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Heterozygosity in FXIII genes and the manifestation of mild inherited FXIII Deficiency.

Journal of thrombosis and haemostasis : JTH

Authors: Sneha Singh, Behnaz Pezeshkpoor, Muhammad Ahmer Jamil, Johannes Dodt, Amit Sharma, Vasanth Ramar, Vytautas Ivaskevicius, Emma Hethershaw, Helen Philippou, Anna Pavlova, Johannes Oldenburg, Arijit Biswas

BACKGROUND: Characterization of inherited mild-FXIII deficiency is imprecise than its rare, inherited severe forms. It is evident that heterozygosity at FXIII genetic loci results in mild FXIII deficiency, characterized by circulating FXIII activity levels ranging from 20-60%. There exists a gap in information on a) how genetic heterozygosity renders clinical bleeding manifestations among these individuals; b) the reversal of unexplained bleeding upon FXIII administration in mild FXIII deficient individuals.

OBJECTIVE: To assess the prevalence and burden of mild-FXIII deficiency among the apparently-healthy German-Caucasian population and to correlate it with genetic heterozygosity at FXIII and Fibrinogen gene loci.

METHODS: Peripheral blood was collected from 752 donors picked from the general population, with essentially no bleeding complications to ensure the asymptomatic predisposition. These were assessed for functional assessments for FXIII and Fibrinogen; as well as to targeted re-sequencing of FXIII and Fibrinogen genes based on Next generation sequencing. To draw a contrast, a retrospective analysis was performed on a cohort of mild inherited FXIII deficiency patients referred to us.

RESULTS: The prevalence of mild FXIII deficiency is high (∼0.8%) among the screened German-Caucasian population, as compared to its rare-severe forms. Although no new heterozygous missense variants were found, certain combinations of heterozygous missense variants were relatively dominant/prevalent among mild FXIII deficient individuals.

CONCLUSION: This extensive, population-based quasi-experimental approach revealed the burden of heterozygosity at FXIII and Fibrinogen gene loci to be causative towards the clinical manifestation of inherited mild-FXIII deficiency that results in ''unexplained bleeding'' upon provocation.

Copyright © 2023. Published by Elsevier Inc.

PMID: 37832789

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