Acquired haemophilia caused by non-haemophilic factor VIII gene variants.
The aetiology of anti-factor VIII (FVIII) autoantibody formation in acquired haemophilia remains unknown. We hypothesised that encounter of antigenically different, allogeneic FVIII may challenge inhibitor formation after presentation on MHC class II. Eighteen consecutive cases with acquired haemophilia were enrolled (nine females, nine males). A control group comprised 50 male and 50 female healthy blood donors. The coding region of the FVIII gene and the HLA-DRB1 genotype were studied. The presentation of foreign FVIII variants on the patient's MHC class II alleles was predicted using SYFPEITHI algorithm. A rare FVIII variant (E2004K) was found in one patient with acquired haemophilia after massive transfusion; the 2004 K allele was predicted to be presented on the patient's HLA-DRB1*0101. Moreover, distribution of a polymorphism (D1241E) was significantly skewed comparing patients and controls. Three of three patients with transfusion-associated disease carried 1241D in homozygous or hemizygous form and were predicted to present 1241E (foreign), but not 1241D (self), on their HLA-DRB1*0301. Therefore, encounter of 1241E may result in the presentation of a new T cell epitope in these patients. The same conditions were not found in any patient with acquired haemophilia of other causes. The expected frequency in the general Caucasoid population undergoing transfusion is 3% to 4%. In conclusion, encounter of variant allogeneic FVIII presented on a suitable MHC background could be a risk factor for inhibitor formation.
Tiede
Andreas
A
Department of Haematology, Hannover Medical School, Feodor Lynen Str 5, 30625 Hannover, Germany. tiede.andreas@mh-hannover.de
Eisert
Roswith
R
Czwalinna
Andreas
A
Miesbach
Wolfgang
W
Scharrer
Inge
I
Ganser
Arnold
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019774:Blood Coagulation Factor Inhibitors / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D004252:DNA Mutational Analysis; D005169:Factor VIII / Q000235:genetics* / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D055815:Young Adult
D019774:Blood Coagulation Factor Inhibitors; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C078147:F8 protein, human; D005169:Factor VIII