Autoantibodies in Autoimmune Coagulation Factor Deficiencies: A Review of Inhibitory and Clearance-Accelerating Mechanisms from Japanese Practice

Abstract

Autoimmune acquired coagulation factor deficiency (AiCFD) represents a rare coagulation disorder that primarily affects older people and sometimes causes fatal bleeding; therefore, clinicians need to consider this when encountering patients with unexplained bleeding. AiCFD is caused by the production of autoantibodies against one's own coagulation factor, which markedly inhibit its function, or accelerate its clearance from plasma, resulting in hemostatic failure. The plasma of affected patients shows various abnormal findings, because anti-coagulation factor autoantibodies are polyclonal, and each clone has different properties. First, inhibitor type autoantibodies target the functional sites of coagulation factors, thereby considerably reducing their activity. Second, clearance-accelerating autoantibodies bind to non-functional sites and cause rapid removal of coagulation factors from the blood, thereby reducing their levels (and their activity in parallel). Third, mixed type autoantibodies (inhibitory clearance-accelerating) substantially reduce coagulation factor activity and level to various degrees. Most anti-coagulation factor autoantibodies are inhibitory clearance-accelerating types, although pure inhibitor types remain clinically significant; however, the pure clearance-accelerating type appears to be rare, possibly because the autoantibody is not detected unless it exceeds the level of the target coagulation factor (pseudo-autoantibody negative). Moreover, anti-factor XIII autoantibodies are particularly complex, as they interfere with the A subunit (Aa type), its activated form (Ab type), and/or the B subunit (B type). Of the three types, Aa type anti-factor XIII autoantibodies contain a mixture of different inhibitor type autoantibodies in various ratios in plasma, resulting in an extremely diverse range of test findings. Therefore, care must be taken when diagnosing and assessing the efficacy of treatment.

Keywords

anti-coagulation factor autoantibodies - coagulation factor inhibitors - inhibitory autoantibodies - clearance-accelerating autoantibodies - hyperclearance autoantibodies

Ethical Approval

The study protocol was reviewed and approved by the Ethics Committee of Yamagata University School of Medicine, Yamagata, Japan (approval number 2022–9). Written informed consent was obtained for participation in this study. All procedures were conducted in accordance with the Declaration of Helsinki.

Authors' Contribution

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

Note: Ordinary antibodies (non-autoantibodies) are underlined to clearly distinguish from “autoantibodies.”

Publication History

Received: 11 November 2024

Accepted: 07 April 2025

Accepted Manuscript online:
08 April 2025

Article published online:
10 May 2025

• References

• 1 Cugno M, Gualtierotti R, Tedeschi A, Meroni PL. Autoantibodies to coagulation factors: from pathophysiology to diagnosis and therapy. Autoimmun Rev 2014; 13 (01) 40-48 Erratum in: Autoimmun Rev. 2015 Jul;14(7):650
• 2 Ichinose A, Osaki T, Souri M. Diagnosis and treatment of autoimmune acquired coagulation factor deficiencies: an evidence-based review of Japanese practice. Semin Thromb Hemost 2024; ; Epub ahead of print
• 3 Osaki T, Souri M, Ichinose A. Plasma proteomics associated with autoimmune coagulation factor deficiencies reveals the link between inflammation and autoantibody development. Int J Hematol 2022; 115 (05) 672-685
• 4 Ichinose A.. Japanese Collaborative Research Group on AH13. Autoimmune acquired factor XIII deficiency due to anti-factor XIII/13 antibodies: a summary of 93 patients. Blood Rev 2017; 31 (01) 37-45
• 5 Ichinose A, Osaki T, Souri M. Autoimmune acquired factor XIII deficiency in Japan 2021 update: focused on annual incidence and clinical features. Haemophilia 2022; 28 (05) e121-e124
• 6 Ogawa Y, Yanagisawa K, Uchiumi H. et al. Clinical characteristics and outcomes of acquired hemophilia A: experience at a single center in Japan. Int J Hematol 2017; 106 (01) 82-89
• 7 Ichinose A, Osaki T, Souri M, Favaloro EJ. A review of autoimmune acquired von Willebrand factor deficiency in Japan. Semin Thromb Hemost 2022; 48 (08) 911-925
• 8 Ichinose A, Osaki T, Souri M. A review of coagulation abnormalities of autoimmune acquired factor V deficiency with a focus on Japan. Semin Thromb Hemost 2022; 48 (02) 206-218 Erratum in: Semin Thromb Hemost. 2022 Mar;48(2):e1
• 9 Ichinose A, Osaki T, Souri M. Autoimmune coagulation factor X deficiency as a rare acquired hemorrhagic disorder: a literature review. Thromb Haemost 2022; 122 (03) 320-328
• 10 Krudysz-Amblo J, Parhami-Seren B, Butenas S. et al. Quantitation of anti-factor VIII antibodies in human plasma. Blood 2009; 113 (11) 2587-2594
• 11 Whelan SF, Hofbauer CJ, Horling FM. et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood 2013; 121 (06) 1039-1048
• 12 Krumdieck R, Shaw DR, Huang ST, Poon MC, Rustagi PK. Hemorrhagic disorder due to an isoniazid-associated acquired factor XIII inhibitor in a patient with Waldenström's macroglobulinemia. Am J Med 1991; 90 (05) 639-645
• 13 Souri M, Osaki T, Ichinose A. Anti-factor XIII A subunit (FXIII-A) autoantibodies block FXIII-A2 B2 assembly and steal FXIII-A from native FXIII-A2 B2. J Thromb Haemost 2015; 13 (05) 802-814
• 14 Souri M, Ozawa T, Osaki T, Koyama T, Muraguchi A, Ichinose A. Cloning of human anti-factor XIII monoclonal antibody dissects mechanisms of polyclonal antibodies in a single patient. J Thromb Haemost 2023; 21 (02) 255-268
• 15 Tsunemine H, Souri M, Kumode W, Arima N, Ichinose A. A case of autoimmune factor XIII deficiency due to clearance-accelerating and inhibitory anti-FXIII autoantibodies. Int J Hematol 2025; 121 (02) 257-264
• 16 Ichinose A, Osaki T, Souri M. Pathological coagulation parameters in as many as 54 patients with autoimmune acquired factor XIII deficiency due to anti-factor XIII autoantibodies. Haemophilia 2021; 27 (03) 454-462
• 17 Osaki T, Souri M, Ogawa Y, Sato H, Mitsui T, Ichinose A. Retrospective examination of coagulation parameters in 33 patients with autoimmune coagulation factor deficiencies in Japan: a single-center analysis. Thromb Res 2022; 213: 154-162
• 18 Osaki T, Souri M, Yokoyama C, Magari Y, Ichinose A. Unmet need for reliable immunological detection method for anti-von Willebrand factor autoantibodies. Thromb Haemost 2023; 123 (04) 478-481
• 19 Souri M, Osaki T, Shimura Y. et al. Identification of non-neutralizing anti-factor X autoantibodies in three Japanese cases of autoimmune acquired factor X deficiency. Haemophilia 2023; 29 (02) 555-563
• 20 Ajzner E, Schlammadinger A, Kerényi A. et al. Severe bleeding complications caused by an autoantibody against the B subunit of plasma factor XIII: a novel form of acquired factor XIII deficiency. Blood 2009; 113 (03) 723-725
• 21 Meenhuis A, van Vliet R, Hudig F, Ypma PF, Schipperus MR, Hollestelle MJ. Successful treatment of a noninhibitory antibody-mediated acquired factor X deficiency in a patient with marginal-zone lymphoma. Clin Case Rep 2015; 3 (07) 587-593
• 22 Souri M, Osaki T, Ichinose A. Detection of factor XIII inhibitors in 33 patients with autoimmune factor XIII deficiency in Japan. Int J Hematol 2024; 120 (04) 472-481
• 23 Kadono M, Souri M, Shimomura T. et al. [Autoimmune acquired coagulation factor XIII/13 deficiency caused by type Ab anti-FXIII-A autoantibody] [Article in Japanese]. Rinsho Ketsueki 2023; 64 (12) 1508-1513
• 24 Osaki T, Sugiyama D, Magari Y, Souri M, Ichinose A. Rapid immunochromatographic test for detection of anti-factor XIII A subunit antibodies can diagnose 90 % of cases with autoimmune haemorrhaphilia XIII/13. Thromb Haemost 2015; 113 (06) 1347-1356
• 25 Osaki T, Yokoyama C, Magari Y, Souri M, Ichinose A. Novel immunochromatographic test for anti-factor XIII B subunit autoantibodies to diagnose autoimmune acquired factor XIII deficiency. Thromb Haemost 2023; 123 (08) 793-803
• 26 Pénzes K, Rázsó K, Katona É, Kerényi A, Kun M, Muszbek L. Neutralizing autoantibody against factor XIII A subunit resulted in severe bleeding diathesis with a fatal outcome—characterization of the antibody. J Thromb Haemost 2016; 14 (08) 1517-1520
• 27 Bovet J, Hurják B, De Maistre E, Katona É, Pénzes K, Muszbek L. Autoimmune factor XIII deficiency with unusual laboratory and clinical phenotype. J Thromb Haemost 2020; 18 (06) 1330-1334
• 28 Katona E, Haramura G, Kárpáti L, Fachet J, Muszbek L. A simple, quick one-step ELISA assay for the determination of complex plasma factor XIII (A2B2). Thromb Haemost 2000; 83 (02) 268-273
• 29 Katona E E, Ajzner E, Tóth K, Kárpáti L, Muszbek L. Enzyme-linked immunosorbent assay for the determination of blood coagulation factor XIII A-subunit in plasma and in cell lysates. J Immunol Methods 2001; 258 (1-2): 127-135
• 30 Ieko M, Ohmura K, Naito S. et al. Measurement of coagulation factor antibody levels is useful for diagnosis and determining therapeutic efficacy in hemorrhagic patients with autoantibodies to coagulation factor VIII and factor V: results from a single center in Japan. Int J Hematol 2022; 115 (01) 11-20
• 31 Ieko M, Naito S, Yoshida M. et al. Lupus anticoagulant-hypoproaccelerin (factor V) syndrome (LAHPS-V): a new hemorrhagic condition associated with lupus anticoagulant. Int J Hematol 2022; 116 (01) 152-154
• 32 Ieko M, Ohmura K, Naito S. et al. Considerations for simultaneous detection of autoantibodies to coagulation factor and lupus anticoagulant. Explor Immunol 2023; 3: 286-299
• 33 Blanco AN, Alcira Peirano A, Grosso SH, Gennari LC, Pérez Bianco R, Lazzari MA. A chromogenic substrate method for detecting and titrating anti-factor VIII antibodies in the presence of lupus anticoagulant. Haematologica 2002; 87 (03) 271-278
• 34 Suzuki A, Suzuki N, Kanematsu T. et al. Performance evaluation of Revohem^™ FVIII chromogenic and Revohem^™ FIX chromogenic in the CS-5100 autoanalyser. Int J Lab Hematol 2019; 41 (05) 664-670
• 35 Jin A, Ozawa T, Tajiri K, Obata T, Kishi H, Muraguchi A. Rapid isolation of antigen-specific antibody-secreting cells using a chip-based immunospot array. Nat Protoc 2011; 6 (05) 668-676
• 36 Kobayashi N, Ogawa Y, Yanagisawa K. et al. [Acquired immune-mediated von Willebrand syndrome accompanied by antiphospholipid syndrome] [Article in Japanese]. Rinsho Ketsueki 2017; 58 (06) 613-618
• 37 Bingo M, Suzuki T, Shinozawa K. et al. Two cases of acquired factor V inhibitor which were initially diagnosed with congenital deficiency by cross mixing tests [Article in Japanese]. Jap J Thromb Hemost 2018; 29 (04) 379-388
• 38 Koga S, Zaizen K, Tagawa K. et al. A case of acquired factor V inhibitor that could be detected early by a cross-mixing test. J Japan Soc Lab Hematol 2016; 17: S148
• 39 Inai K, Yamaguchi H, Kaito Y. et al. A case of acquired factor V deficiency that was difficult to diagnose due to fresh frozen plasma replacement. Rinsho Ketsueki 2019; 60 (05) 520-521 [Abstract]