Masayoshi Souri1, Sho Mokuda2, Hiroshi Inanami3, Tsukasa Osaki1, Kiyoshi Takasugi4, Akitada Ichinose5. 1. Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. 2. Department of Internal Medicine, Center for Rheumatic Diseases, Dohgo Spa Hospital, Matsuyama, Ehime, Japan; Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan. 3. Department of Internal Medicine, Center for Rheumatic Diseases, Kobe Midori Hospital, Kobe, Hyogo, Japan. 4. Department of Internal Medicine, Center for Rheumatic Diseases, Dohgo Spa Hospital, Matsuyama, Ehime, Japan. 5. Department of Molecular Patho-Biochemistry & -Biology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. Electronic address: aichinos@med.id.yamagata-u.ac.jp.
Abstract
INTRODUCTION: Coagulation factor XIII (FXIII) is a plasma fibrin-stabilizing factor comprising A and B subunits (FXIII-A and FXIII-B, respectively) in the form of a heterotetramer (FXIII-A2B2). A humanized monoclonal antibody to the interleukin-6 receptor (tocilizumab, TCZ) has emerged as an effective treatment for rheumatoid arthritis (RA), because it drastically reduces the inflammation of RA. We previously reported that two TCZ-treated RA patients with acquired FXIII deficiency developed pelvic hemorrhage. METHODS: Because TCZ treatment had been shown to be related to low FXIII ammonia release activity and FXIII antigen in the two RA cases, we further examined FXIII-related parameters in 36 TCZ-treated RA patients and compared to 29 healthy controls by employing functional and immunologic assays for FXIII. RESULTS: FXIII-A antigen and FXIII amine incorporation and ammonia release activities were significantly lower in the TCZ-treated group than the control group. The TCZ-treated group also showed mildly low FXIII-A2B2 and FXIII-B levels, and their fibrinogen levels were the lower limit of normal. A significant correlation between FXIII-B and fibrinogen was observed in the control and the TCZ groups, suggesting a common metabolic mechanism(s) for these two hepatic proteins. Because the specific activities of FXIII were normal and neither anti-FXIII-A nor anti-FXIII-B antibody was detected, the overall low FXIII level may have resulted from its impaired synthesis under an unbalanced cytokine milieu caused by TCZ treatment. CONCLUSION: Concomitant deficiencies in multiple hemostatic factors, including FXIII, may lead to an increased risk for hemorrhage in TCZ-treated RA patients.
INTRODUCTION: Coagulation factor XIII (FXIII) is a plasma fibrin-stabilizing factor comprising A and B subunits (FXIII-A and FXIII-B, respectively) in the form of a heterotetramer (FXIII-A2B2). A humanized monoclonal antibody to the interleukin-6 receptor (tocilizumab, TCZ) has emerged as an effective treatment for rheumatoid arthritis (RA), because it drastically reduces the inflammation of RA. We previously reported that two TCZ-treated RApatients with acquired FXIII deficiency developed pelvic hemorrhage. METHODS: Because TCZ treatment had been shown to be related to low FXIII ammonia release activity and FXIII antigen in the two RA cases, we further examined FXIII-related parameters in 36 TCZ-treated RApatients and compared to 29 healthy controls by employing functional and immunologic assays for FXIII. RESULTS: FXIII-A antigen and FXIII amine incorporation and ammonia release activities were significantly lower in the TCZ-treated group than the control group. The TCZ-treated group also showed mildly low FXIII-A2B2 and FXIII-B levels, and their fibrinogen levels were the lower limit of normal. A significant correlation between FXIII-B and fibrinogen was observed in the control and the TCZ groups, suggesting a common metabolic mechanism(s) for these two hepatic proteins. Because the specific activities of FXIII were normal and neither anti-FXIII-A nor anti-FXIII-B antibody was detected, the overall low FXIII level may have resulted from its impaired synthesis under an unbalanced cytokine milieu caused by TCZ treatment. CONCLUSION: Concomitant deficiencies in multiple hemostatic factors, including FXIII, may lead to an increased risk for hemorrhage in TCZ-treated RApatients.
Authors: Joshua A Hill; Manoj P Menon; Shireesha Dhanireddy; Mark M Wurfel; Margaret Green; Rupali Jain; Jeannie D Chan; Joanne Huang; Danika Bethune; Cameron Turtle; Christine Johnston; Hu Xie; Wendy M Leisenring; H Nina Kim; Guang-Shing Cheng Journal: J Med Virol Date: 2020-11-22 Impact factor: 20.693