Thromb Haemost 2023; 123(09): 841-854
DOI: 10.1055/a-2057-8710
Coagulation and Fibrinolysis

Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin Crosslinking

Masayoshi Souri
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
3   Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science, Yonezawa, Japan
,
Chikako Yokoyama
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
4   Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, Yamagata, Japan
,
Tsukasa Osaki
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
3   Department of Public Health and Hygiene, Yamagata University Graduate School of Medical Science, Yonezawa, Japan
,
1   Department of Molecular Patho-Biochemistry and Patho-Biology, Yamagata University School of Medicine, Yamagata, Japan
2   The Japanese Collaborative Research Group (JCRG) on Autoimmune Acquired Coagulation Factor Deficiencies supported by the Japanese Ministry of Health, Labor and Welfare (MHLW), Yamagata, Japan
› Author Affiliations
Funding This study was supported in part by research aids to A.I. from the Japanese Ministry of Health, Labor, and Welfare (21FC1008), the Japanese Ministry of Education, Culture, Sports, Science, and Technology (16K09820), and the Japan Agency for Medical Research and Development (AMED; JP16ek0109043).


Abstract

Background Coagulation factor XIII (FXIII) is a proenzyme of plasma transglutaminase. It comprises two catalytic A subunits (FXIII-A) and two carrier B subunits (FXIII-B). We previously reported that alloantibodies against FXIII-B could promote FXIII clearance in a patient with congenital FXIII-B deficiency who had received infusions of plasma-derived human FXIII (A2B2 heterotetramer).

Objectives We aimed to investigate whether anti-FXIII-B antibodies affect the catalytic function of FXIII.

Methods FXIII activation and fibrin crosslinking were examined in the presence of patient plasma, isolated patient IgG, or rat anti-FXIII-B monoclonal antibodies.

Results Alloantibody levels were increased by repeated infusions of plasma-derived A2B2 heterotetramer, which enhanced binding to the functionally important FXIII-B sushi domains. The patient plasma strongly inhibited cleavage of the FXIII-A activation peptide, amine incorporation, and fibrin crosslinking in normal plasma. Furthermore, anti-FXIII-B alloantibodies blocked the formation of the complex of FXIII-B with FXIII-A, and fibrinogen. Rat monoclonal antibodies against the 10th sushi domain of FXIII-B inhibited the incorporation of FXIII-B to fibrin, FXIII activation (i.e., cleavage of FXIII-A activation peptide), and ultimately fibrin crosslinking in normal plasma, independent of their effect on heterotetramer assembly with FXIII-A. Alloantibody binding to the A2B2 heterotetramer blocked the access of thrombin to the FXIII-A cleavage site, as indicated by the reaction of the alloantibodies to the A2B2 heterotetramer and FXIII-B, but not to FXIII-A.

Conclusion Anti-FXIII-B antibodies binding to the A2B2 heterotetramer and FXIII-B inhibited FXIII activation and its crosslinking function despite being directed against its noncatalytic subunit (FXIII-B).

Authors' Contribution

A.I. created the research project and wrote and edited the manuscript. M.S. and T.O. performed experiments, wrote, and proofread the manuscript. C.Y. provided rat monoclonal antibodies against human factor XIII-B and proofread the manuscript.


Supplementary Material



Publication History

Received: 17 December 2022

Accepted: 14 March 2023

Accepted Manuscript online:
19 March 2023

Article published online:
19 April 2023

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