Combined Congenital Hypodysfibrinogemia and Factor XI Deficiency in a Chinese Family

Abstract

Both congenital hypodysfibrinogenemia and factor XI deficiency are rare coagulopathies caused by mutations within the fibrinogen and F11 genes, respectively. To investigate the pathogenesis of combined congenital hypodysfibrinogenemia with factor XI (FXI) deficiency in a Chinese family, coagulation assays, FXI activity (the 1-stage method), fibrinogen activity (the Clauss method), and antigen (prothrombin time [PT]-derived method) were performed. The sequences of fibrinogen genes and F11 were amplified by PCR and analyzed by direct sequencing. The proband as well as his grandmother, father, aunt, and sister showed a low plasma concentration of fibrinogen measured by the Clauss method and a slightly decreased result by the PT-derived method; finally, c.1097A>G in exon 8 of FGG was detected in the pedigree, which caused His340Arg mutation. His grandfather had a slightly prolonged activated partial thromboplastin time (APTT) due to low FXI activity. FXI deficiency was a compound heterozygote inherited with missense mutations of c.434A>G in exon 5 as well as c.1253G>T in exon 11 which caused HGV p.His145Arg and Gly400Val mutations, respectively. The grandfather had no qualitative or quantitative defect in fibrinogen. The proband and his father and aunt had c.434A>G at the exon 5 mutation site and no decrease in FXI activity. His mother had no fibrinogen or F11 gene mutations. Plasma fibrin polymerization was delayed. The proband in our study showed typical changes of congenital hypodysfibrinogemia in the clotting analyses with delayed fibrin polymerization, but although he was a heterozygous carrier of the c.434A>G variant in the F11 gene, he had no decrease in FXI activity and no bleeding tendency, thus questioning the pathogenicity of the identified variant in the F11 gene. To our knowledge, this is the first report of a case of combined hypodysfibrinogenemia and FXI deficiency confirmed by molecular genetic tests.

Gene Variants in Two Families with Inherited Coagulation Factor XI Deficiency and Identification of Mutations

“…According to the level of FXI activity (FXI:C) and FXI antigen (FXI:Ag), congenital FXI deficiency can be divided into two types. The cross-reactive material (CRM)-negative is characterized by a parallel reduction in both FXI:C and FXI:Ag, while CRM-positive is featured by normal FXI:Ag but reduced FXI:C [10].…”