acids 1705 to 1721 has been eluted from a DR15 cell line and therefore may be of significance for the immune response towards FVIII [6].
Conclusions
The DR16 and DQB0502 alleles were more frequent in acquired hemophilia A than in the normal population. Although not statistically significant, the HLA profile in acquired hemophilia A gains importance because of its antipodal expression com- pared to inhibitors in inherited hemophilia A.
0 5 10 15 20 25 30 35 40
Inhibitors with intron 22 inv.
(n = 58 alleles)
Acquired inhibitors (n = 90) alleles)
DR16 DQ0501 DQ0502 DQ0503
DQ0601 DQ0602
DQ0603
DR15 DQ 0604
