Fibrinogen Ales: a homozygous case of dysfibrinogenemia (gamma-Asp(330) ->Val) characterized by a defective fibrin polymerization site "a"

Congenital homozygous dysfibrinogenemia was diagnosed in a man with a histo ry of 2 thrombotic strokes before age 30. His hemostatic profile was charac terized by a dramatically prolonged plasma thrombin clotting time, and no c lotting was observed with reptilase, Complete clotting of the abnormal fibr inogen occurred after a prolonged incubation of plasma with thrombin. The r elease of fibrinopeptides A and B by thrombin and of fibrinopeptide A by re ptilase were both normal. Thrombin-induced fibrin polymerization was impair ed, and no polymerization occurred with reptilase. The polymerization defec t was characterized by a defective site "a," resulting in an absence of int eraction between sites A and a, indicated by the lack of fragment D-1 (or f ibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A o nly (Des-AA fm). By SDS-PAGE, the defect was detected on the gamma -chain a nd in its fragment D-1. The molecular defect deter-mined by analysis of gen omic DNA showed a single base change (A-->T) in exon VIII of the gamma -cha in. The resulting change in the amino acid structure is gamma 330 aspartic acid (GAT) --> valine (GTT). It is concluded that the residue gamma -Asp(33 0) is essential for the normal functioning of the polymerization site a on the fibrinogen gamma -chain. (C) 2000 by The American Society of Hematology .