Abstract
Factor XIII (FXIII) is the final enzyme in the coagulation cascade. Acquired FXIII deficiency is caused by inhibitors of FXIII or decreased synthesis and/or increased consumption of FXIII, which leads to severe bleeding. Recently, we experienced a case of hemorrhagic-acquired factor XIII deficiency that occurred during treatment with the IL-6 inhibitor tocilizumab for rheumatoid arthritis. A 48-year-old man was referred because of right hip pain due to a hematoma. Laboratory findings showed that routine coagulation tests were normal, while FXIII activity was slightly low (52.4 %). The patient was successfully treated with plasma-derived factor XIII concentrates. The time course of recovery suggests that tocilizumab might have inhibited FXIII production. To our knowledge, this is the first report of acquired factor XIII deficiency associated with administering of tocilizumab. When recurrent bleeding is seen during administering of tocilizumab, acquired factor XIII deficiency may have been induced, thus attending physicians should consider this disease in a differential diagnosis.
This is a preview of subscription content, log in via an institution to check access.
References
Schwartz ML, Pizzo SV, Hill RL, McKee PA. Human Factor XIII from plasma and platelets. Molecular weights, subunit structures, proteolytic activation, and cross-linking of fibrinogen and fibrin. J Biol Chem. 1973;248:1395–407.
Curtis CG, Brown KL, Credo RB, Domanik RA, Gray A, Stenberg P, et al. Calcium-dependent unmasking of active center cysteine during activation of fibrin stabilizing factor. Biochemistry. 1974;13:3774–80.
Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 2008;14:1190–200.
Nijenhuis AV, van Bergeijk L, Huijgens PC, Zweegman S. Acquired factor XIII deficiency due to an inhibitor: a case report and review of the literature. Haematologica. 2004;89:ECR14.
Ajzner E, Schlammadinger A, Kerényi A, Bereczky Z, Katona E, Haramura G, 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;113:723–5.
Ichinose A. Hemorrhagic acquired factor XIII (13) deficiency and acquired hemorrhaphilia 13 revisited. Semin Thromb Hemost. 2011;37:382–8.
Lopaciuk S, Bykowska K, McDonagh JM, McDonagh RP, Yount WJ, Fuller CR, et al. Difference between type I autoimmune inhibitors of fibrin stabilization in two patients with severe hemorrhagic disorder. J Clin Invest. 1978;61:1196–203.
Ivaskevicius V, Biswas A, Bevans C, Schroeder V, Kohler HP, Rott H, et al. Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function. Haematologica. 2010;95:956–62.
Iwasa T, Nakamura K, Ogino H, Itaba S, Akiho H, Okamoto R, et al. Multiple ulcers in the small and large intestines occurred during tocilizumab therapy for rheumatoid arthritis. Endoscopy. 2011;43(1):70–2.
European Medicines Agency http://www.medicines.org.uk/EMC/medicine/22311/SPC/RoActemra+20mg+ml+Concentrate+for+Solution+for+Infusion/.
Birnbaum J, Klotz E, Spies CD, Hein OV, Mallin K, Kawka R, et al. The combinations C1 esterase inhibitor with coagulation factor XIII and N-acetylcysteine with tirilazad mesylate reduce the leukocyte adherence in an experimental endotoxemia in rats. Clin Hemorheol Microcirc. 2008;40:167–76.
Pabst MJ, Pabst KM, Handsman DB, Beranova-Giorgianni S, Giorgianni F. Proteome of monocyte priming by lipopolysaccharide, including changes in interleukin-1beta and leukocyte elastase inhibitor. Proteome Sci. 2008;6:13.
McDevitt NB, McDonagh J, Taylor HL, Roberts HR. An acquired inhibitor to factor XIII. Arch Intern Med. 1972;130:772–7.
Milner GR, Holt PJ, Bottomley J, Maciver JE. Practolol therapy associated with a systemic lupus erythematosus-like syndrome and an inhibitor to factor XIII. J Clin Pathol. 1977;30:770–3.
Otis PT, Feinstein DI, Rapaport SI, Patch MJ. An acquired inhibitor of fibrin stabilization associated with isoniazid therapy: clinical and biochemical observations. Blood. 1974;44:771–81.
Fraccarollo D, Galuppo P, Schraut S, Kneitz S, van Rooijen N, Ertl G, et al. Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension. 2008;51:905–14.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Matsuoka, M., Majima, T., Onodera, T. et al. Hemorrhagic-acquired factor XIII deficiency associated with tocilizumab for treatment of rheumatoid arthritis. Int J Hematol 96, 781–785 (2012). https://doi.org/10.1007/s12185-012-1191-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-012-1191-x