Congenital Dysfibrinogenemia - Clinical Manifestations in Relation to the Fibrinogen Gene Mutation.

The congenital dysfibrinogenemia is a rare clotting disorder which is based on a structural defect in the fibrinogen molecule. Approximately 350 cases of unrelated families with dysfibrinogenemia have been reported. Of these, the structural defects have been determined in nearly 170 families.

Patients and methods:

We describe the clinical manifestations in 50 patients from 19 families from Frankfurt. Up to now the underlying structural defect could be found in 43/50 (86 %) of the patients and 14/19 (74 %) of the families (Galanakis, New York, von Depka, Hannover).

Results:

In 19 families, 50 patients were found with dysfibrinogenemia (52% female, age median: 52 years-old, 9 - 89 years old). The fibrinogen level, according to Clauss decreased in median with 51 mg% (15 – 86 mg/dl, norm: 150 – 450 mg/dl). The determination of the other fibrinogen levels resulted in the normal range. Fibrinogen according to Schulz: 240 mg/dl, immunological fibrinogen: 244 mg/dl. The Reptilase time was prolonged to 55 sec (median, norm: − 20 sec.). 50% of the patients stated a distinct bleeding tendency and mostly a tendency for haematoma (59%) and secondary haemorrhaging (45%). 13 patients had a thrombotic disease, of which 80% were arterially caused. 12 % of the patients stated a tendency for bleeding as well as for thrombosis. 19% of the patients had miscarriages, partly recurrent and 18/50 (36 %) of the patients were asymptomatic. Furthermore, it was observed that the clinical symptoms are often similar in the affected families. By administration of fibrinogen concentrates, the pregnancy in 4 patients who suffered from abortions in the first weeks of pregnancy resulted in healthy children. Fibrinogen was administered from the beginning of the pregnancy till the delivery (aiming fibrinogen levels of Clauss up to 100 mg%). In 11 of the families, an Aalpha 16 Arg-Cys mutation was found. In the other three families there were found gamma mutations, e.g., gamma 356 Ala-Thr, gamma 318–319 del and gamma 318 Ap-Gly. The clinical manifestations in the families with Aalpha 16 Arg-Cys mutation were bleeding (65 %), thrombosis (22 %) and abortions (16 %). 25 % were asymptomatic and 12 % of the patients experienced both, bleeding and thrombosis.

Conclusion:

The investigations of the Frankfurt patient group with dysfibrinogenemia showed a high rate of clinical manifestations, mostly the tendency for haematoma and secondary haemorrhaging. The tendency for thrombosis is concerned rather with the arterial vessels. The high tendency for miscarriage is striking, which makes the administration of fibrinogen concentrate during pregnancy necessary. The most common found fibrinogen mutation was at the Aaplha chain in position 16. In patients with this mutation mostly both, bleeding and thrombosis occurred. Thus, management of patients with this mutation may be complicated by the variablility of clinical manifestations of congenital dysfibrinogenemia.