Abnormal fibrinogen with an Aα 16Arg → Cys substitution is associated with multiple cerebral infarctions

Abstract

We found a heterozygous dysfibrinogenemia caused by a substitution of AαArg16Cys. The proband suffered multiple cerebral infarctions. Routine coagulation tests revealed a prolonged thrombin time. The fibrinogen levels in the functional assays were considerably lower than the levels in the immunological assays. The polymerization of the purified fibrinogen was strongly impaired in the presence of calcium. As previously observed in other heterozygous Aα R16C variants, the release rate and amount of fibrinopeptide A (FPA) were lower in the proband than those in normal controls. Additionally, the release of fibrinopeptide B (FpB) was delayed. The immunoblotting analysis using antibodies against human serum albumin indicated that albumin is bound to Aα R16C. The mass spectrometry analysis showed that the Aα R16C fibrinogen chains appeared in the patient's circulation. The clot structure analysis using scanning electron microscopy (SEM) revealed that the fibrin network was dense and consisted of thin and highly branched fibres. Using overlaid fibrinolytic enzymes in a clot lysis experiment, clot degradation was observed to be delayed. These results indicated that the thrombotic tendency may be ascribed to a fibrinolytic resistance caused by an abnormal clot structure with thin fibres and fibrinogen-albumin complexes.

Congenital dysfibrinogenemia caused by γAla327Val mutation: structural abnormality of D region

“…CD is a congenital blood disease caused by defects in fibrinogen genes, which lead to abnormal structure and function of fibrinogen molecules, and may affect coagulation. The clinical manifestations of CD are diverse; most patients with CD are asymptomatic [4], but a small number of patients with CD have thrombosis [5,6] and bleeding events, and some patients have pulmonary hypertension and other symptoms [7]. According to the latest published study, bleeding was present in 42% of patients with dysfibrinogenemia [8].…”

Schwangerschaftsbegleitende Behandlung bei hereditärer Dysfibrinogenämie nach wiederkehrendem Schwangerschaftsverlust

“…Nach Literatur scheint bei der FGA-Mutation c.103C>T (p.Arg35Cys) sowohl die Gerinnselbildung als auch die Fibrinolyse herabgesetzt zu funktionieren, wobei sich beide Effekte offenbar einigermaßen die Waage halten [5]. In einzelnen Familien mit dieser Genvariante traten nach veröffentlichten Fallbeschreibungen Blutungsprobleme, in anderen auch Thrombosen auf [3,6,7]. In einer neuen Übersichtsarbeit wird allerdings festgestellt, dass bei der Variante c.103C>T (p.Arg35Cys) im FGA-Gen weder Blutungen noch Thrombosen statistisch übernormal häufig aufträten und dass auch der Verlauf von Schwangerschaften durch diese Variante nicht beeinflusst werde [3].…”