Subscribe to RSS
Antibodies against Noncatalytic B Subunit of Factor XIII Inhibit Activation of Factor XIII and Fibrin CrosslinkingFunding This study was supported in part by research aids to A.I. from the Japanese Ministry of Health, Labor, and Welfare (21FC1008), the Japanese Ministry of Education, Culture, Sports, Science, and Technology (16K09820), and the Japan Agency for Medical Research and Development (AMED; JP16ek0109043).
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).
Keywordsautoantibody - activation peptide - fibrin crosslinking - A2B2 heterotetramer - sushi domain
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.
Received: 17 December 2022
Accepted: 14 March 2023
Accepted Manuscript online:
19 March 2023
Article published online:
19 April 2023
© 2023. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Yee VC, Pedersen LC, Le Trong I, Bishop PD, Stenkamp RE, Teller DC. Three-dimensional structure of a transglutaminase: human blood coagulation factor XIII. Proc Natl Acad Sci U S A 1994; 91 (15) 7296-7300
- 2 Souri M, Kaetsu H, Ichinose A. Sushi domains in the B subunit of factor XIII responsible for oligomer assembly. Biochemistry 2008; 47 (33) 8656-8664
- 3 Ichinose A, Bottenus RE, Davie EW. Structure of transglutaminases. J Biol Chem 1990; 265 (23) 13411-13414
- 4 Takagi T, Doolittle RF. Amino acid sequence studies on factor XIII and the peptide released during its activation by thrombin. Biochemistry 1974; 13 (04) 750-756
- 5 Lorand L, Gray AJ, Brown K. et al. Dissociation of the subunit structure of fibrin stabilizing factor during activation of the zymogen. Biochem Biophys Res Commun 1974; 56 (04) 914-922
- 6 Chen R, Doolittle RF. γ-γ cross-linking sites in human and bovine fibrin. Biochemistry 1971; 10 (24) 4487-4491
- 7 McKee PA, Mattock P, Hill RL. Subunit structure of human fibrinogen, soluble fibrin, and cross-linked insoluble fibrin. Proc Natl Acad Sci U S A 1970; 66 (03) 738-744
- 8 Kimura S, Aoki N. Cross-linking site in fibrinogen for alpha 2-plasmin inhibitor. J Biol Chem 1986; 261 (33) 15591-15595
- 9 Hethershaw EL, Cilia La Corte AL, Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12 (02) 197-205
- 10 Dorgalaleh A, Rashidpanah J. Blood coagulation factor XIII and factor XIII deficiency. Blood Rev 2016; 30 (06) 461-475
- 11 Biswas A, Ivaskevicius V, Seitz R, Thomas A, Oldenburg J. An update of the mutation profile of Factor 13 A and B genes. Blood Rev 2011; 25 (05) 193-204
- 12 Ivaskevicius V, Seitz R, Kohler HP. et al; Study Group. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007; 97 (06) 914-921
- 13 Saito M, Asakura H, Yoshida T. et al. A familial factor XIII subunit B deficiency. Br J Haematol 1990; 74 (03) 290-294
- 14 Li B, Bechtler C, Jenny L, Ricklin D, Schroeder V. Exploring the function of factor XIII free B subunit: interactions with complement factors and a novel approach to identify potential binding partners. Res Pract Thromb Haemost 2022; 6 (05) e12766
- 15 Lorand L, Urayama T, De Kiewiet JW, Nossel HL. Diagnostic and genetic studies on fibrin-stabilizing factor with a new assay based on amine incorporation. J Clin Invest 1969; 48 (06) 1054-1064
- 16 Godal HC. An inhibitor to fibrin stabilizing factor (FSF, factor XIII). Scand J Haematol 1970; 7 (01) 43-48
- 17 Godal HC, Ly B. An inhibitor of activated factor XIII, inhibiting fibrin cross-linking but not incorporation of amine into casein. Scand J Haematol 1977; 19 (05) 443-448
- 18 Henriksson P, McDonagh J, Villa M. Type I autoimmune inhibitor of factor XIII in a patient with congenital factor XIII deficiency. [abstract] Thromb Haemost 1983; 50 (01) 272
- 19 Seiving B, Henriksson P, Stenberg P, Nilsson IM. A reversed activity staining procedure for detection of an acquired antibody against factor XIII in a girl with factor XIII deficiency. Br J Haematol 1992; 82 (02) 414-416
- 20 Manco-Johnson M, Nuss R, Lefkowitz J, Nugent D. Characterization and quantitation of an inhibitor to the A chain of Factor XIII (FXIII) in a child with severe factor XIII deficiency. [abstract] Blood 1993; 82: 596a
- 21 Huth-Kühne A, Lages P, Zimmermann R. Intracranial hemorrhage in a patient with congenital factor XIII deficiency and inhibitor – successful treatment with Ig-immunoadsorption and high dose continuous factor XIII infusion. [abstract] Blood 1998; 92: 106b
- 22 Rivard GE, St Louis J, Lacroix S, Champagne M, Rock G. Immunoadsorption for coagulation factor inhibitors: a retrospective critical appraisal of 10 consecutive cases from a single institution. Haemophilia 2003; 9 (06) 711-716
- 23 Pénzes K, Vezina C, Bereczky Z. et al. Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody. Haemophilia 2016; 22 (02) 268-275
- 24 Sosa R, Gailani D, Neff AT. Development of anti-factor XIII antibodies in a patient with hereditary factor XIII deficiency receiving therapy for chronic hepatitis C. Haemophilia 2014; 20 (06) e429-e432
- 25 Guzman MP, Alderuccio JP, Harrington T. Immunotolerance approach to refractory CNS bleeding in a patient with congenital factor XIII deficiency and acquired alloantibody. Haemophilia 2018; 24 (04) e252-e254
- 26 Karaman S, Akkaya E, Genc S. et al. Congenital factor XIII deficiency with the presence of inhibitor: a case study. J Pediatr Hematol Oncol 2021; 43 (01) e99-e102
- 27 Wada H, Souri M, Matsumoto R, Sugihara T, Ichinose A. Alloantibodies against the B subunit of plasma factor XIII developed in its congenital deficiency. Thromb Haemost 2013; 109 (04) 661-668
- 28 Lewis SD, Janus TJ, Lorand L, Shafer JA. Regulation of formation of factor XIIIa by its fibrin substrates. Biochemistry 1985; 24 (24) 6772-6777
- 29 Souri M, Osaki T, Ichinose A. The non-catalytic B subunit of coagulation factor XIII accelerates fibrin cross-linking. J Biol Chem 2015; 290 (19) 12027-12039
- 30 Kishiro Y, Kagawa M, Naito I, Sado Y. A novel method of preparing rat-monoclonal antibody-producing hybridomas by using rat medial iliac lymph node cells. Cell Struct Funct 1995; 20 (02) 151-156
- 31 Katona E, Pénzes K, Csapó A. et al. Interaction of factor XIII subunits. Blood 2014; 123 (11) 1757-1763
- 32 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
- 33 Lorand L, Maldonado N, Fradera J, Atencio AC, Robertson B, Urayama T. Haemorrhagic syndrome of autoimmune origin with a specific inhibitor against fibrin stabilizing factor (factor XIII). Br J Haematol 1972; 23 (01) 17-27
- 34 Lorand L, Velasco PT, Rinne JR, Amare M, Miller LK, Zucker ML. Autoimmune antibody (IgG Kansas) against the fibrin stabilizing factor (factor XIII) system. Proc Natl Acad Sci U S A 1988; 85 (01) 232-236
- 35 Fukue H, Anderson K, McPhedran P, Clyne L, McDonagh J. A unique factor XIII inhibitor to a fibrin-binding site on factor XIIIA. Blood 1992; 79 (01) 65-74
- 36 Tosetto A, Rodeghiero F, Gatto E, Manotti C, Poli T. An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide. Am J Hematol 1995; 48 (01) 34-39
- 37 Lorand L, Velasco PT, Murthy SN, Lefebvre P, Green D. Autoimmune antibody in a hemorrhagic patient interacts with thrombin-activated factor XIII in a unique manner. Blood 1999; 93 (03) 909-917
- 38 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
- 39 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
- 40 Protopopova AD, Ramirez A, Klinov DV, Litvinov RI, Weisel JW. Factor XIII topology: organization of B subunits and changes with activation studied with single-molecule atomic force microscopy. J Thromb Haemost 2019; 17 (05) 737-748