FXIII Protein Inhibitor against the FXIII-A Subunit in an 8-Year-Old Boy with Inherited Severe Factor XIII Deficiency Complicated by Multiple Intracerebral Cavernomas

An 8-year-old boy from Aserbaidschan with consanguineous parents suffered from recurrent mucosal, soft-tissue, muscular, and joint bleedings. His sister with umbilical cord bleeding died at the age of 6 months without further analyses. The patient himself received multiple plasma transfusions before transfer to Germany where diagnosis of severe factor XIII deficiency was established. An intraventricular bleed probably caused by rupture of one of multiple bilateral supra- and infratentorial cavernomas at the age of 4 years led to a hydrocephalus which required ventriculo-peritoneal shunting.

Diagnosis of severe factor XIII deficiency (FXIII <10%) was confirmed by evidence of a homozygous mutation in the FXIII-A gene (exon 10, F13A1:c.[1241C>T];[ 1241C<T], p.(Ser- 414Leu).

First recombinant factor XIII substitution was performed due to rebleeding after adenotomy with previous FFP treatment. Two weeks later, prophylaxis was started. Treatment was complicated by an allergic infusion reaction after the second prophylactic FXIII application as well as by decreasing FXIII trough levels due to FXIII protein inhibitors against the FXIII-A subunit (10.66 BE/mL).

Immunomodulatory treatment with rituximab, mycophenolate-mofetil, corticosteroids, and intravenous immunoglobulins was started and continued for 50 days. Probably due to rituximab, Grade 2 transient leucopenia and neutropenia were noted. Only intravenous (IV) immunoglobulin treatment was continued together with once weekly FXIII prophylaxis (40 IE/kg bw). Upon treatment, 1 week trough levels of FXIII activity were within 52 to 63%. A repeated attempt to discontinue immunoglobulin treatment resulted in a marked decrease of FXIII trough levels to 27%. B-cells returned to normal after 4 months. Inhibitor was no longer detectable. No further bleeding events occurred.

In conclusion, a patient with inherited severe factor XIII deficiency at high risk for life-threatening bleedings due to cerebral vascular malformations developed an FXIII inhibitor while on recombinant factor XIII substitution. Control of an inhibitor was reached by continued IV immunoglobulin therapy after intensive immunosuppression. No further bleedings occurred. There were no infections or other complications of immunosuppression.

Publication History

Article published online:
13 November 2020