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

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).

Keywords

autoantibody - activation peptide - fibrin crosslinking - A₂B₂ heterotetramer - sushi domain

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.

Publikationsverlauf

Eingereicht: 17. Dezember 2022

Angenommen: 14. März 2023

Accepted Manuscript online:
19. März 2023

Artikel online veröffentlicht:
19. April 2023

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