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Introduction: Autoimmune factor X (FX or F10) deficiency (AiF10D) is an extremely rare acquired haemorrhagic disorder characterized by a severe reduction in FX activity due to autoantibodies against FX., Aim: Anti-FX autoantibodies were investigated in four patients with suspected AiF10D, and their properties were analysed., Methods and Results: Anti-FX auto antibodies in plasma were detected by ELISA with three of four cases. One case of anti-FX autoantibody negativity was later diagnosed as AL-amyloidosis. IgG1 and IgG3 coexisted in all anti-FX autoantibodies of the three patients with AiF10D (cases X1, X2, and X3). Western blot analysis showed that the antibodies were bound to the FX light chain for cases X2 and X3, but the binding was weak for case X1. When the fusion proteins of a secretory luciferase with full-length FX or its γ-carboxylated glutamic acid (Gla) domain were added to the plasma of the three patients, both fusion proteins were immunoprecipitated as antigen-antibody complexes. Contrarily, the latter fusion protein produced in the presence of warfarin demonstrated a decrease in the collection rate, suggesting that their autoantibodies recognized the light chain and regions containing Gla residues. Since all three patients were essentially negative for FX inhibitors, it was concluded that the anti-FX autoantibodies for these cases were predominantly non-neutralizing. The concentration of the FX antigen also significantly reduced in these patients, suggesting that anti-FX autoantibodies promote the clearance of FX., Conclusion: Immunological anti-FX autoantibody detection is highly recommended to ensure that AiF10D cases are not overlooked, and to start necessary immunosuppressive therapies., (© 2022 John Wiley & Sons Ltd.)

Introduction: Autoimmune factor XIII (FXIII) deficiency (AiF13D) due to anti-FXIII autoantibodies is an extremely rare, life-threatening bleeding disorder that mostly occurs in the elderly. The number of patients diagnosed with AiF13D has been increasing in Japan, probably because of the nationwide survey on AiF13D supported by the Japanese Ministry of Health, Labour and Welfare., Aim: To explore the pathologic characteristics of coagulation parameters in AiF13D., Methods: AiF13D-suspected cases were consulted, and underwent unified/integrated coagulation screening and were definitively diagnosed as AiF13D separately., Results: AiF13D patients had lower FXIII antigen levels than non-AiF13D patients, but their values overlapped. Among a series of 22-item screening tests and their resulting parameters, the 'FXIII inhibitory potential' yielded by a 1:1 mixing test of the patient's and healthy control's plasma and its 'residual FXIII activity' in 54 AiF13D cases were most distinguishable from 139 non-AiF13D cases, followed by FXIII activity per se and FXIII-specific activity. While the cross-linked α 2 -plasmin inhibitor level reduced, the levels of D-dimer, fibrin/fibrinogen degradation products and plasmin-plasmin inhibitor complex increased, probably because the patients' haematoma nonspecifically induced secondary fibrinolysis in both AiF13D and non-AiF13D patients., Conclusion: AiF13D appears to induce a hypocoagulopathy combined with a hyper-fibrinolytic state secondary to severe FXIII deficiency caused by anti-FXIII autoantibodies, and the consequent bleeding further modifies its pathological conditions. In addition, the 1:1 mixing test of FXIII activity was confirmed to be a reliable screening method for AiF13D, especially when its derivative parameter, such as the 'FXIII inhibitory potential' or 'FXIII inhibitory potential ratio', is employed., (© 2021 John Wiley & Sons Ltd.)

Introduction: Autoimmune haemophilia-like disease (or haemorrha-philia) due to anti-factor XIII (FXIII; F13 to avoid confusion with FVIII or FXII) antibodies (termed AH13) is a severe bleeding disorder. Although AH13 is thought to be rare, 'the number of its diagnosed patients' has recently increased in Japan. However, its prevalence remains unknown., Aim: To improve understanding of this disease, we examined and diagnosed 32 'new' Japanese patients with AH13., Methods: The presence of antibodies against F13-A subunit and/or F13-B subunit was confirmed by using a dot blot test and enzyme-linked immunosorbent assays., Results: Most of our patients had autoantibodies against the F13-A subunit (88%). A predominance of men (59%) was observed. The mean age and residual F13 activity of our AH13 cohort were 71.7 years and 10.5% of normal, respectively, and 53% of cases were idiopathic. Autoimmune disorders and malignancies were the leading underlying disease (both 16%). Intramuscular and subcutaneous bleeding were the leading symptoms (both 72%). Most of our patients were treated with F13 concentrates (72%) to arrest bleeding and with prednisolone (81%) to eradicate anti-F13 autoantibodies. Cyclophosphamide and rituximab (both 25%) were also administered. The mortality of AH13 was high (22%), and haemorrhage was the major cause of death (71%). Moreover, 13% of our AH13 patients were diagnosed after haemorrhagic death., Conclusion: Physicians/haematologists must raise the awareness of AH13 as a life-threatening disease. This report represents the only experience of a nationwide survey, and may contribute to a diagnosis on potentially overlooked non-Japanese AH13 patients in other countries in the world., (© 2015 John Wiley & Sons Ltd.)

Factor XIII (FXIII) consists of the A and B subunits (FXIII-A and FXIII-B) and stabilizes fibrin clots. Defects in either the FXIII-A or FXIII-B gene lead to congenital FXIII deficiency, which manifests a life-long haemorrhagic tendency. Thus, prophylactic FXIII replacement therapy is recommended. To establish a management plan for a 30-year-old male patient with 'indefinite' FXIII deficiency (<40% of the normal FXIII), he was characterized by state-of-the-art techniques as guided by the FXIII/Fibrinogen subcommittee of ISTH/SSC. FXIII activity turned out to be virtually undetectable by three functional assays. Four immunological assays detected essentially no FXIII protein, FXIII-A antigen, and A2 B2 antigen, but normal FXIII-B antigen. Accordingly, he was diagnosed as a 'severe' FXIII-A deficiency case. He had no anti-FXIII antibodies, because a 1:1 cross-mixing test (ammonia release assay) and a five-step mixing test (amine incorporation assay) between his plasma and normal plasma demonstrated deficiency patterns. Furthermore, a dosing test using plasma-derived FXIII concentrates revealed its normal recovery. DNA sequencing analysis identified two novel mutations, W187X & G273V, in the F13A gene. Genetic analyses confirmed that he was a compound heterozygote and his mother and sister were heterozygotes of either one of these mutations, indicating the hereditary nature of this disorder. Molecular modelling predicted that the G273V mutation would cause clashes with the surrounding residues in the core domain of FXIII-A, and ultimately would result in the instability of the mutant molecule. Detailed characterization of 'indefinite' FXIII deficiency made it possible to make its definite diagnosis and best management plan., (© 2013 John Wiley & Sons Ltd.)

Congenital factor XIII (FXIII) deficiency is a severe bleeding disorder. We previously identified an Arg260Cys missense mutation and an exon-IV deletion in patients' A subunit genes, F13A. To characterize the molecular/cellular basis of this disease, we expressed a wild type and these mutant A subunits in baby hamster kidney (BHK) cells. The mutant proteins were expressed less efficiently than the wild type. These mutants gradually decreased inside BHK cells, whereas the wild type remained largely unchanged. The decline/decrease in these mutants was completely blocked/restored by a potent proteasome inhibitor, MG-132. This was consistent with the prediction by molecular modelling that the mutant molecules would lose the native structure of wild-type molecule, leading to their instability and degeneration and ultimately to degradation. These mutants might have significantly altered conformations, resulting in the rapid degradation by the proteasome inside the synthesizing cells, and ultimately leading to FXIII deficiency., (© 2012 Blackwell Publishing Ltd.)

Acquired factor XIII (FXIII) deficiency due to an autoantibody against FXIII is a very rare, yet potentially life-threatening bleeding disorder. As the standard coagulation tests (prothrombin time and activated partial thromboplastin time) are normal, the specialized tests are required to make an accurate diagnosis. Here, we report a case of acquired FXIII deficiency with severe bleeding symptoms. A 75-year-old man was referred to our hospital because of severe bleeding tendency after a tooth extraction. Laboratory findings showed that routine coagulation studies were normal, but factor XIII (FXIII) activity was low (3%). The presence of FXIII inhibitor was detected with dot blotting studies. Although the bleeding tendency was very severe, it was successfully controlled by infusion of FXIII concentrates combined with immunosuppressive treatment (oral prednisolone). Fibrin cross-linking study showed the significant delay of the γ-chain dimer and α-chain polymer formation. Western blotting revealed the marked decrease in FXIII-A level. The mixing study of FXIII activity measured using amine-incorporation assay showed the incomplete inhibition pattern. There seems to be little agreement as to the treatment strategy of acquired FXIII deficiency. In this patient, the use of FXIII concentrates was very useful in the initial treatment of bleeding symptom. The use of steroids was also effective in increasing FXIII activity without any serious complications., (© 2012 Blackwell Publishing Ltd.)