Fibrinogen Alès: a homozygous case of dysfibrinogenemia (γ-Asp330 →Val) characterized by a defective fibrin polymerization site “a”

Abstract

Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site “a,” resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D1 (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the γ-chain and in its fragment D1. The molecular defect determined by analysis of genomic DNA showed a single base change (A→T) in exon VIII of the γ-chain. The resulting change in the amino acid structure is γ 330 aspartic acid (GAT) → valine (GTT). It is concluded that the residue γ-Asp330 is essential for the normal functioning of the polymerization site a on the fibrinogen γ-chain.