title: Fibrinogen Philadelphia, a hypodysfibrinogenemia characterized by abnormal polymerization and fibrinogen hypercatabolism due to gamma S378P mutation.
abstract: Fibrinogen Philadelphia, a hypodysfibrinogenemia described in a family with a history of bleeding, is characterized by prolonged thrombin time, abnormal fibrin polymerization, and increased catabolism of the abnormal fibrinogen. Turbidity studies of polymerization of purified fibrinogen under different ionic conditions reveal a reduced lag period and lower final turbidity, indicating more rapid initial polymerization and impaired lateral aggregation. Consistent with this, scanning and transmission electron microscopy show fibers with substantially lower average fiber diameters. DNA sequence analysis of the fibrinogen genes A, B, and G revealed a T>C transition in exon 9 resulting in a serine-to-proline substitution near the gamma chain C-terminus (S378P). The S378P mutation is associated with fibrinogen Philadelphia in this kindred and was not found in 10 controls. This region of the gamma chain is involved in fibrin polymerization, supporting this as the polymerization defect causing the mutation. Thus, this abnormal fibrinogen is characterized by 2 unique features: (1) abnormal polymerization probably due to a major defect in lateral aggregation and (2) hypercatabolism of the mutant protein. The location, nature, and unusual characteristics of this mutation may add to our understanding of fibrinogen protein interactions necessary for normal catabolism and fibrin formation.
authors.affiliation: Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Keller
authors.forename: Josè
authors.initials: J
authors.lastname: Martinez
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Baradet
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Nagaswami
authors.forename: Irina N
authors.initials: IN
authors.lastname: Chernysh
authors.forename: Meggin K
authors.initials: MK
authors.lastname: Borowski
authors.forename: Saul
authors.initials: S
authors.lastname: Surrey
authors.forename: John W
authors.initials: JW
authors.lastname: Weisel
mesh_terms: D000347:Afibrinogenemia / Q000235:genetics* / Q000378:metabolism; D001777:Blood Coagulation; D003432:Cross-Linking Reagents / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D015241:Fibrinogens, Abnormal / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008958:Models, Molecular; D010375:Pedigree; D017354:Point Mutation; D011108:Polymers
chemical_list: D003432:Cross-Linking Reagents; D015241:Fibrinogens, Abnormal; D011108:Polymers; D005340:Fibrinogen