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

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.