Molecular and Clinical Aspects of Aα Dysfibrinogenemia in 25 Patients from the Czech Republic

Fibrinogen is a 340 kDA glycoprotein that plays a vital role in the hemostasis. The three pairs of polypeptide chains (Aα, Bβ and γ) form a heterodimer structure of fibrinogen, each chain is encoded by a distinct gene (FGA, FGB and FGG). Congenital dysfibrinogenemia is a rare qualitative disorder characterized by structural alterations in fibrinogen molecule resulting in its defective function. The clinical manifestation of majority cases is asymptomatic (50%); about 30% are associated with bleeding tendencies and only some cases are thrombotic (20%).

In this study, we evaluated 25 patients with heterozygous missense mutations in exon 2 of FGA gene from 13 unrelated families, all with low levels of functional fibrinogen and prolonged clotting time. All mutations were located around thrombin cleavage site at N-terminus of a fibrinogen Aα chain. Mutation Aα G13E was found in 6 families (13 patients), Aα R16H in 4 families (6 patients), Aα R16C in 1 family (4 patients), and Aα R19G in 1 family (2 patients). Correlations between the genotype and phenotype were studied by fibrin polymerization, fibrinolysis, kinetics of fibrinopeptides release, and electron and confocal microscopy. The viscoelastic properties of fibrin clots were measured. All mutations caused a delay or absence of fibrinopeptide A release and prolonged fibrin polymerization. Clinical phenotypes of mutations were, unexpectedly and importantly, highly heterogeneous. Out of 25 patients 17 were asymptomatic, 7 had the bleeding tendencies and 1 patient had thrombosis. One woman with Aα G13E had 2 spontaneous abortions and 3 pregnant women with Aα G13E, Aα R16C and Aα R19G mutations suffered for hemorrhages or postpartum bleeding. Eventually, all had successful delivery under provided care with a hematologist. Small surgeries were performed to patients with Aα R16H supplied with fibrinogen concentrates and antifibrinolytics. Our observations show that the patients should be carefully treated based both on the results of the laboratory analyzes and personal and family history.

This work was supported by the project of the Ministry of Health, Czech Republic, for conceptual development of research organization 00023736, by Grant from the Academy of Sciences, Czech Republic nr. P205/12/G118, and by ERDF OPPK CZ.2.16/3.1.00/24001.