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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3162-3168.
Prepublished online as a Blood First Edition Paper on January 4, 2005; DOI 10.1182/blood-2004-04-1621.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Fibrinogen Philadelphia, a hypodysfibrinogenemia characterized by abnormal polymerization and fibrinogen hypercatabolism due to  S378P mutation
Margaret A. Keller,
Josè Martinez,
Timothy C. Baradet,
Chandrasekaran Nagaswami,
Irina N. Chernysh,
Meggin K. Borowski,
Saul Surrey, and
John W. Weisel
From the Division of Hematology and Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA; and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA.
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  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 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.
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[Abstract]
[Full Text]
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