Two novel fibrinogen variants found in patients with pulmonary embolism and their families

The occurrence of dysfibrinogen is quite rare in comparison with other hemostatic defects, specially in cases of venous thrombosis.

Fibrinogen is known to have multiple functions, which are not evaluated by simple coagulation testing. We have used gel electrophoresis to search for new mutations.

Specimens of purified fibrinogen from 217 consecutive patients with familial or recurrent or early thrombosis and from 490 control subjects were evaluated by electrophoresis. Plasma fibrinogen levels and coagulation-dependent tests (electromechanical and optical coagulometric determinations, immunological measurement, thrombin and Reptilase(R) times) were normal.

Two novel familial variants were detected. For a 42-year-old patient, an in-frame 117 base pair insertion in the Aalpha-chain gene caused a 5-kDa mobility shift of the Aalpha chain. This corresponds to a 39 amino acid duplication in the connector domain (fibrinogen Champagne au Mont d'Or). This pattern was also found in the patient's mother and child. A second 31-year-old patient presented an extra band under non-reducing conditions, 30 kDa larger than HMW fibrinogen and reacting with antifibrinogen antibodies (fibrinogen Lozanne). A heterozygous 5909A-->G mutation was found on the Bbeta-chain gene leading to heterozygous Bbeta Tyr236--> stop codon. The predicted truncated Bbeta chain could participate in chain assembly. Two family members were also affected, one of whom had suffered early venous thrombosis.

Electrophoretic testing of apparently normal fibrinogens can reveal new variants which may be clinically relevant.