Immune-Related and Non-Immune-Related Acquired Factor XIII Deficiency

Abstract

Coagulation factor XIII (FXIII) is an essential protein that stabilizes the hemostatic plug formed in the final stage of the coagulation reaction and controls its dissolution. In the blood, it exists as a heterotetramer consisting of A subunit dimers and B subunit dimers. Genetic defects in each subunit result in a congenital deficiency, which causes fatal or mild bleeding symptoms. Acquired FXIII deficiency can develop owing to reduced production or increased consumption of FXIII, and its severe form can cause various bleeding symptoms. In particular, autoimmune FXIII deficiency (AiF13D) causes fatal bleeding symptoms due to the suppression of FXIII activity by anti-FXIII autoantibodies and/or accelerated clearance of FXIII. AiF13D is characterized by extremely severe FXIII deficiency and severe bleeding symptoms. It is associated with the highest hemorrhagic mortality rate among autoimmune coagulation factor deficiencies, making it essential to differentiate it from other non-immune FXIII deficiencies (NiF13D), such as those arising from liver cirrhosis or leukemia. The probable and definitive diagnosis of AiF13D require the presence of FXIII inhibitors and anti-FXIII autoantibodies, respectively. FXIII inhibitors can be detected by a general FXIII activity assay in the mixed plasma of patients and healthy controls, and can be measured in a regular laboratory. In contrast, immunological assays are conducted in limited research facilities because they are not commercially available. NiF13D is usually treated by hemostatic therapy with FXIII concentrates, but AiF13D requires hemostatic therapy plus autoantibody eradication therapy with immunosuppressants. Since the disease often becomes resistant to treatment, long-term follow-up is strongly recommended.

Keywords

anti-factor XIII autoantibody - factor XIII inhibitor - hyper-clearance - hypo-production - hyper-consumption

Note

Core members of the Japanese Collaborative Research Group (JCRG) on autoimmune coagulation factor deficiencies (AiCFDs): A. Ichinose, T. Konta, M. Souri, T. Osaki, C. Yokoyama, M. Ieko, Y. Ogawa, H. Asakura, H. Wada, T. Hashiguchi, and I. Maruyama.

Author Contribution

A.I. initiated and designed the study, extracted data, wrote, edited, and proofread the manuscript.

Ethical Approval

The study protocol was reviewed and approved by the Ethics Committee of Yamagata University School of Medicine, Yamagata, Japan (approval number 2021–273). Written informed consent was obtained for participation in this study. All procedures were conducted in accordance with the Declaration of Helsinki.

Publication History

Received: 01 March 2025

Accepted: 11 June 2025

Accepted Manuscript online:
12 June 2025

Article published online:
09 July 2025

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