M Souri1, T Osaki, A Ichinose. 1. Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan; The Japanese Collaborative Research Group (JCRG) on Acquired hemorrha-philia due to anti-factor XIII autoantibodies (AH13), Yamagata, Japan.
Abstract
BACKGROUND: Autoimmune hemophilia-like disease (hemorrha-philia or hemorrhagic disorder) caused by anti-factor XIII antibodies (termed AH13) or 'autoimmune FXIII deficiency' is a life-threatening bleeding disorder. AH13 was thought to be rare worldwide. OBJECTIVES: Because the number of diagnosed AH13 cases has recently been increasing, at least in Japan, we conducted a nationwide survey supported by the Japanese Ministry of Health, Labor, and Welfare, and explored the pathologic mechanism(s) of AH13. METHODS: We diagnosed AH13 cases during the last 11 years according to the presence of anti-FXIII autoantibodies confirmed by a dot blot assay and ELISA, and characterized 33 of these both immunologically and biochemically. RESULTS: The AH13 cases were immunologically classified into three types, Aa, Ab, and B. Type Aa autoantibodies, observed in 27 cases, were directed against the native FXIII A subunit (FXIII-A), and blocked FXIII activation. The autoantibodies not only prevented assembly of new FXIII-A2 B2 heterotetramers, but also removed FXIII-A from native FXIII-A2 B2 heterotetramers by forming an FXIII-A-IgG complex. Type Ab autoantibodies, detected in three cases, preferentially bound to activated FXIII-A and inhibited its activity. Type Aa and Ab autoantibodies were 'neutralizing' FXIII antibodies (or FXIII inhibitors), and thus could be screened with functional assays. Type B antibodies, detected in two cases, were non-neutralizing anti-FXIII B subunit (FXIII-B) autoantibodies that possibly accelerated the clearance of FXIII, and thus could be diagnosed exclusively with immunologic methods. CONCLUSION: There are three major types of anti-FXIII autoantibody, with distinct targets and mechanisms that cause AH13.
BACKGROUND:Autoimmune hemophilia-like disease (hemorrha-philia or hemorrhagic disorder) caused by anti-factor XIII antibodies (termed AH13) or 'autoimmune FXIII deficiency' is a life-threatening bleeding disorder. AH13 was thought to be rare worldwide. OBJECTIVES: Because the number of diagnosed AH13 cases has recently been increasing, at least in Japan, we conducted a nationwide survey supported by the Japanese Ministry of Health, Labor, and Welfare, and explored the pathologic mechanism(s) of AH13. METHODS: We diagnosed AH13 cases during the last 11 years according to the presence of anti-FXIII autoantibodies confirmed by a dot blot assay and ELISA, and characterized 33 of these both immunologically and biochemically. RESULTS: The AH13 cases were immunologically classified into three types, Aa, Ab, and B. Type Aa autoantibodies, observed in 27 cases, were directed against the native FXIII A subunit (FXIII-A), and blocked FXIII activation. The autoantibodies not only prevented assembly of new FXIII-A2 B2 heterotetramers, but also removed FXIII-A from native FXIII-A2 B2 heterotetramers by forming an FXIII-A-IgG complex. Type Ab autoantibodies, detected in three cases, preferentially bound to activated FXIII-A and inhibited its activity. Type Aa and Ab autoantibodies were 'neutralizing' FXIII antibodies (or FXIII inhibitors), and thus could be screened with functional assays. Type B antibodies, detected in two cases, were non-neutralizing anti-FXIII B subunit (FXIII-B) autoantibodies that possibly accelerated the clearance of FXIII, and thus could be diagnosed exclusively with immunologic methods. CONCLUSION: There are three major types of anti-FXIII autoantibody, with distinct targets and mechanisms that cause AH13.