Two cases of congenital dysfibrinogenemia associated with thrombosis – Fibrinogen Praha III and Fibrinogen Plzeň

Abstract

Congenital dysfibrinogenemia is a rare disease characterised by inherited abnormality in the fibrinogen molecule, resulting in functional defects. Two patients, a 26-year-old woman and a 61-year-old man, both with history of thrombotic events, had abnormal coagulation test results. DNA sequencing showed the heterozygous gamma Y363N mutation (Fibrinogen Praha III) and the heterozygous Aalpha N106D mutation (Fibrinogen Plzen), respectively. Fibrin polymerisation, after addition of either thrombin or reptilase, showed remarkably delayed polymerisation in both cases. Fibrinolysis experiments showed slower tPA initiated lysis of clots. SDS-PAGE did not show any difference between normal and Praha III and Plzen fibrinogens. Both mutations had a significant effect on platelet aggregation. In the presence of either ADP or TRAP, both mutations caused the decrease of platelet aggregation. SEM revealed abnormal clot morphology, with a large number of free ends and narrower fibres of both fibrin Praha III and Plzen. Praha III mutation was situated in the polymerisation pocket "a". The replacement of the bulky aromatic side chain of tyrosine by the polar uncharged small side chain of asparagine may lead to a conformational change, possibly altering the conformation of the polymerisation pocket. The Plzen mutation is situated in the coiled-coil connector and this replacement of polar uncharged asparagine residue by polar acidic aspartate changes the alpha-helical conformation of the coiled-coil connector; and may destabilise hydrogen bonds in its neighborhood. Although both mutations are situated in different regions of the molecule, both mutations have a very similar effect on fibrinogen functions and both are connected with thromboses.

Why dysfibrinogenaemias still matter

“…So, with all of this information, why should clinicians or basic scientists care about newly identified dysfibrinogenaemias? A paper by Kotlín et al published in this issue of Thrombosis and Haemostasis provides one answer (4). …”

“…The paper by Kotlín et al (4) presents two new dysfibrinogenaemias, fibrinogen Praha III with a γY363N mutation and fibrinogen Plzen with an AαN106D mutation. Both patients presented with thrombotic problems, and both mutations have major effects on fibrin polymerisation, fibrinolysis, and platelet aggregation.…”

A novel fibrinogen mutation: FGA g. 3057 C > T (p. Arg104 > Cys) impairs fibrinogen secretion

“…Other mutations in this region cause dysfibrinogenemia. For example, fibrinogen Plzen (Aα Asn106Asp) and Vizovice (Aα Phe98Ile) are characterized by low functional fibrinogen, 1.13 g/l and 1.66, but normal immunologic fibrinogen concentration 3.99 g/l and 2.89, respectively [ 23 , 24 ]. The normal fibrinogen antigenic concentration excludes that these abnormal fibrinogens have impaired secretion.…”

Abnormal Fibrinogen Zlín (γThr21Ile) with Missense Mutation Causing Hypofibrinogenemia

“…1). Samples for scanning electron microscopy were prepared by mixing plasma with thrombin (2 NIH U/ml final concentration) and were incubated for 3 h. They were dried by the CO 2 critical point method and sputter-coated with platinum [9]. Images were evaluated using ImageJ data analysis software.…”