Alloantibody developed in a factor XIII A subunit deficient patient during substitution therapy; characterization of the antibody

作者：Penzes K; Vezina C; Bereczky Z; Katona E; Kun M; Muszbek L; Rivard G E^*

来源：Haemophilia, 2016, 22(2): 268-275.

DOI：10.1111/hae.12786

• acquired FXIII deficiency
• alloantibody
• bleeding diathesis
• FXIII
• inherited FXIII deficiency

Introduction: In factor XIII A subunit (FXIIIA) deficiency, the development of alloantibodies is extremely rare. Only four reports have been published and the antibodies were not characterized. Aim: The aim of this study was to describe the clinical course and the laboratory diagnosis of a FXIII-A deficient patient who developed alloantibodies. Methods: FXIII activity was assessed with an ammonia release assay. FXIII-A, FXIII B subunit (FXIII-B) and the complex plasma FXIII (FXIII-A(2)B(2)) antigens were determined by ELISA. The causative mutation was detected by fluorescent DNA sequencing. The binding of alloantibody to FXIII-A(2) and FXIII-A(2)B(2) was studied by surface plasmon resonance. The cleavage of FXIII-A by thrombin and Ca2+-induced activation of thrombin-cleaved FXIII were followed by western blotting and activity measurement, respectively. Results: FXIII activity, FXIII-A(2)B(2) and FXIII-A antigens were below the limit of detection in the patient's plasma. The severe FXIII-A deficiency was due to a novel homozygous mutation resulting in early stop codon (c.127C>T, p. Gln42STOP). The alloantibody bound to FXIII-A(2) and FXIII-A(2)B(2) with equally high affinity (K-d similar to 10(-8)). It accelerated the elimination of administered FXIII concentrate from the circulation, interfered with thrombin and Ca2+-induced activation and inhibited FXIII activity. Attempts to eliminate the alloantibody resulted only in transient improvement. Patient developed intracerebral haemorrhage after a minor trauma and died in spite of aggressive replacement therapy with FXIII concentrate. Conclusion: The anti-FXIII-A alloantibody caused an unmanageable bleeding complication. The antibody was of combined subtype which accelerated the elimination of FXIII and exerted a multiple inhibitory effect on FXIII activation/activity.

• 出版日期2016-3