Blood, 15 November 2000, Vol. 96, No. 10, pp. 3473-3479
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Fibrinogen Alès: a homozygous case of dysfibrinogenemia
(
-Asp330 
Val) characterized by a defective fibrin
polymerization site "a"
Karim Chabane Lounes,
Claudine Soria,
Shah Sultan Mirshahi,
Pierre Desvignes,
Massoud Mirshahi,
Olivier Bertrand,
Pierre Bonnet,
Jaap Koopman, and
Jeannette Soria
From the Laboratoire Sainte Marie, Laboratoire de
Biochimie A, and INSERM E 99-12, Hôtel-Dieu, Paris; Laboratoire
Diféma, Faculté de Médecine et de Pharmacie, Rouen;
INSERM U. 153, Hôpital Saint Louis, Paris; Centre Hospitalier
Régional, Martigues; INSERM U.76, Agence du sang, Paris; Centre
Hopitalier Régional, Alès, France; and TNO-PG, Gaubius
Laboratory, and Pharming, Leiden, The Netherlands.
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 
-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 -chain. The resulting change in the amino acid structure
is 330 aspartic acid (GAT) valine (GTT). It is concluded that
the residue -Asp330 is essential for the normal
functioning of the polymerization site a on the fibrinogen
-chain.
